FIELD OF THE INVENTION

The invention relates to anti -bacterial and/or anti-viral compounds and agents as well as their uses in the treatment or prevention of bacterial and/or viral infections. The invention also provides a method for prevention, alleviation, and/or treatment of bacterial and/or viral infections comprising applying the anti -bacterial and/or anti-viral compounds or agents of the invention to a subject in need thereof.

BACKGROUND OF THE INVENTION

Antibiotics are medicines used to prevent and treat bacterial infections. Penicillin was the first antibiotic discovery in 1928 by Alexander Fleming. After this, a series of new antibiotics have been developed. Actually, there are different types of antibiotics, but most of them can be classified into different major groups as follow: beta-lactams, gly copeptides quinolones/ fluoroquinolones, moenomycin, tetracyclines, macrolides, oxazolidinones, lipopetides, aminocoumarin, co-trimoxazole, lincosamides, polypeptides and derivatives thereof.

The misuse and also the overuse of antibiotics resulted in the rapid emergence of resistant bacterial strains worldwide in the past years. ¹ Antibiotic resistance occurs when bacteria change in response to the use of these medicines. As a result, bacteria acquire or develop antibiotic- resistance. These bacteria may infect humans and animals, and the infections they cause are harder to treat than those caused by non-resistant bacteria. Antibiotic resistance leads to higher medical costs, prolonged hospital stays, and increased mortality.

Original chemical structures with novel mechanisms of action are particularly needed in drug discovery to fight such multi-resistant pathogenic bacterial strains. For example, resistance in E. colt to one of the most widely used medicines for the treatment of urinary tract infections (fluoroquinolone antibiotics) is very widespread. There are countries in many parts of the world where this treatment is now ineffective in more than half of patients (WHO report). Among these multi-resistant bacteria a particular attention should be given to the Gram-positive bacterium Staphylococcus aureus which causes superficial and invasive infections, potentially fatal, such as sepsis and pneumonia. ² Today classical antibiotic treatments are ineffective against the methicillin-resistant strains of S. aureus (MRSA). ³ Resistance to first-line drugs to treat infections caused by Staphylococcus aureus — a common cause of severe infections in health facilities and the community — is widespread. People with MRSA (methicillin- resistant Staphylococcus aureus) are estimated to be 64% more likely to die than people with a non-resistant form of the infection. ³

On the other hand, Tuberculosis, a disease caused by the bacilli Mycobacterium tuberculosis, remains the world’s leading cause of death from an infectious disease. In 2017, the WHO reported 10.4 M new cases and 1.67 M deaths, making Tuberculosis the ninth leading cause of death worldwide (WHO report 2017). The Emergence of multidrug resistant (MDR) and extremely drug resistant (XDR) strains reduced drastically the treatment options and transformed this disease into a challenging global public health burden. The 2017 WHO Global Tuberculosis Report estimated that only 50% of the MDR tuberculosis cases were successfully treated. Based on these numbers, there are hundreds of thousands of untreated active TB- patients worldwide, who continue to spread the drug-resistant form of the disease. Thus, there is an obvious and urgent need for the development of new anti-Mycobacteria drugs that are effective against drug resistant M tuberculosis strains.

Natural products (NPs) have been the starting point of a very large number of innovative drugs. ⁴ Living organisms such as plants, fungi and marine organisms are capable of producing a vast variety of natural products with an extreme structural diversity, some of which confer selective advantages against microbial attack. In order to be used as antimicrobial drugs, these compounds have to be isolated or produced by synthesis in large scale. ⁴

Bioactive compounds can also be obtained using biological methods such as biotransformation reactions. Biotransformation can be defined as the use of an intact whole organism or an isolated enzyme system to induce chemical modifications in organic compounds. ⁵ Biotransformation has a number of advantages when compared to classical organic chemistry. The reactions can occur in mild conditions, near neutral pH, ambient temperatures, and atmospheric pressure, and protection of certain functional groups is often not necessary. ⁶

Recently, the application of an enriched fraction of enzymes from fungi (define as ‘fungal secretome’) for the transformation of conventional NPs was effective to create complex chemodiverse compounds with enhanced biological activity. ⁷ This approach takes advantage of the catalytic promiscuity of various enzymes constituting the secretome. In comparison to pure enzyme, the enzymatic diversity of a secretome produced by fungi for the degradation and/or transformation of various substrates has the potential to catalyze different chemical reactions at the same time. The use of the secretome for biotransformation has thus great chances to transform various types of substrates with less specificity than pure enzymes and is probably well suited to generate high chemodiversity by transformation of related rather simple initial natural compounds substrates. ⁷

Building on this knowledge, the purpose of the present invention is to provide efficient compounds that meet the requirement of potent antimicrobial and/or antiviral activity, preserved activity in biological environment and low toxicity against healthy cells and tissues.

BRIEF DESCRIPTION OF THE INVENTION

The classical technique to perform a biotransformation using a given microorganism is by adding the compound to be transformed to the culture medium containing the microorganism. Even though this approach has been used successfully, the purification process at the end of the reaction can be extremely complicated because the targeted metabolites are mixed with the microorganism metabolites. Moreover, the compounds to be processed must have low toxicity against the microorganism used, otherwise they will kill the microorganism and the transformation cannot be achieved.

Another way to perform the biotransformation is to use a purified enzyme. Because of the attractive chemo-, regio- and enantioselectivities of the reactions commonly displayed by enzymes, enzymatic biostransformation has become an important alternative to traditional organic synthesis. This methodology has also been successfully used in the biotransformation of NPs. A series of natural product biotransformations have been performed by using the pure horseradish peroxidase enzyme (HRP). ⁷ The bottleneck in this case is the limited number of commercially available purified enzymes that can be used for those biotransformations.

For example, in the present work, the fungal enzymatic secretome was used to performed the biotransformation of resveratrol, pterostilbene and the mixture of both. The reaction was optimized by using different percentages of organic solvent (2% of acetone and 50% of methanol) in the reaction mixture in view of improving solubility and increasing the chemodiversity of compounds generated. This approach afforded twenty structurally complex stilbenes. These derivatives were evaluated for their antimicrobial properties against Grampositive and Gram-negative bacteria. In parallel, the anti-mycobacterial activity of these compounds was assessed in vitro , in broth, against Mycobacterium marinum, a close relative of M tuberculosis. In addition, their anti-infective activity was monitored with quantitative fluorescence measurements and high-content microscopy by infecting the amoebae Dictyostelium discoideum, a model professional phagocyte, with M. marinum.

One aspect of the present invention provides an anti-bacterial and/or anti-viral compound of the general formula (I) wherein

R ₁ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ;

R ₂ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ;

R ₃ is H, CO(CH ₂ ) ₆ CH ₃ , CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , O(OH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ ) ₇ CH3;

R4 is independently at each occurrence H, Br, Cl or I R ₅ is independently at each occurrence H, Br, Cl or I provided that when R ₁ , R ₂ and R ₃ are H, then R ₄ and/or R ₅ is Br, Cl or I, when R ₁ and R2 are CH3 and R3 is H, then R4 and/or R5 is Br, Cl or I or an enantiomer thereof or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides an anti -bacterial and/or anti-viral agent comprising one or more compounds of the general formula (I) of the invention. Another aspect of the present invention provides a pharmaceutical composition comprising an effective amount of one or more anti -bacterial and/or anti-viral compounds of the general formula (I) of the invention and at least one pharmaceutically acceptable excipient, carrier and/or diluent.

Another aspect of the present invention provides a compound of the general formula (I) wherein

R ₁ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ R ₂ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ R ₃ is H, CO(CH ₂ ) ₆ CH3, CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , O(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ ) ₇ CH ₃

R ₄ is independently at each occurrence H, Br, Cl or I R ₅ is independently at each occurrence H, Br, Cl or I provided that when R ₁ , R ₂ and R ₃ are H, then R ₄ and/or R ₅ is Br, Cl or I, when R ₁ and R ₂ are CH ₃ and R ₃ is H, then R ₄ and/or R ₅ is Br, Cl or I or an enantiomer thereof or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of bacterial infections.

Another aspect of the present invention provides a compound of the general formula (I)

wherein R ₁ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃

R ₂ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ R ₃ is H, CO(CH ₂ ) ₆ CH ₃ , CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , O(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ )7CH ₃

R ₄ is independently at each occurrence H, Br, Cl or I R ₅ is independently at each occurrence H, Br, Cl or I provided that when R ₁ and R ₂ are CH ₃ and R ₃ is H, then R ₄ and/or R ₅ is Br, Cl or I or an enantiomer thereof or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of viral infections.

Another aspect of the present invention provides an intermediate compound of formula (II) wherein

R ₁ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ;

R ₂ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ;

MOM is methoxymethyl (a protecting group).

BRIEF DESCRIPTION OF THE FIGURES

Figure 1: illustrates the structure of compounds generated and identified from the biotransformation reaction with the secretome of Botrytis cinerea of resveratrol and pterostilbene using 50% of methanol/water (1-15), and from the biotransformation reaction of pterostilbene with 2% of acetone (16-20). ⁷

Figure 2: illustrates a representative experiment of the growth kinetics of wild-type (WT) Mycobacterium marinum msp12:GFP grown in 7H9 broth in the presence of the four compounds or Rifabutin (white square) compared to WT treated with the vehicle only (black dots).

Figure 3: shows the characterization of the anti-infective activity of the four compounds using the Dictyostelium discoideum -M. marinum infection assay with (A) a plate reader assay and (B) High-Content Microscopy (HCM). Fluorescence was used as a proxy to assess the intracellular bacterial growth ⁸ .

Figure 4: represents HCM images collected at various time points illustrating the lack of cytotoxicity of the tested compounds. D. discoideum and M. marinum mspl2::GFP were recorded in transmitted light (TL) and the FITC channel, respectively. Images from both channels were merged prior to quantification.

Figure 5: IC50 determination of compounds 11 (A, B) and 14 (C, D) using the D. discoideum - M. marinum infection assay. Luminescence was used as a proxy to assess the intracellular bacterial growth. Compounds of interest were assayed at a concentration ranging from 20 μM to 0.625 μM. ⁸ A 4PL nonlinear regression model was used for curve-fitting analysis and the calculation of the absolute IC50.

Figure 6: illustrates the structure of halogenated compounds generated (21-45).

Figure 7: Cell’s viability assay of 6, 11, 14 and 15 δ-Viniferins in MDCK cells at 24 hours post treatment. A) Experiment performed in serum-free DMEM. B) Experiment performed in serum-free DMEM + TPCK-Trypsin 0.2 μg/ml. Percentages of viability were calculated by comparing the absorbance in treated wells and untreated. 50% cytotoxic concentration (CC50) were calculated with Prism 8 (GraphPad, USA). The results represent the average of two independent experiments performed in duplicate. Figure 8: Pre-incubation of the δ-Viniferins with influenza A(H1N1)pdm09 virus. All results are presented as the mean values from two independent experiments performed in duplicate. The half-maximal antiviral effective concentration (EC50) values for inhibition curves were calculated by regression analysis using the program GraphPad Prism version 8.0 (GraphPad Software, San Diego, California, U.S.A.).

Figure 9: Post-treatment with δ-Viniferins against Influenza A(H1N1)pdm09 virus. The results of two independent experiments were averaged. Significance was calculated by Two-way ANOVA comparison.

DETAILED DESCRIPTION OF THE INVENTION

Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

The invention includes all such variation and modifications. The invention also includes all of the steps and features referred to or indicated in the specification, individually or collectively and any and all combinations or any two or more of the steps or features.

In the case of conflict, the present specification, including definitions, will control.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used herein, the following definitions are supplied in order to facilitate the understanding of the present invention.

The term “comprise” is generally used in the sense of include, that is to say permitting the presence of one or more features or components. Also as used in the specification and claims, the language "comprising" can include analogous embodiments described in terms of "consisting of “ and/or "consisting essentially of’. As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise.

As used in the specification and claims, the term "and/or" used in a phrase such as "A and/or B" herein is intended to include "A and B", "A or B", "A", and "B".

The presence of broadening words and phrases such as “one or more,” “at least,” “but not limited to” or other like phrases in some instances shall not be read to mean that the narrower case is intended or required in instances where such broadening phrases may be absent.

As used herein the terms "subject" or "patient" are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human. In some embodiments, the subject is a subject in need of treatment or a subject with a disease or disorder or the subject being infected by bacteria and/or by virus. However, in other embodiments, the subject can be a normal subject. The term does not denote a particular age or sex. Thus, adult and new-born subjects, whether male or female, are intended to be covered.

The term “an effective amount” refers to an amount necessary to obtain a physiological effect. The physiological effect may be achieved by one application dose or by repeated applications. The dosage administered may, of course, vary depending upon known factors, such as the physiological characteristics of the particular composition; the age, health and weight of the subject; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired and can be adjusted by a person skilled in the art.

By “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient or subject without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term “pharmaceutically acceptable” is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration. A “carrier” or a “pharmaceutical acceptable carrier” refers to, for example, a diluent, adjuvant, preservative (e.g., Thimersol, benzyl alcohol), anti-oxidant (e.g., ascorbic acid, sodium metabi sulfite), solubilizer (e.g., Tween™ 80, Polysorbate 80), emulsifier, buffer (e.g., Tris HC1, acetate, phosphate), antimicrobial, bulking substance (e.g., lactose, mannitol), excipient, auxiliary agent or vehicle with which an active agent of the present invention is administered. Pharmaceutically acceptable carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin. Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin (Mack Publishing Co., Easton, Pa.); Gennaro, A. R., Remington: The Science and Practice of Pharmacy, 20th Edition, (Lippincott, Williams and Wilkins), 2000; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3<rd >Ed.), American Pharmaceutical Association, Washington, 1999.

The term “anti-viral” refers to an agent or a compound that kills a virus or that suppresses its ability to replicate and, hence, inhibits its capability to multiply and reproduce.

A “virus” refers to a large group of sub microscopic infectious agents that are usually regarded as non-living extremely complex molecular assemblies, that typically contain a protein coat surrounding an RNA or DNA core of genetic material but no semipermeable membrane, that are capable of growth and multiplication only in living cells, and that cause various important diseases in humans, animals, and plants.

The term “anti-bacterial” as used herein indicates an agent or a compound or a substance that kills or inhibits the growth of bacteria.

The term “bacteria” (singular: bacterium) are classified as prokaryotes, which are single-celled organisms with a simple internal structure that lacks a nucleus, and contains DNA that floats freely in a twisted, thread-like mass called the nucleoid. Sometimes additional DNA in circular form, called plasmids, may also be present. Bacterial cells are generally surrounded by two protective coverings: an outer cell wall and an inner cell membrane. The Gram stain is a test used to identify bacteria by the composition of their cell walls. The test stains Gram-positive bacteria, or bacteria that do not have an outer membrane. Gram-negative bacteria don’t keep the stain. For example, Streptococcus pneumoniae ( S . pneumoniae ), which causes pneumonia, is a Gram-positive bacterium, but Escherichia coli ( E . coli ) and Vibrio cholerae , which causes cholera, are Gram -negative bacteria. Mycobacteria, such as M. tuberculosis , the causative agent of human Tuberculosis, M. lepreae , causing leprosy, and M. marinum , responsible for fish tuberculosis and human opportunistic infections, possess an inner membrane, surrounded by a layer of peptidoglycan itself enclosed in an extremely hydrophobic, waxy lipid layer called the myco-membrane. Several species of bacteria are pathogenic and cause infectious diseases, including cholera, syphilis, anthrax, leprosy and bubonic plague. The most common fatal bacterial diseases are respiratory infections. Tuberculosis alone kills about 2 million people per year, mostly in sub-Saharan Africa. Antibiotics are used to treat bacterial infections and are also used in farming, making antibiotic resistance a growing problem.

“Treatment” or “treating” refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already being infected by bacteria and/or by virus, as well as those in which the bacterial infection and/or the viral infection is to be prevented. Hence, the mammal, preferably human, to be treated herein may have been diagnosed as being infected by bacteria and/or by virus, or may be predisposed or susceptible to be infected by bacteria and/or virus. Treatment includes ameliorating at least one symptom of, curing and/or preventing the development of a disease or condition due to bacterial infection and/or viral infection and/or preventing the number of people contaminated by an infected subject. Preventing is meant attenuating or reducing the ability of bacteria and/or virus to cause infection or disease, for example by affecting a post-entry viral event or bacterial infectivity.

As used herein, the term “disease” is intended to include disorder, condition or any equivalent thereof.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacteria or fungi. Sources of resveratrol in food include the skin of grapes, blueberries, raspberries, mulberries, parsley and peanuts.

Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is a stilbenoid chemically related to resveratrol. In plants, it serves a defensive phytoalexin role. Pterostilbene is found in almonds, various Vaccinium berries (including blueberries), grapevine leaves, berries and rootstocks and Pterocarpus marsupium heartwood. Pterostilbene differs from resveratrol by exhibiting increased bioavailability (80% compared to 20% in resveratrol) due to the presence of two methoxy groups which cause it to exhibit increased lipophilic and oral absorption.

Stilbenoids are hydroxylated derivatives of stilbene. They have a C6-C2-C6 structure. In biochemical terms, they belong to the family of phenylpropanoids and share most of their biosynthesis pathway with chalcones. Stilbenoids can be produced by plants and bacteria. Stilbene is either of two isomeric hydrocarbons, diphenylethylene, but especially the trans isomer, used in the manufacture of dyes and many other compounds.

Embodiments of the present invention are described below. Preferred features of each aspect of the present invention are as for each of the other aspects mutatis mutandis. Moreover, it will be appreciated that the features specified in each embodiment may be combined with other specified features, to provide further embodiments.

An aspect of the invention provides an anti -bacterial and/or anti-viral compound of the general formula (I) wherein

R ₁ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ; preferably R ₁ is independently at each occurrence H or CH ₃

R ₂ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ; preferably R ₂ is independently at each occurrence H or CH ₃

R ₃ is H, CO(CH ₂ ) ₆ CH ₃ , CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , O(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ ) ₇ CH ₃ ; preferably R ₃ is H or preferably R ₃ is CO(CH ₂ ) ₆ CH ₃ , CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , O(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ ) ₇ CH ₃ R ₄ is independently at each occurrence H, Br, Cl or I R ₅ is independently at each occurrence H, Br, Cl or I provided that when R ₁ , R ₂ and R ₃ are H, then R ₄ and/or R ₅ is Br, Cl or I, when R ₁ and R ₂ are CH ₃ and R ₃ is H, then R ₄ and/or R ₅ is Br, Cl or I or an enantiomer thereof or a pharmaceutically acceptable salt thereof.

In one embodiment of the compound of the general formula (I),

R ₁ is independently at each occurrence H or CH ₃ R ₂ is independently at each occurrence H or CH ₃

R ₃ is H, CO(CH ₂ ) ₆ CH3, CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , CO(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ ) ₇ CH ₃

R ₄ is independently at each occurrence H, Br, Cl or I R ₅ is independently at each occurrence H, Br, Cl, or I. provided that when R ₁ , R ₂ and R ₃ are H, then R ₄ and/or R ₅ is Br, Cl or I, when R ₁ and R ₂ are CH ₃ and R ₃ is H, then R ₄ and/or R ₅ is Br, Cl or I or an enantiomer thereof or a pharmaceutically acceptable salt thereof.

In another embodiment of the compound of the general formula (I),

R ₃ is CO(CH ₂ ) ₆ CH ₃ , CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , CO(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ ) ₇ CH ₃ .

In a further embodiment of the compound of the general formula (I), R ₁ is independently at each occurrence H or CH ₃ R2 is independently at each occurrence H or CH ₃ R ₃ is H R ₄ is independently at each occurrence H, Br, Cl or I R ₅ is independently at each occurrence H, Br, Cl, or I. provided that when R ₁ , R ₂ and R ₃ are H, then R ₄ and/or R ₅ is Br, Cl or I, when R ₁ and R ₂ are CH ₃ and R ₃ is H, then R ₄ and/or R ₅ is Br, Cl or I or an enantiomer thereof or a pharmaceutically acceptable salt thereof.

In another embodiment of the compound of the general formula (I) R ₁ is H, CH ₃ or CH ₂ CH ₃ ; preferably R ₁ is H or CH ₃ R ₂ is H, CH ₃ or CH ₂ CH ₃ ; preferably R ₂ is H or CH ₃ R ₃ is H, CO(CH ₂ ) ₆ CH3, CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , 0(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ ) ₇ CH ₃ ; preferably R ₃ is H or preferably R ₃ is CO(CH ₂ ) ₆ CH ₃ , CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH3, O(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ )7CH ₃ R ₄ is independently at each occurrence H, Br, Cl or I R ₅ is independently at each occurrence H, Br, Cl or I provided that when R ₁ , R ₂ and R ₃ are H, then R ₄ and/or R ₅ is Br, Cl or I, when R ₁ and R ₂ are CH ₃ and R ₃ is H, then R ₄ and/or R ₅ is Br, Cl or I or an enantiomer thereof or a pharmaceutically acceptable salt thereof.

In another embodiment of the compound of the general formula (I) R ₁ is H, CH ₃ or CH ₂ CH ₃ ; preferably R ₁ is H or CH ₃ R ₂ is H, CH ₃ or CH ₂ CH ₃ ; preferably R ₂ is H or CH ₃ R ₃ is H, CO(CH ₂ ) ₆ CH3, CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , 0(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ ) ₇ CH ₃ ; preferably R ₃ is H or preferably R ₃ is CO(CH ₂ ) ₆ CH ₃ , CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH3, O(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ )7CH ₃ R ₄ is H, Br, Cl or I R ₅ is H, Br, Cl or I provided that when R ₁ , R ₂ and R ₃ are H, then R ₄ and/or R ₅ is Br, Cl or I, when R ₁ and R ₂ are CH ₃ and R ₃ is H, then R ₄ and/or R ₅ is Br, Cl or I or an enantiomer thereof or a pharmaceutically acceptable salt thereof. The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halo" represents chloro, fluoro, bromo or iodo.

The term “substituted” as used herein in reference to a moiety means that one or more, especially up to 5, more especially 1, 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of the described substituents. The term “optionally substituted” as used herein means substituted or un-substituted. It will, of course, be understood that substituents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible.

Where one, two or more moieties are described as being “each independently” or "independently at each occurrence" selected from a list of atoms or groups, this means that the moieties may be the same or different and/or may be the same or different at each occurrence. The identity of each moiety is therefore independent of the identities of the one or more other moieties (same or different moieties).

Double bonds in principle can have E- or Z-configuration. The compounds of this invention may therefore exist as isomeric mixtures or single isomers. If not specified both isomeric forms are intended. Where a compound of the invention contains one chiral center, the compound can be provided as a single isomer (R or S) or as a mixture of isomers, for example a racemic mixture. Where a compound of the invention contains more than one chiral center, the compound can be provided as an enantiomerically pure diastereoisomer or as a mixture of diastereoisomers.

The term “enantiomer” as used herein means one of two stereoisomers that have mirror images of one another.

The term “racemate” as used herein means a mixture of equal amounts of enantiomers of a chiral molecule.

The term “diastereoisomer” as used herein means one of a class of stereoisomers that are not enantiomers, but that have different configurations at one or more of the equivalent chiral centers. Example of diastereoisomers are epimers that differ in configuration of only one chiral center.

The term “stereoisomer” as used herein means one of a class of isomeric molecules that have the same molecular formula and sequence of bonded atoms, but different three-dimensional orientations of their atoms in space.

A “prodrug” is a medication that is administered as an inactive (or less than fully active) chemical derivative that is subsequently converted to an active pharmacological agent in the body, often through normal metabolic processes.

A “chemical derivative” is a compound that is derived from a similar compound by a chemical reaction. In the present invention a derivative also encompasses a compound that can be imagined to arise from another compound, if one atom or group of atoms is replaced with another atom or group of atoms, this also refers to the term structural analog for this meaning. The term "structural analogue" and “chemical derivative” are interchangeable.

As used herein, the term “salt” or "pharmaceutically acceptable salt" refers to forms of the disclosed compounds, wherein the parent compound is modified by making acid or base salts thereof, that possess the desired pharmacological activity of the parent compound. Generally, pharmaceutically acceptable salts of the compound of the invention as defined above may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, hydrochloride or acetic acid, to afford a physiologically acceptable anion. It may also be possible to make a corresponding alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques. Such salts include acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3 -(4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2 -hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-I-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; and salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine, and the like.

As used herein, the term “compounds or pharmaceutically acceptable salts” include hydrates and solvates thereof. In some preferred embodiments of the invention, the compound of general formula (I) is selected from the group comprising

or an enantiomer thereof or a pharmaceutically acceptable salt thereof. In the present invention, the anti -bacterial and/or anti-viral compounds of the invention were generated by a biotransformation process using a mixture of enzymes (called secretome) obtained from the phytopathogenic fungus Botrytis cinerea (according to Gindro et al, 2017). ⁷ The secretome is first obtained from the culture of B. cinerea. In a second step, the secretome is used to biotransform resveratrol, pterostilbene and a mixture of the two. The compounds obtained in each reaction were purified by semi-preparative HPLC. Finally, the structure of each isolated compound was determined by spectroscopic methods such as nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). All these procedures are described in experimental part below.

According to another embodiment of the present invention, the anti -bacterial and/or anti-viral compounds of the invention can be prepared by a chemical synthesis. An example of chemical synthesis is according to the following scheme: wherein R ₁ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ; preferably R ₁ is independently at each occurrence H or CH ₃ or preferably R ₁ is H or CH ₃ ; R ₂ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ; preferably R ₂ is independently at each occurrence H or CH ₃ or preferably R ₂ is H or CH ₃ ;

MOM is methoxymethyl (a protecting group)

In an embodiment, the present invention provides an intermediate compound of formula (II) wherein R ₁ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ; preferably R ₁ is independently at each occurrence H or CH ₃ or preferably R ₁ is H or CH ₃ ;

R ₂ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ; preferably R ₂ is independently at each occurrence H or CH ₃ or preferably R ₂ is H or CH ₃ ;

MOM is methoxymethyl (a protecting group) In particular, Methicillin-resistant Staphylococcus aureus (MRSA, ATCC 33591) and vancomycin-resistant Staphylococcus aureus (VRSA 510) were used for the antibacterial assay. The minimum inhibitory concentration (MIC) of the different compounds were determined in triplicate using the broth dilution method in 96-well microtiter plates. Briefly, compounds were resuspended at 10.24 mg/mL in DMSO and serially diluted in Mueller-Hinton broth (MHB, Oxoid). The maximum initial concentration used for this assay was 256 μg/mL for P. aeruginosa and 128 μg/mL for S. aureus. After an incubation of 24h at 37°C, iodonitrotetrazolium chloride (INT, Sigma-Aldrich) was added to each well, as growth indicator, and incubated for several hours. The highest dilution of a compound in which no growth appears corresponds to its MIC. Gentamicin sulfate (Applichem) and vancomycin hydrochloride (Sigma-Aldrich) were used as control of inhibition for P. aeruginosa and S. aureus , respectively, and compared to the reference values.

Advantageously, the anti -bacterial and/or anti-viral compound of the general formula (I) of the invention is active against bacteria and/or viruses and also against bacterial and/or viral infections.

The compound of the general formula (I) of the invention is also active against parasitic infections. A “parasite” is an organism that lives and feeds on or in an organism of a different species and causes harm to its host. In the context of the present invention a parasite is an animal organism that lives in or on another and takes its nourishment from that other organism. Parasitic diseases include infections that are due to protozoa, helminths, or arthropods. For example, malaria is caused by Plasmodium, a parasitic protozoa.

Another aspect of the invention provides an anti -bacterial and/or anti-viral agent comprising compounds of the general formula (I) of the invention. In an embodiment, the anti -bacterial and/or anti-viral agent of the invention comprises one or more compounds of the general formula (I) of the invention, preferably comprises a mixture of two or more compounds of the general formula (I) of the invention.

An aspect of the invention provides a compound of the general formula (I) of the invention for use in the treatment or prevention of bacterial and/or viral infections.

An embodiment of the invention provides a method of treating or preventing bacterial and/or viral infections, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the general formula (I) of the invention. Another embodiment of the invention provides a method for the treatment of pathologies associated with bacterial infections, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the general formula (I) of the invention.

An embodiment of the invention provides an anti -bacterial and/or anti-viral agent of the invention for use in the treatment or prevention of bacterial and/or viral infections, wherein the anti -bacterial and/or anti-viral agent comprises one or more compounds of the general formula (I) of the invention, preferably comprises a mixture of two or more compounds of the general formula (I) of the invention.

As outlined below, some embodiments of the invention provide treatment or prevention of bacterial and/or viral infections, comprising co-administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the general formula (I) of the invention and on or more antimicrobial agents, such as antibiotics or antiviral agents.

Another embodiment of the invention provides a compound of the general formula (I) of the invention for use in the treatment or prevention of bacterial infections.

One specific embodiment of the invention provides a compound of the general formula (I) wherein R ₁ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ; preferably R ₁ is independently at each occurrence H or CH ₃

R ₂ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ; preferably R ₂ is independently at each occurrence H or CH ₃

R ₃ is H, CO(CH ₂ ) ₆ CH ₃ , CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , 0(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ )7CH ₃ ; preferably R ₃ is H or preferably R ₃ is CO(CH ₂ ) ₆ CH ₃ , CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , 0(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ )7CH ₃

R4 is independently at each occurrence H, Br, Cl or I R ₅ is independently at each occurrence H, Br, Cl or I provided that when R ₁ , R ₂ and R ₃ are H, then R ₄ and/or R ₅ is Br, Cl or I, when R ₁ and R ₂ are CH ₃ and R ₃ is H, then R ₄ and/or R ₅ is Br, Cl or I or an enantiomer thereof or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of bacterial infections.

An embodiment of the invention provides a method of treating or preventing bacterial infections, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the general formula (I) of the invention.

Preferably, the bacterial infection is an infection with Gram-positive bacteria or Mycobacteria.

More preferably, the bacterial infection is an infection with Staphylococcus, Streptococcus, Clostridioides, Clostridium, Bacillus, Enterococcus, Corynebacterium, Listeria, or Mycobacteria.

Even more preferably, the bacterial infection is an infection with Staphylococcus aureus MRSA, Staphylococcus aureus VRSA, Streptococcus pneumoniae, Streptococcus pyogenes, Clostridium difficile, Clostridium sporogenes, Clostridium tetani, Bacillus cereus, Bacillus anthracis, Enterococcus feacalis , Mycobacterium tuberculosis “drug sensitive, MDR, and XDR clinical strains”, Mycobacterium ajricanum, Mycobacterium orygis, Mycobacterium bovis and the Bacillus Calmette-Guerin strain, Mycobacterium microti, Mycobacterium canetti, Mycobacterium caprae, Mycobacterium pinnipedii, Mycobacterium suricattae, Mycobacterium leprae, Mycobacterium mungi, Mycobacterium abscessus, Mycobacterium ulcerans, Mycobacterium gordonae, Mycobacterium marinum , and Mycobacterium smegmatis.

As outlined below, some embodiments of the invention provide treatment or prevention of bacterial infections, comprising co-administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the general formula (I) of the invention and on or more antimicrobial agents, such as antibiotics.

Another embodiment of the invention provides a compound of the general formula (I)

wherein R ₁ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ; preferably R ₁ is independently at each occurrence H or CH ₃

R ₂ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ; preferably R ₂ is independently at each occurrence H or CH ₃

R ₃ is H, CO(CH ₂ ) ₆ CH ₃ , CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , O(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ ) ₇ CH ₃ ; preferably R ₃ is H or preferably R ₃ is CO(CH ₂ ) ₆ CH ₃ , CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , 0(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ )7CH ₃

R ₄ is independently at each occurrence H, Br, Cl or I R ₅ is independently at each occurrence H, Br, Cl or I provided that when R ₁ and R ₂ are CH ₃ and R ₃ is H, then R ₄ and/or R ₅ is Br, Cl or I or an enantiomer thereof or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of viral infections.

An embodiment of the invention provides a method of treating or preventing viral infections, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the general formula (I) of the invention. In a specific embodiment, the compound of the general formula (I) is

wherein R ₁ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ; preferably R ₁ is independently at each occurrence H or CH ₃

R ₂ is independently at each occurrence H, CH ₃ or CH ₂ CH ₃ ; preferably R ₂ is independently at each occurrence H or CH ₃

R ₃ is H, CO(CH ₂ ) ₆ CH ₃ , CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , O(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ ) ₇ CH ₃ ; preferably R ₃ is H or preferably R ₃ is CO(CH ₂ ) ₆ CH ₃ , CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , O(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ ) ₇ CH ₃

R ₄ is independently at each occurrence H, Br, Cl or I R ₅ is independently at each occurrence H, Br, Cl or I provided that when R ₁ and R ₂ are CH ₃ and R ₃ is H, then R ₄ and/or R ₅ is Br, Cl or I or an enantiomer thereof or a pharmaceutically acceptable salt thereof,

In some embodiments of anti-bacterial and/or anti-viral compound of the general formula (I), R ₁ is independently at each occurrence H or CH ₃

R ₂ is independently at each occurrence H or CH ₃ R ₃ is H, CO(CH ₂ ) ₆ CH ₃ , CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , CO(CH ₂ ) ₁₆ CH ₃ , or

CO(CH ₂ )CH=CH(CH ₂ ) ₇ CH ₃

R ₄ is independently at each occurrence H, Br, Cl or I R ₅ is independently at each occurrence H, Br, Cl, or I. provided that when R ₁ and R ₂ are CH ₃ and R ₃ is H, then R ₄ and/or R ₅ is Br, Cl or I or an enantiomer thereof or a pharmaceutically acceptable salt thereof,

Preferably, R ₃ is CO(CH ₂ ) ₆ CH ₃ , CO(CH ₂ ) ₁₀ CH ₃ , CO(CH ₂ ) ₁₂ CH ₃ , CO(CH ₂ ) ₁₆ CH ₃ , or CO(CH ₂ )CH=CH(CH ₂ )VCH ₃ .

In some embodiments of anti-bacterial and/or anti-viral compound of the general formula (I), R ₁ is independently at each occurrence H or CH ₃ R ₂ is independently at each occurrence H or CH ₃ R ₃ is H

R4 is independently at each occurrence H, Br, Cl or I R ₅ is independently at each occurrence H, Br, Cl, or I. provided that when R ₁ and R ₂ are CH ₃ and R ₃ is H, then R ₄ and/or R ₅ is Br, Cl or I or an enantiomer thereof or a pharmaceutically acceptable salt thereof,

Preferably, the viral infection is an infection with enveloped viruses or non-enveloped viruses. Preferably, the enveloped viruses are influenza virus, coronavirus, herpes virus and/or lentivirus (such as HIV). Preferably, the non-enveloped viruses are rhinoviruses and/or enteroviruses. In some embodiments, the viral infection is an infection with enveloped viruses; preferably the enveloped viruses are influenza virus, coronavirus, herpes virus and/or lentivirus (such as HIV). In some other embodiments, the viral infection is an infection with non-enveloped viruses; preferably the non-enveloped viruses are rhinoviruses and/or enteroviruses.

As used herein, "influenza virus” refers to sialic acid-seeking, airborne transmissible (human or animal) enveloped negative stranded RNA viruses. In an embodiment, influenza virus is selected from the group comprising influenza A virus, influenza B virus, influenza C virus and influenza D virus. Influenza A and B are the causative agent of influenza disease. In contrast to Influenza B that infect only humans, Influenza A virus contains a wide range of viral subtypes circulating both in animal species (mostly avian) and in humans. Influenza A H2N2, H3N2 and H1N1 have successfully established in the human population while subtypes with H5, H7, H9, H10 and N7, N8 et N9 have episodically infected humans. In an embodiment, coronavirus, an airborne transmissible enveloped positive stranded RNA virus is selected from the group comprising MERS-CoV virus, SARS-CoV-1 virus and SARS- CoV-2 virus.

In an embodiment, herpes virus, an enveloped DNA virus, transmitted by contact or via sexual intercourse, is selected from the group comprising herpes simplex viruses 1 and 2 (HSV-1 and HSV-2, also known as HHV-1 and HHV-2). varicella zoster virus (HHV-3), Epstein-Barr virus (EBV or HHV-4), human cytomegalovirus (HCMV or HHV-5), human herpesvirus 6A and 6B (HHV-6A and HHV-6B), human herpesvirus 7 (HHV-7), and Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8).

In an embodiment, the airborne transmissible non-enveloped, positive-stranded rhinoviruses are selected from species A and B.

As outlined below, some embodiments of the invention provide treatment or prevention of viral infections, comprising co-administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the general formula (I) of the invention and on or more antimicrobial agents, such as antiviral agents.

Suitable compounds for use in the treatment or prevention of bacterial and/or viral infections according to the invention are compounds of the general formula (I) or the individual compounds as defined above, as well as enantiomers thereof, pharmaceutically acceptable salts thereof or mixtures thereof.

An aspect of the invention discloses a pharmaceutical composition comprising an effective amount of one or more anti -bacterial and/or anti-viral compounds of the general formula (I) of the invention and at least one pharmaceutically acceptable excipient, carrier and/or diluent. Optionally, the pharmaceutical composition of the invention further comprises one or more additional active agents, preferably antimicrobial agents, such as antibiotics or antiviral agents. Preferably, said pharmaceutical composition is formulated for medical or veterinary use.

As to the appropriate excipients, carriers and diluents, reference may be made to the standard literature describing these, e.g. to chapter 25.2 of Vol. 5 of "Comprehensive Medicinal Chemistry", Pergamon Press 1990, and to "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete", by H.P. Fiedler, Editio Cantor, 2002. The term "pharmaceutically acceptable carrier, excipient and/or diluent" means a carrier, excipient or diluent that is useful in preparing a pharmaceutical composition that is generally safe and possesses acceptable toxicities. Acceptable carriers, excipients or diluents include those that are acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable carrier, excipient and/or diluent" as used in the specification and claims includes both one and more than one such carrier, excipient and/or diluent.

The anti -bacterial and/or anti-viral compounds of the general formula (I) of the invention that are used in the methods of the present invention can be incorporated into a variety of formulations and medicaments for therapeutic administration. Suitable formulations for use in the present invention are found in Remington's Pharmaceutical Sciences (Mack Publishing Company (1985) Philadelphia, PA, 17th ed.), which is incorporated herein by reference. Moreover, for a brief review of methods for drug delivery, see, Langer, Science (1990) 249:1527-1533, which is incorporated herein by reference.

The route of administration of compounds or pharmaceutical compositions of the invention may be oral, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingual, intramuscular, subcutaneous, topical, intranasal, intraperitoneal, intravenous, epidural, intrathecal, intracerebroventricular and by injection into the joints. Preferably, the route of administration of compounds or pharmaceutical compositions of the invention is topical or oral or parenteral. More preferably, the route of administration of compounds or pharmaceutical compositions of the invention is parenteral.

The parenteral route of administration of compounds or pharmaceutical compositions of the invention may be subcutaneous or intravenous. Preferably, the parenteral route of administration of compounds or pharmaceutical compositions of the invention is subcutaneous.

The frequency and optimum dosage of administration of the invention will depend on the particular condition being treated and its severity; the age, sex, size and weight, and general physical condition of the particular patient; other medication the patient may be taking; the route of administration; the formulation; and various other factors known to physicians and others skilled in the art. For example, the frequency of administration will vary for the infection or disease being treated from once weekly to once monthly. Preferably, the frequency of administration is every 7 to 31 days. Depending on the dose, the frequency of administration may be once every 7 to 10 days, or very 7 to 14, or 21 or 31 days. More preferably, the frequency of administration is every 2, 3 or 4 weeks. Yet more preferably, the frequency of administration is every 2 weeks. Most preferably, the frequency of the administration is every 4 weeks or calendar month.

For instance, dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art. Thus, the skilled artisan can readily determine the amount of compound and optional additives, vehicles, excipients and/or carrier in compositions to be administered in methods and uses of the invention. For example, the antibacterial and/or antiviral compound or agent according to the invention is of a concentration ranging from 0.25 mM to 100 mM in the method for preventing or reducing the growth of Gram-positive bacteria or Gram-negative bacteria or Mycobacteria.

The compounds, agents or pharmaceutical compositions of the invention can be administered to an animal, in particular a mammal, more particularly a human, in order to treat, inhibit, and/or prevent bacterial and/or viral infection (e.g., the composition may be administered before, during, and/or after the infection). The compounds, agents or pharmaceutical compositions of the invention may also comprise at least one other antimicrobial agent (e.g., an antibiotic or antiviral agent). The additional antimicrobial agent may also be administered in a separate composition from the anti -bacterial and/or anti-viral compounds of the invention. The compounds, agents or pharmaceutical compositions of the invention may be administered at the same time and/or at different times (e.g., sequentially) with the additional antimicrobial agent. The composition(s) comprising at least one anti -bacterial and/or anti-viral compounds of the invention and the composition(s) comprising at least one additional antimicrobial agent may be contained within a kit.

As used herein, the term “antibiotic” refers to antimicrobial agents for use in mammalian, particularly human, therapy. Antibiotics include, without limitation, beta-lactams (e.g., penicillin, ampicillin, oxacillin, cloxacillin, methicillin, and cephalosporin, carbacephems, cephamycins, carbapenems, monobactams), aminoglycosides (e.g., gentamycin, tobramycin), glycopeptides (e.g., vancomycin), quinolones/ fluoroquinolones (e.g., ciprofloxacin), moenomycin, tetracyclines, macrolides (e.g., erythromycin), , oxazolidinones (e.g., linezolid), lipopetides (e.g., daptomycin), aminocoumarin (e.g., novobiocin), co-trimoxazole (e.g., trimethoprim and sulfamethoxazole), lincosamides (e.g., clindamycin and lincomycin), polypeptides (e.g., colistin), and derivatives thereof.

As used herein, the term "antiviral agent" refers to antimicrobial agents for use in mammalian, particularly human, therapy. Antivirals or antiviral agents include, without limitation, virus adsorption inhibitors (e.g.: polysulphates, polysulphonates, polycarboxylates, polyoxometalates, zintevir, cosalane derivitives, Tromantine, ), entry and fusion inhibitors (e.g.: enfuvir, docosanol, enfuvirtide, Maraviroc, Pleconaril, Vicriviroc), uncoating inhibitors (e.g.: Pleconaril, Amantadine, rimantadine), viral synthesis inhibitors (including those that affecting, replication, transcription, reverse transcription, integration of viral genome into host cell genomes, protein synthesis and processing (e.g.: Zidovudin, Lamivudine, Zalcitabine, Nevirapine, Efavirenz, Delavirdines, Saquinavir, Ininavir, fomivirsen, adefovir, atazanavir, mozenavir, tipranavir, abacavir, Acyclovir, Amprenavir,Cidovir, Darunavir, Didanosine Edoxudine, efavirenz, Emtricitabine, Entevavir, Famciclovir, Fosamprenavir,

Methisazone,Nelfmavir, Norvir, Nevirapine, Penciclovir, Podophyllotoxin, Raltegravir, Ribavirin, Rimantadine, Ritonavir, Saquinavir, Sofobuvir, Stavudine, Trifluridine,Valaciclovir, ganciclovir, valganciclovir, Vidarabine, Ribavirin, Zalcitabine, azidothymidine)), viral assembly (e.g.: rifampicin, atazanavir, Fosfonet, Indinavir, Lopinavir, Loviride, tipranavir), and viral release (e.g.: zanamivir, oseltamivir, RWJ270201, Mycophenolic acid, EICAR, VX487).

Thus in some embodiments of the invention, one or more compounds of the general formula (I) of the invention is administered adjunctively with one or more additional antimicrobial agents (antibiotics or antiviral agents). Administration of one or more compounds of the general formula (I) of the invention and one or more additional antimicrobial agents (antibiotics or antiviral agents) may be concurrent (in the same dosage form or in separate dosage forms administered to the patient at approximately the same time), or not. Coadministration of compounds may help to prevent emergence of viral resistance.

As described above, some embodiments include co-administering a compound of the general formula (I) of the invention and one or more additional antimicrobial agent. By "co administration" or “co-administering”, it is meant that a compound of the general formula (I) of the invention and the one or more additional antimicrobial agent (antibiotic or antiviral agent) are administered in such a manner that administration of a compound of the general formula (I) of the invention has an effect on the efficacy of the treatment of the one or more additional antimicrobial agent, regardless of when or how they are actually administered. Thus in one embodiment, one or more compounds of the general formula (I) of the invention and the one or more additional antimicrobial agent (antibiotic or antiviral agent) are administered simultaneously. In one such embodiment, administration in combination is accomplished by combining a compound of the general formula (I) of the invention and the one or more additional antimicrobial agent in a single dosage form. In another embodiment, one or more compounds of the general formula (I) of the invention and the one or more additional antimicrobial agents (antibiotic or antiviral agent) are administered sequentially. In one embodiment a compound of the general formula (I) of the invention and the one or more additional antimicrobial agent are administered through the same route. In another embodiment, a compound of the general formula (I) of the invention and the one or more additional antimicrobial agent are administered through different routes, such as one being administered orally and another being administered parenterally and/or topically. In some embodiments, the time period between administration of one or more compounds of the general formula (I) of the invention and administration of the co-administered one or more additional antimicrobial agent can be about 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 1 8 hours,

20 hours, 24 hours, 36 hours, 48 hours, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days,

21 days, 28 days, or 30 days.

Pharmaceutical composition containing the compounds of the invention as the active ingredient in intimate admixture with pharmaceutically acceptable excipient, carrier and/or diluent can be prepared according to conventional pharmaceutical compounding techniques. The excipient, carrier and diluent may take a wide variety of forms depending on the form of pharmaceutical composition desired for administration, e.g., intravenous, oral, direct injection, topical, intracranial, and intravitreal.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications without departing from the spirit or essential characteristics thereof. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. The present disclosure is therefore to be considered as in all aspects illustrated and not restrictive, the scope of the invention being indicated by the appended Claims, and all changes which come within the meaning and range of equivalency are intended to be embraced therein.

Various references are cited throughout this specification, each of which is incorporated herein by reference in its entirety.

The foregoing description will be more fully understood with reference to the following Examples. Such Examples, are, however, exemplary of methods of practising the present invention and are not intended to limit the scope of the invention.

MATERIALS AND METHODS

The active compounds were generated by a biotransformation process using a mixture of enzymes (called secretome) obtained from the necrogenous saprophytic fungus Botrytis cinerea (according to Gindro et al, 2017). ⁷ The secretome is first obtained from liquid cultures of B. cinerea. In a second step, the secretome is used to biotransform resveratrol, pterostilbene and a mixture of the two. The compounds obtained in each reaction were purified by semi-preparative high-performance liquid chromatography (semi-prep. HPLC). Finally, the structure of each isolated compound was determined by spectroscopic methods such as nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). All these procedures are described in detail below:

1. General Experimental Procedures:

The optical rotations were measured in methanolic solutions on a JASCO P-1030 polarimeter in a 1 cm tube. UV spectra were measured on a HACH UV-vis DR/4000 instrument. The electronic circular dichroism (ECD) spectra were recorded on a JASCO J-815 CD spectrometer in acetonitrile (MeCN). NMR data were recorded on a 500 MHz Varian INOVA NMR spectrometer or on a Bruker Avance III HD 600 MHz NMR spectrometer equipped with a QCI 5mm Cryoprobe and a SampleJet automated sample changer (Bruker BioSpin). Chemical shifts are reported in parts per million (d) using the residual DMSO-d6 signal (δ _H 2.50; δ _C 39.5) as internal standards for 'H and ¹³ C NMR, respectively, and coupling constants (J) are reported in Hz. Complete assignments were obtained based on 2D-NMR experiments (COSY, NOESY, HSQC and HMBC). HRESIMS data were obtained on a Micromass-LCT Premier time-of- flight mass spectrometer with an electrospray (ESI) interface (Waters). The biotransformation reactions were controlled on a multi detection ultra-high-performance liquid chromatography coupled to the photodiode array, evaporative light scattering and mass spectrometry detectors (UHPLC-PDA-ELSD-MS) (Waters) platform fit with on a single quadrupole detector (QDa) using a heated electrospray ionization, Analytical HPLC was carried out on a HP 1260 Agilent system equipped with a photodiode array detector (Agilent technologies). Semi-preparative HPLC was performed on a modular semi-preparative HPLC-ELSD-UV-ESI/MS system (Puriflash-MS 4250, Interchim) equipped with a quaternary pump, a UV detector module, a fraction collector and an ESI-single-quadrupole mass spectrometer (Advion). The split system consisted of a make-up pump combined to a dilution pump (Dynamic split, Interchim). Resveratrol (99% purity) and pterostilbene (99% purity) were purchased from Hangzhou Apichem Technology Co. Ltd.

2. Secretome isolation from Botrytis cinerea culture

Botrytis cinerea Pers.:Fr., isolate P-69 was obtained from natural sporulation grape berries in applicants experimental vineyards in 1995. The strain was purified, determined phenotypically as well as by molecular tools (sequencing of the ITS regions) and maintained in applicants dynamic my cotheca. The fungus was grown on oatmeal agar, conidia are sampled by vacuum aspiration and stored dry at -80°C until use, as described by Gindro et al., 2017. ⁷ A clear filtrate (5 L) was brought to 80% saturation ((NH ₄ ) ₂ SO ₄ , 24 hours at 4 °C) and then centrifuged (10'000 x g, 4 °C, 1 h). The supernatant was discarded and the resulting pellet was solubilized in distilled water (crude extract) and dialyzed against water overnight at 4 °C. The resulting extract was concentrated on polyethylene glycol (PEG 20'000) in the dialyzed tube. The protein content was determined by the method of Bradford, using a Bio-Rad protein assay kit with BSA as a standard. The volume of the extract was adjusted to obtain a final protein concentration of 20 μg/μL. The resulting crude extract (considered as secretome) was aliquoted to 1 mL and stored at -20 °C until use.

3. Biotransformation of the resveratrol

The biotransformation of resveratrol was performed using 100 mg of the pure compound and 10 mL of the Botrytis secretome. Resveratrol was solubilized in 10 mL of acetone. This solution was diluted in 500 mL of water. 10 mL of the enzymatic extract was added. This mixture was incubated for 5 hours at 22 °C in the dark with agitation. The reaction mixture was extracted by liquid/liquid partition with ethyl acetate (3 x 500 mL), affording 182.74 mg. This ethyl acetate fraction was further fractionated by reverse-phase semi-preparative HPLC. The crude reaction extract (50 mg injection/ 3 injections) was purified by semi-preparative HPLC on an X Bridge ^® RP C ₁₈ column (5 μm, 250 x 10 mm, i.d.; Waters). The mobile phase used was (A) H ₂ O containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid. The elution followed a step gradient: 5% to 20% of B in 15 min; 20% to 23% of B in 25 min; and 23% to 100% of B in 15 min. Flow rate 10 mL/min, UV 254 and 280 nm, injection of 200 μL (cone. 4.2 mg/300 μL), yielding trans-δ-5-viniferin (6 2.4 mg) and other compounds described in the article of Gindro et al., 2017. ⁷

4. Biotransformation of the pterostilbene

Biotransformation of pterostilbene was performed as described above, using 100 mg of each compound and 10 mL of the Botrytis secretome. The resulting reaction mixture was extracted by liquid/liquid partitioning with ethyl acetate (3 x 500 ml), affording 193.46 mg. This ethyl acetate fraction was purified by reverse-phase flash chromatography (FC). The FC conditions were optimized using an analytical HPLC column (15 μm, 250 x 4.6 mm i.d.) loaded with Uptisphere Strategy C ₁₈ -HQ ^® as the stationary phase (Interchim). The optimized HPLC analytical conditions were geometrically transferred by gradient transfer to the FC. The crude reaction extract (190 mg) was fractionated using two flash chromatographic columns connected in series. Both C ₁₈ -HQ FC columns (25 g x 2 columns, 15 μm C ₁₈ HQ, Interchim) had a surface area of 60 Å - 500 m ² /g. The mobile phase used was (A) H ₂ O containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid. The elution followed a linear gradient from 35% to 100% of B during 81 min. Flow rate 16 ml/min, UV detection at 210, 254 and 307 nm, liquid injection (190 mg/500 μL) yielding 130 fractions. Fractions F33 afforded 19 (0.4 mg); F35 afforded 18 (1.1 mg); F38-39 afforded 17 (0.7 mg); F44 afforded 16 (0.2 mg); F54-55 afforded 20 (1 mg); and F73-74-75 afforded pterostilbene-trans -dehydrodimer (15 2.5 mg). ⁷

5. Biotransformation of the mixture of pterostilbene and resveratrol

The biotransformation of pterostilbene and resveratrol was performed using 100 mg of each compound and 10 mL of the Botrytis secretome. The compounds were dissolved in 10 mL of acetone. This solution was diluted in 500 mL of water. 10 mL of the enzymatic extract was added. This mixture was incubated for 5 hours at 22 °C in the dark under constant agitation. The resulting solution was lyophilized and the dry extract weighed (353 mg). The obtained crude reaction mixture was purified by MPLC. The preparative separation conditions were optimized using an analytical HPLC column (15-25 pm, 250 x 4.6 mm i.d.) loaded with Zeoprep® C ₁₈ 15-25 μm as the stationary phase (Zeochem). The optimized HPLC analytical conditions were geometrically transferred by gradient transfer to the MPLC. ⁷ The crude reaction extract (500 mg) was fractionated using reverse-phase MPLC with a 460 x 70 mm i.d. column (BuchÏ) loaded with Zeoprep® C ₁₈ 15-25 μm as the stationary phase (Zeochem), with a linear gradient of MeOH and H2O, from 5% to 100% MeOH with 0.1% formic acid, a flow rate of 20 mL/min for 12.7 h, and UV detection at 210, 254 and 366 nm. The extract was introduced in MPLC using a dry load cell. This cell was a small aluminum column (11.5 x 2.7 cm i.d.) connected between the pumps and the MPLC column. The extract was mixed with the stationary phase (C ₁₈ Zeoprep® 40-63 μm) in a proportion of 1 part of extract to 5 parts of stationary phase. The separation yielded 81 fractions (250 mL each). To isolate the putative new natural compounds, 1 mL of each fraction was collected and analyzed by UHPLC-TOF- MS. Using this approach, it was possible to isolate the targeted molecular ions among the MPLC fractions. Fraction F15 was purified by semi-preparative HPLC on an XBridge® RP C ₁₈ column (5 μm, 250 x 10 mm, i.d.; Waters). The mobile phase used was (A) H ₂ O containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid. The elution followed a step gradient: 5% to 20% of B in 15 min; 20% to 23% of B in 25 min; and 23% to 100% of B in 15 min. Flow rate 10 ml/min, UV 254 and 280 nm, injection of 200 μL (cone. 4.2 mg/300 μL), yielding 11',13'-dimethoxy-trans-δ-viniferin (11 17.1 mg) and 11 , 13-dimethoxy-trans-δ- viniferin (14 24.6 mg). The reactions also afforded a series of other compounds described in the article of Gindro et al., 2017. ⁷

6. Biotransformation of the mixture of pterostilbene and resveratrol in presence of methanol

The biotransformation of pterostilbene and resveratrol was performed using 50 mg of each compound. First, the two compounds were solubilized in 100 mL of MeOH. This solution was diluted in 90 mL of water. 10 mL of the enzymatic extract was added. This mixture was incubated for 24 hours at 22°C in the dark under constant gentle agitation. After evaporation of the methanol under vacuum with a rotary evaporator, the solution was lyophilized and the dry extract weighted (107.5 mg). This crude reaction mixture, obtained from the biotransformation of a mixture of pterostilbene and resveratrol, was then purified by semi-preparative HPLC-UV- ESI/MS. Waters X-Bridge C ₁₈ column (250 x 4.6 mm i.d., 5 μm; Waters) equipped with a Waters C ₁₈ pre-column cartridge holder (10 x 2.1 mm i.d.); solvent system MeOH (B) and H ₂ O (A), both containing 0.1% of formic acid (FA). The column was equilibrated with 20% of B during 15 min. The separation was performed in the gradient mode as follows: 20% of B during 10 min, followed by the gradient of 20 to 100% of B in 70 min. Flow rate 1 mL/min; injection volume 10 μL; sample concentration 10 mg/mL in methanol. The UV absorbance was measured at 254 nm and the UV-PDA spectra were recorded between 190 and 600 nm (step 2 nm). The optimized HPLC analytical conditions were geometrically transferred by gradient transfer to the semi-preparative HPLC scale. The crude reaction extract (100 mg) was fractionated using reverse-phase semi-preparative HPLC with a Waters X-Bridge C ₁₈ column (250 x 19 mm i.d., 5 pm) equipped with a Waters C ₁₈ pre-column cartridge holder (10 x 19 mm i.d.). The separation was performed with a step gradient of MeOH (B) and H ₂ O (A) with 0.1% formic acid. The method started with 20% of B during 10 min, followed by the gradient of 20 to 100% of B in 70 min. The flow rate was set to 17 mL/min, and UV detection 210, 254, and 366 nm. The ESI-MS conditions were as follows: capillary voltage, 180 V; capillary temperature, 250°C; source voltage offset, 30 kV; source voltage span, 30 kV; source gas temperature, 280°C. The isolation was performed in negative ion (NT) mode in the 400-600 amu range with an acquisition time of 1 s. The MS-detection of specific extracted ion chromatogram (XIC) was acquired over three m/z ranges: 531-532, 559-560, and 587-588. The conditions for the split system were as follows: the flow rate of the make-up pump was fixed at 0.1 mL/min, the dilution pump at 0.05 mL/min and the valve rotation period at 1.5 sec. Both pumps delivered acetonitrile with 0.1% formic acid. The extract (100 mg) was introduced on the semi-preparative HPLC column using a dry load methodology recently developed in applicant's laboratory. ⁹ The separation yielded 120 fractions (12 mL each). The semi-preparative HPLC fractions F34, 35 afforded 1 (1 mg), F38, 39, 40 afforded 2 (9.1 mg), F54 afforded 3 (1.9 mg), F55 afforded 4 (1.1 mg), F60, 61 afforded 5 (8.7 mg), F63,64 afforded trans-δ-viniferin (6 10.2 mg), F67 afforded 7 (1.3 mg), F69, 70 afforded 8 (11.1 mg), F72 afforded 9 (1.7 mg), F79, 80 afforded 10 (3.1 mg), F85 afforded 11',13'-dimethoxy-trans-δ-viniferin (11 1.5 mg), F87 afforded 12 (1.8 mg), F89 afforded 13 (2.5 mg), F91, 92 afforded 1 l,13-dimethoxy- trans-δ-viniferin (14 2.9 mg) and FI 11-112 afforded pterostilbene trans-dehydromer (15 5.3 mg).

7. Preparation of halogenated derivatives

About 10 mg of starting material (6, 11, 14 or 15) were solubilized in 3 mL of a 50:50 MeCN : H ₂ O mixture in a 10 mL round-bottom flask. The mixture was placed at 40 °C and stirred. 0.5 to 100 eq. of NaX (X being Cl, Br or I) was added, followed by 2 mL of CH ₃ COOH and 21 equivalents of H ₂ O ₂ . After 2 to 7 hours, the reaction was stopped by extraction with 2 times 4 mL of AcOEt. The combined organic layers were analyzed by UHPLC-PDA-ELSD-MS. The crude reaction mixture was fractionated by reverse-phase chromatography. The separation conditions were optimized by HPLC on a 250 x 4.6 mm i.d., 5 μm C18 column and geometrically transferred to the semipreparative scale (250 x 10 mm i.d., 5 μm C18 column) to obtain the pure halogenated derivatives 21 to 45.

8. Antibacterial assay against Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA, ATCC 33591) and vancomycin-resistant Staphylococcus aureus (VRSA 510) were used for the antibacterial assay. The minimum inhibitory concentration (MIC) of the different compounds were determined in triplicate using the broth dilution method in 96-well microtiter plates as previously described. Briefly, compounds were resuspended at 10.24 mg/mL in DMSO and serially diluted in Mueller-Hinton broth (MHB, Oxoid). The maximum initial concentration used for this assay was 256 pg/mL for P. aeruginosa and 128 pg/mL for S. aureus. After an incubation of 24h at 37°C, Iodonitrotetrazolium chloride (Sigma-Aldrich) was added to each wells, as growth indicator, and incubated for several hours. The highest dilution of a compound in which no growth appears corresponds to its MIC. Gentamicin Sulfate (Applichem) and Vancomycin Hydrochloride (Sigma-Aldrich) were used as control of inhibition for P. aeruginosa and S. aureus , respectively, and compared to the reference values. ¹⁰

9. Antibacterial assay against Mycobacterium marinum

M. marinum is a genetically close relative of M. tuberculosis and is used as a relevant model organism to study the mechanisms of Mycobacteria pathogenicity in a variety of experimental systems, including cultured macrophages, amoebae and zebrafish. Briefly, GFP-expressing M marinum were cultivated in a shaking culture at 32 °C up to an OD600 of 0.8-1 in 7H9 medium supplemented with OADC. 10 ⁵ GFP-expressing M marinum were transferred into each well of a 96-well plate (white MicroWell plate Nunc). Bacterial growth at 32 °C was monitored by measuring the fluorescence as a proxy for bacterial growth in a fluorescence plate reader (Synergy HI) for at least 72 hours with a time point taken every 1 hour. ⁸ The four compounds were tested at 20 μM and Rifabutin was added as a positive control at 10 μM. Fluorescence excitation was at 485nm and emission was monitored at 509nm.

10. Anti-infective assay against Mycobacterium marinum

Two whole cell-based techniques were used to determine the anti-infective activity of the tested compounds, a plate reader population assay and a High Content Microscopy (HCM) assay. Both methods aim at monitoring the activity of the compounds on intracellularly growing bacteria, a crucial characteristic in anti-infective drug discovery and development. Dictyostelium discoideum an environmental amoeba has been developed as a model professional phagocyte to study the function of phagocytes of the innate immune system. In particular, this model allows to study in a 3R-compliant manner the evolutionarily conserved interactions and defences between a eukaryotic host and various bacterial pathogens, including Mycobacteria. D. discoideum was cultured in HL5c medium in 10 cm Petri dishes at 22°C, and passaged the day before the infection to reach 90% confluency. GFP-expressing Mycobacterium marinum were grown as described above. The infection was performed as described previously. ¹¹ Briefly, infected cells were re-suspended in HL5c containing Penicillin/Streptomycin (to prevent extracellular M. marinum growth); 5 x 10 ⁴ infected cells were transferred to each well of a 96-well plate (Cell Carrier, black, transparent bottom from Perkin Elmer) and compounds were added at 20 mM except for Rifabutin (added at 10 pM). The course of infection at 25°C was monitored by measuring bacterial fluorescence in a plate reader (Synergy HI, BioTek) for 72 h with time points taken every 1 h. In parallel, an HCM assay was performed in 96-well plates (black, transparent bottom from Ibidi). Recording of transmitted light and GFP fluorescence were performed using the ImageXpress Micro XL confocal High-content Screening System (20x0.75 NA, air). Quantification of the fluorescence intensity of bacteria inside D. discoideum , in each of 16 fields of view was used to determine the anti -proliferative effect of the four compounds versus the vehicle control. In order to strictly evaluate the compounds activity on the intracellular M marinum , I), discoideum was segmented on the phase contrast image prior to the fluorescence intensity quantification.

11. IC ₅₀ determination

In order to determine the IC ₅₀ of compounds 11 and 14, the same infection procedure as mentioned above (anti-infective assay) was used. 5 ^x 10 ⁴ infected cells were transferred to each well of a 96-well plate (Cell Carrier, black, transparent bottom from Perkin Elmer) and a two- fold serial dilution was employed to obtain decreasing compound concentrations from 20 μM to 0.625 μM. The course of infection at 25°C was monitored by measuring bacterial luminescence in a plate reader (Synergy HI, BioTek) for 72 h with time points taken every 1 h. Rifabutin was used at 10 pM as a positive control. The values of the data points at 3 days post- infection were used to build dose response curves in Graph Pad Prism to determine the IC ₅₀ . A mean value from at least two biological replicates is given for each compound. The absolute IC50 was calculated using a 4PL curve fiting analysis. 12. Cells viability assay

MDCK cells (2xlE4 cells per well) were seeded in a 96-well plate one day before the assay. A dose range of each d-Viniferin (spanning from 1.58 μg/ml to 128 μg/ml) was added on the cells in serum-free DMEM or serum-free DMEM + TPCK-Trypsin 0.2 pg/ml for 24 hours. MTT reagent (Promega) was added on the cells for 3h at 37°C according to manufacturer instructions. Subsequently, the absorbance was read at 570 nm. Percentages of viability were calculated by comparing the absorbance in treated wells and untreated conditions.

13. Antiviral activity of δ-Viniferins against influenza A pdm09 virus in pre incubation

Influenza A virus, at the multiplicity of infection (MOI) of 0.1 PFU/cell, was added to a dose range of 6, 11 or 14, spanning from 175 ng/ml to 14.2 μg/ml, or of 15 spanning from 527 ng/ml to 42.67 pg/ml. The mix virus + compounds was incubated in serum-free DMEM for 1 hour at 37°C and then inoculated for 1 hour at 37°C on a confluent layer of MDCK cells seeded in a 96 multiwell. The inoculum was then removed and the cells were overlaid with serum-free DMEM containing 1% penicillin/streptomycin. 12 hours post infection (hpi) at 37°C the number of infected cells was calculated by immunocytochemistry. Upon fixation in methanol the primary antibody (mouse monoclonal Influenza A anti -body 1:100 dilution, Chemicon®) was added for 1 hour at 37°C. The cells were then washed with DPBS/Tween 0.05% three times and the secondary antibody (Anti -mouse IgG, HRP -linked 1:500 dilution, Cell signaling technology) was added. After 1 hour the cells were washed and the DAB solution was added. Infected cells were counted and percentages of infection were calculated comparing the number of infected cells in treated and untreated conditions.

14. Post-treatment of the d-Viniferins against Influenza A pdm09 virus

Confluent layers of MDCK cells seeded in 96 multiwells were infected with a MOI of 0.01 PFU/cell of Influenza A virus in serum-free DMEM for lh at 37°C. One hour post infection the inoculum was removed and two concentrations of each d-Viniferin (1.5 ug/ml and 4.7 ug/ml) were added on the cells for 24h. Then the supernatant was collected and infectious virus yields were determined by Plaque Assay as the number of PFU/ml in MDCK cells. 15. Antibiotic activity assays:

Growth inhibition assay

In a 96-well plate containing 150 μL Mueller-Hinton broth (MHB)/well, compounds were tested at a fixed concentration of 100 μM. Positive control of growth was DMSO. The following antibiotics were added as a growth-inhibiting control: vancomycin 8 μg/ml for Gram -positive bacteria, aztreonam 16 μg/ml for Gram -negative bacteria. Inoculation of strains was done as described in the MIC paragraph above. The inoculated plate was then incubated for 22 hours at 37°C before measurement of OD ₆₀₀ with a Synergy HI microplate reader.

Minimal inhibitory concentrations

MICs were determined in a 96-well plate by 2-fold microdilution following the Clinical and Laboratory Standards Institute (CLSI) guidelines in Mueller-Hinton broth I (MHB). Briefly, 2- fold serial dilutions were performed to have concentrations of compounds ranging from 128- 0.5 μM. Bacterial cultures grown for 6 h, were diluted 1:1000 in NaCl 0.9% and 4 μL of this dilution was added to each well in order to achieve a final inoculum size equivalent to 1 ^x 10 ^5±0.5 CFUs/well. To verify the inoculum, 5 μL of a 10 ^-7 dilution of the starter culture were plated on a LB agar plate. The 96-well plate and control agar plate were incubated at 37°C during 16-20h and MIC values were reported. The MIC was defined as the lowest compound concentration, which inhibits visible bacterial growth (transparent well with no turbidity). MIC determination assays were performed at two or three different occasions for each strain and antimicrobial agent tested. When required, MICs were confirmed by addition of 0.1 mg/ml Thiazolyl Blue Tetrazolium Bromide (MTT).

Killing assay

Killing assays were performed as described in Ben Jeddou et al. 2020. ¹¹ Briefly, an overnight culture of the bacterial strain was centrifuged and resuspended in M9 salts medium supplemented with 2 mM MgSO ₄ to an OD ₆₀₀ of 2. Twenty μl of this suspension were added to 180 μL of the same media containing 64 μM of resveratrol derivatives or 3% DMSO (negative control) and the plate was incubated at 37°C. At selected timepoints, 10-fold serial dilutions of 5 μL aliquots were spotted on LB agar plates and CFU (colony-forming unit) counts were determined after overnight incubation at 37°C. Description of the compounds

Pallidol (1)

Amorphous solid; ¾ NMR (DMSO-d ₆ , 500 MHz) d 6.84 (4H, d , J = 8.4 Hz, H-2, H-2', H-6, H-6'), 6.61 (4H, d, J= 8.4 Hz, H-3, H-3', H-5, H-5'), 6.39 (2H, d, J= 2.0 Hz, H-10, H-10'), 6.06 (2H, d, J = 2.0 Hz, H-12, H-12'), 4.30 (2H, s, H-7, H-7'), 3.61 (2H, s, H-8, H-8'); ¹³ C NMR (DMSO-d ₆ , 126 MHz) d 158.1 (C-11, 1-11'), 155.3 (C-4, C-4'), 154.2 (C-13, C-13'), 148.6 (C- 9, C-9'), 136.2 (C-1, C-1'), 127.8 (C-2, C-2', C-6, C-6'), 121.7 (C-14, C-14'), 114.8 (C-3, C-3', C-5, C-5'), 101.8 (C-10, C-10'), 101.4 (C-12, C-12'), 58.7, 52.4 (C-7, C-7'). HRESIMS m/z 453.1346 [M-H]- (calcd for C ₂₈ H ₂₁ O ₆ , 453.1338, Δ= 1.8 ppm).

Parthenostilbenin A+B (2)

Amorphous solid; Parthenostilbenin A (7S) ¹ H NMR (DMSO-d ₆ , 600 MHz) d 6.65 (1H, d, J = 9.5 Hz, H-2', H-6'), 6.60 (4H, m, H-2, H-6, H-3', H-5'), 6.42 (1H, d, J= 2.1 Hz, H-14), 6.17 (1H, d, 7= 2.1 Hz, H-12), 5.92 (1H, t, J = 2.3 Hz, 12'), 5.60 (2H, d, J = 2.3 Hz, H-10', H-14'), 3.96 (1H, d, J = 2.6 Hz, H-7'), 3.75 (1H, d, J = 9.1 Hz, H-7), 3.11 (1H, dd, J = 9.1, 2.6 Hz, H- 8), 2.92 (3H, s, OCH ₃ -7), 2.60 (1H, t, J = 2.6, 2.6 Hz, 8'); ¹³ C NMR (DMSO-d ₆ , 151 MHz) d 158.0 (C-l l', C-13'), 157.7 (C-13), 156.6 (C-4), 155.1 (C-4'), 154.1 (C-l l), 149.7 (C-9'), 147.6 (C-9), 136.2 (C-l'), 130.4 (C-l), 128.5 (C-2, C-6), 128.0 (C-2', C-6'), 120.8 (C-10), 114.8 (C- 3', C-5'), 114.6 (C-3, C-5), 104.6 (C-14), 104.2 (C-10', C-14'), 101.4 (C-12), 100.1 (C-12'), 86.4 (C-7), 59.2 (C-8), 57.4 (C-8'), 56.0 (OCH ₃ -7), 54.4 (C-7'). Parthenostilbenin B (7R) 'H NMR (DMSO-d ₆ , 600 MHz) d 6.91 (2H, d, J = 8.6 Hz, H-2, H-6), 6.68 (2H, d, J = 8.6 Hz, H-3, H-5), 6.68 (2H, d, J = 8.8 Hz, H-2', H-6'), 6.60 (2H, m, H-3', H-5'), 6.06 (1H, d, J = 2.1 Hz, H-12), 5.99 (1H, t, J = 2.2 Hz, H-12'), 5.92 (2H, d, J = 2.2 Hz, H-10', H-14'), 5.42 (1H, d, J = 2.1 Hz, H-14), 4.02 (1H, d, J = 2.7 Hz, H-7'), 3.72 (1H, d, J = 8.7 Hz, H-7), 3.20 (2H, m, H-8, H-8'), 2.83 (3H, s, OCH ₃ -7); ¹³ C NMR (DMSO-d ₆ , 151 MHz) d 158.2 (C-11', C-13'), 157.2 (C-13), 156.8 (C-4), 155.0 (C-4'), 154.0 (C-11), 149.8 (C-9'), 145.2 (C-9), 136.7 (C-1'), 129.9 (C-1), 129.2 (C-2, C-6), 128.0 (C-2', C-6'), 121.6 (C-10), 114.7 (C-3', C-5'), 114.6 (C-3, C-5), 104.7 (C-10', C-14'), 104.0 (C-14), 101.5 (C-12), 100.1 (C-12'), 86.1 (C-7), 59.7 (C-8), 57.7 (C-8'), 55.7 (OCH ₃ -7), 54.5 (C-7'). HRESIMS m/z 485.1606 [M-H] ^' (calcd for C ₂₉ H ₂₅ O ₇ , 485.1600, Δ= 1.2 ppm). Resvepterol A+B (3)

Resvepterol A (7S). ¾ NMR (DMSO-i¾ 500 MHz) δ 6.73 (2H, m, H-2, H-6), 6.69 (2H, d, J = 8.5 Hz, H-2', H-6'), 6.60 (4H, m, H-3, H-5, H-3',H-5'), 6.39 (1H, d, J= 2.1 Hz, H-14), 6.22 5 (1H, t, J= 2.2 Hz, H-12'), 6.15 (1H, d , J= 2.1 Hz, H-12), 5.82 (2H, d , J= 2.2 Hz, H-10', H-

14'), 4.21 (1H, d , J= 8.3 Hz, H-7), 4.03 (1H, d, J= 3.8 Hz, H-7'), 3.59 (6H, s, OCH3-I I', OCH ₃ - 13'), 3.11 (1H, dd, J= 8.3, 3.8 Hz, H-8), 2.79 (1H, t, J= 3.8 Hz, H-8'); ¹³ C NMR (DMSO-^, 126 MHz) δ 159.7 (C-l l ', C-13'), 157.1 (C-l l), 155.8 (C-4), 154.8 (C-4'), 153.6 (C-13), 136.5 (C-l'), 134.6 (C-l), 127.7 (C-2', C-6'), 127.6 (C-2, C-6), 120.7 (C-l 4), 114.4 (C-3, C-5, C-3', 10 C-5'), 104.4 (C-10), 104.3 (C-10', C-14'), 101.0 (C-12), 96.8 (C-12'), 74.8 (C-7), 60.6 (C-8),

57.6 (C-8'), 54.5 (OCH ₃ -l V, OCH ₃ -13', C-7'); HRESIMS m/z 499.1751 [M-H] ^" (calcd for C _3O H ₂₇ 0 ₇ , 499.1757, Δ = -1.2 ppm). Resvepterol B (7R). ¾ NMR (DMSO-^, 500 MHz) δ 6.95 (2H, d, J= 8.4 Hz, H-2, H-6), 6.73 (2H, m, H-2', H-6'), 6.60 (4H, m, H-3, H-5, H-3', H- 5'), 6.27 (1H, t, J= 2.3 Hz, H-12'), 6.09 (2H, d, J= 2.3 Hz, H-10', H-14'), 6.06 (1H, d, J= 2.0

15 Hz, H-12), 5.61 (1H, d, J= 2.0 Hz, H-14), 4.34 (1H, d, J= 7.4 Hz, H-7), 4.07 (1H, d, J= 3.9

Hz, H-7'), 3.65 (6H, s, OCH3-I I', OCTE-13'), 3.35 (1H, t, J= 3.9 Hz, H-8'), 3.22 (1H, dd, J = 7.4, 3.9 Hz, H-8); ¹³ C NMR (DMSO-^, 126 MHz) δ 159.9 (C-l 1', C-13'), 157.0 (C-l l), 155.8 (C-4), 154.7 (C-4'), 153.4 (C-13), 135.8 (C-l'), 134.1 (C-l), 127.8 (C-2, C-6), 127.6 (C-2', C- 6'), 121.1 (C-10), 114.4 (C-3, C-5, C-3', C-5'), 104.6 (C-10', C-14'), 103.3 (C-14), 101.0 (C- 20 12), 96.8 (C-12'), 74.6 (C-7), 60.8 (C-8), 56.9 (C-8'), 54.6 (0CH ₃ -1 V, OCH ₃ -13'), 53.5 (C-7');

HRESIMS m/z 499.1751 [M-H] ^" (calcd for C30H27O7, 499.1757, Δ = -1.2 ppm).

Resvepterodimer A (4)

Amorphous solid; [a] ²³ _D +18.0° (c 0.02, MeCN); UV (MeOH) X _max (log ε) 216 (sh) (4.38), 277

25 (3.27) nm; ECD (c = 9.2 10 ⁵ M, MeCN) [0]2io -4.7, [Θ]2ΐ4 +0.8, [θ] ₂ 25 -0.5, [θ]239 +0.3; ¾ NMR (DMSO-i¾ 600 MHz) δ 7.20 (2H, d, J=8.4 Hz, H-2', 6'), 6.88 (2H, d, J= 8.6 Hz, H-2, 6), 6.74 (2H, d, J=8.4 Hz, H-3', 5'), 6.37 (2H, d, J= 8.6 Hz, H-3, 5), 6.28 (1H, t, J=23 Hz, H-12'), 5.88 (1H, t, J= 2.2 Hz, H-12), 5.60 (2H, brs, H-10', 14'), 5.38 (1H, brs, H-10, 14), 4.43 (1H, d, J=9.4 Hz, H-7'), 4.06 (1H, dd, J=12.8, 2.9 Hz, H-8), 3.75 (1H, d, J=12.8 Hz, H-7), 3.57 (6H, s,

30 OCHa-l l', OCH ₃ -13'), 3.36 (3H, s, OCH ₃ -7'a), 3.00 (1H, dd, J=9.4, 2.9 Hz, H-8'), 2.84 (3H, s, OCH ₃ -7'b); ¹³ C NMR (DMSO-i¾ 151 MHz) δ 158.8 (C-Ι Γ, 13'), 156.6 (C-l l, 13), 155.5 (C- 4'), 154.5 (C-4), 140.4 (C-9), 139.3 (C-9'), 135.5 (C-l), 135.2 (C-Γ), 128.9 (C-2', 6'), 128.3 (C- 2, 6), 115.3 (C-3', 5'), 114.7 (C-3, 5), 109.3 (C-10, 14), 108.1 (C-10', 14'), 104.2 (C-7'), 100.4 (C-12), 99.3 (C-12'), 54.6 (OCH3-I I', OCH ₃ -13'), 52.5 (OCH ₃ -7'b), 52.3 (OCH ₃ -7'a), 51.0 (C-

42 7), 48.2 (C-8'), 47.2 (C-8); HRESIMS m/z 591.2253 [M+FA-H]- (calcd for C33H35O10, 591.2230, D = 3.9 ppm).

7-O-methylresvepterol B (5)

Amorphous solid; [α] ²³ _D -4.6° (c 0.06, MeCN); UV (MeOH) λ _max (log ε) 223 (sh) (4.05), 283 (3.41), 306 (3.17) nm; ¹ H NMR (DMSO-d ₆ , 600 MHz) d 6.67 (2H, d, J= 8.5 Hz, H-2', 6'), 6.66 (2H, d, J= 8.5 Hz, H-2, 6), 6.62 (2H, d, J= 8.5 Hz, H-3', 5'), 6.59 (2H, d, J= 8.5 Hz, H-3, 5), 6.45 (1H, d, J= 2.0 Hz, H-14), 6.20 (1H, t, J=22 Hz, H-12'), 6.17 (1H, d, J= 2.0 Hz, H-12), 5.72 (2H, d, J=22 Hz, H-10', 14'), 4.05 (1H, d, J= 3.5 Hz, H-7'), 3.82 (1H, d, .7=9.1 Hz, H-7), 3.57 (6H, s, OCH ₃ -13', OCH ₃ -H'), 3.15 (1H, dd, J=9.1, 3.5 Hz ,H- 8), 2.97 (3H, s, OCH ₃ -7), 2.67 (1H, t, J=3.5 Hz, H-8’); ¹³ C NMR (DMSO-d ₆ , 151 MHz) d 160.1 (C- 11', 13’), 157.8 (C-13), 156.8 (C- 4), 155.2 (C-4 ^' ), 154.0 (C-11), 149.3 (C-9 ^' ), 147.1 (C-9), 136.0 ( C-1)', 130.3 (C-1), 128.7 (C-2, 6), 128.1 (C-2 ^' , 6’), 120.9 (C-10), 114.7 (C-3, 5), 114.7 (C-3 ¹ , 5’), 104.5 (C-10 ¹ , 14’), 104.4 (C- 14), 101.5 (C-12), 97.2 (C-12 ¹ ), 86.6 (C-7), 59.6 (C-8), 57.8 (C-8 ¹ ), 55.9 (OCH ₃ -7), 54.8 (OCH ₃ - 11', OCH ₃ -13’), 54.2 (C-7'); HRESIMS m/z 559.1995 [M+FA-H] ^' (calcd for C ₃₂ H _{3 1} O ₉ , 559.1968, D = 4.8 ppm). trans-δ-viniferin (6)

Amorphous solid; ¹ H NMR (DMSO-d ₆ , 600 MHz) d 4.44 (1H, d, J=7.9 Hz, H-8'), 5.39 (1H, d, J=1.9 Hz, H-7'), 6.03 (2H, d, J=2.1 Hz, H-10', H-14'), 6.10 (1H, t, J=22 Hz, H-12), 6.11 (1H, t, J=22 Hz, H-12'), 6.37 (2H, d, J=22 Hz, H-10, H-14), 6.76 (2H, d, J= 8.6 Hz, H-3', H-5'), 6.83 (1H, d, J=16.3 Hz, H-8), 6.89 (1H, d, J=8.3 Hz, H-3), 6.98 (1H, d, J=16.3 Hz, H-7), 7.18 (2H, d, J= 8.6 Hz, H-2', H-6'), 7.23 (1H, d, .7=1.8 Hz, H-6), 7.42 (1H, dd, .7=8.3, 1.8 Hz, H-2). HRESIMS m/z 453.1346 [M-H] ^' (calcd for C ₂₈ H ₂₁ O ₆ , 453.1338 , Δ= 1.8 ppm).

7-O-methylisoresvepterol B (7)

Amorphous solid; [α] ²³ _D -1.7° (c 0.11, MeCN); UV (MeOH) λ _max (log e) 223 (sh) (4.12), 283 (3.49) nm; ECD (c = 9.7 x 10-5 M, MeCN) [θ] ₂₁₂ -0.4, [θ] ₂ 28 +0.3, [θ] ₂₆ 2 -0.1; ¹ H NMR (DMSO-d ₆ , 600 MHz) d 6.64 (1H, d, J= 2.0 Hz, H-14), 6.62 (8H, m, H-2, 3, 5, 6, 2', 3', 5', 6'), 6.45 (1H, d, J= 2.0 Hz, H-12), 5.93 (1H, t, J=22 Hz, H-12'), 5.59 (2H, d, J=22 Hz, H-10', 14'), 4.00 (1H, d, J= 2.8 Hz, H-7'), 3.83 (1H, d, J=8.8 Hz, H-7), 3.79 (3H, s, OCH ₃ -13), 3.58 (3H, s, OCH ₃ -I I), 3.21 (1H, dd, .7=8.8, 2.8 Hz, H-8), 2.96 (3H, s, OCH ₃ -7), 2.67 (1H, t, J= 2.8 Hz, H- 8'); ¹³ C NMR (DMSO-d ₆ , 151 MHz) d 160.3 (C-13), 158.1 (C-11', 13'), 156.7 (C-4), 156.4 (C- 11), 155.2 (C-4'), 149.4 (C-9'), 147.3 (C-9), 135.8 (C-l'), 130.1 (C-l), 128.4 (C-2, 6), 127.8 (C- 2', 6'), 123.9 (C-10), 114.8 (C-3, 5, 3', 5'), 104.2 (C-10', 14'), 103.0 (C-14), 100.2 (C-12'), 97.3 (C-12), 86.2 (C-7), 59.5 (C-8), 57.3 (C-8 ^' ), 56.1 (OCH ₃ -7), 55.2 (OCH ₃ -13), 55.1 (OCH ₃ -I I),

54.8 (7'); HRESIMS m/z 559.1981 [M+FA-H] ^' (calcd for C32H31O9, 559.1968, D = 2.3 ppm).

7-O-methylresvepterol A (8)

Amorphous solid; [a] ²³ _D +0.5° (c 0.6, MeCN); UV (MeOH) λ _max (log ε) 223 (sh) (4.06), 283 (3.30) nm; ECD (c = 9.7 x 10-5 M, MeCN) [θ] ₂₂₂ +1.4, [θ] ₂₂₉ -0.2, [θ] ₂₃₆ 0, [q] ₂ 47 -0.1; ¹ H NMR (DMSO-d ₆ , 600 MHz) d 6.92 (2H, d, J= 8.5 Hz, H-2, 6), 6.71 (2H, d, J= 8.6 Hz, H-2', 6'), 6.67 (2H, d, J= 8.5 Hz, H-3, 5), 6.60 (2H, d, J= 8.6 Hz, H-3', 5'), 6.29 (1H, t, J= 2.3 Hz, H-12'), 6.12 (2H, d, J= 2.3 Hz, H-10', 14'), 6.07 (1H, d, J=2.1 Hz, H-12), 5.57 (1H, d, J=2.1 Hz, H-14), 4.04 (1H, d, J= 3.2 Hz, H-7'), 3.83 (1H, d, J=7.3 Hz, H-7), 3.66 (6H, s, OCH ₃ -13', OCH ₃ -H'), 3.30 (2H, m, H-8, 8'), 2.86 (3H, s, OCH ₃ -7); ¹³ C NMR (DMSO-d ₆ , 151 MHz) d 160.3 (C- 11', 13'), 157.4 (C-13), 156.8 (C-4), 155.1 (C-4'), 154.1 (C-11), 149.6 (C-9'), 145.3 (C-9), 136.3 (C-G),

129.8 (C-1), 129.1 (C-2, 6), 128.1 (C-2', 6'), 121.4 (C-10), 114.7 (C-3, 5), 114.6 (C-3', 5'), 105.0 (C-10', 14'), 103.8 (C-14), 101.5 (C-12), 97.2 (C-12'), 85.6 (C-7), 59.4 (C-8), 57.7 (C-8'), 55.8 (OCH ₃ -7), 55.0 (OCH ₃ -11', OCH ₃ -13'), 54.7 (C-7'); HRESIMS m/z 559.1979 [M+FA-H] ^' (calcd for C32H31O9, 559.1968, D = 2.0 ppm).

Pterodimer C (9)

Amorphous solid; LTV (MeOH) λ, _max (log e) 226 (sh) (4.72), 280 (4.19), 324 (4.00) nm; Ή NMR (DMSO-d ₆ , 600 MHz) d 7.27 (2H, d, J=8.3 Hz, H-2', 6'), 6.93 (2H, d, J=8.8 Hz, H-2, 6), 6.76 (2H, d, J=8.3 Hz, H-3', 5'), 6.35 (2H, d, J=8.8 Hz, H-3, 5), 6.32 (1H, t, J= 2.3 Hz, H-12'), 6.16 (1H, t, J= 2.3 Hz, H-12), 5.60 (2H, brs, H-10', 14'), 5.53 (2H, brs, H-10, 14), 4.40 (1H, d, J=9.4 Hz, H-7'), 4.19 (1H, dd, J=12.8, 2.8 Hz, H-8), 3.85 (1H, d, J=12.8 Hz, H-7), 3.58 (6H, s, OCH ₃ - 11', OCH ₃ -13'), 3.53 (6H, s, OCH ₃ -11, OCH ₃ -13), 3.39 (3H, s, OCH ₃ -7'a), 3.07 (1H, dd, J=9.4,

2.8 Hz, H-8'), 2.87 (3H, s, OCH ₃ -7'b); ¹³ C NMR (DMSO-^, 151 MHz) d 159.6 (C-l 1/13),

159.3 (C-l 1/13), 158.9 (C-11', 13'), 155.5 (C-4'), 154.5 (C-4), 141.0 (C-9/9'), 139.1 (C-9/9'),

135.4 (C-l), 134.9 (C-l'), 128.9 (C-2', 6'), 128.5 (C-2, 6), 115.4 (C-3', 5'), 114.7 (C-3, 5), 104.1 (C-7'), 99.0 (C-12'), 98.0 (C-12), 54.8 (OCH ₃ -11, OCH ₃ -13), 54.7 (OCH ₃ - 11', OCH ₃ -13'), 52.9 (OCH ₃ -7'a), 52.5 (OCH ₃ -7'b), 51.0 (C-7), 48.2 (C-8'), 47.8 (C-8); HRESIMS m/z 619.2560 [M+FA-H] ^' (calcd for C ₃₅ H ₃₉ O ₁₀ , 619.2543, D = 2.7 ppm). 7'-O-methylresveptero open dimer (10)

Amorphous solid; [α] ²³ _D -1.3° (c 0.13, MeCN); UV (MeOH) λ _max (log e) 223 (sh) (4.24), 305 (3.61), 322 (3.59) , 285 (3.58) nm; ¾ NMR (DMSO-d ₆ , 600 MHz) d 7.38 (2H, , d, J= 8.6 Hz, H-2, 6), 7.00 (2H, d, J= 8.5 Hz, H-2', 6'), 6.88 (2H, d, .7=16.5 Hz, H-7), 6.88 (2H, d, J= 8.6 Hz, H-3, 5), 6.82 (1H, d, .7=16.5 Hz, H-8), 6.62 (2H, d, J= 8.5 Hz, H-3', 5'), 6.36 (2H, d, J=22 Hz, H-10, 14), 6.30 (2H, d, J=2.3 Hz, H-10', 14'), 6.23 (1H, t, J=23 Hz, H-12'), 6.10 (1H, t, J= 2.2 Hz, H-12), 5.33 (1H, d, J= 6.8 Hz, H-8'), 4.43 (1H, d, J= 6.8 Hz, H-7'), 3.59 (6H, s, OCH ₃ -I I', OCH ₃ -13'), 3.15 (3H, s, OCH ₃ -7'); ¹³ C NMR (DMSO-d ₆ , 151 MHz) d 159.8 (C- 11', 13'), 158.5 (C-11, 13), 157.4 (C-4), 156.8 (C-4'), 140.4 (C-9'), 139.0 (C-9), 129.7 (C-1), 129.1 (C-2', 6'), 127.9 (C-1'), 127.5 (C-2, 6), 127.4 (C-7), 126.7 (C-8), 116.0 (C-3, 5), 114.6 (C-3', 5'), 105.7 (C-10', 14'), 104.4 (C-10, 14), 101.9 (C-12), 99.0 (C-12'), 85.9 (C-7'), 82.3 (C-8'), 56.3 (OCH ₃ - 7'), 55.0 (OCH ₃ -H', OCH ₃ -13'); HRESIMS m/z 559.1981 [M+FA-H] ^' (calcd for C32H31O9, 559.1968, D = 2.3 ppm).

11 ',13 '-dimethoxy- trans-δ-viniferin (11)

Amorphous solid; ¹ H NMR (DMSO-d ₆ , 500 MHz) d 3.70 (6H, s, OCH ₃ -I I', OCH ₃ -13'), 4.59 (1H, d, .J=8.1 Hz, H-8'), 5.56 (1H, d, .7=8.1 Hz, H-7'), 6.12 (1H, t, J= 2.2 Hz, H-12), 6.37 (4H, m, H-10, H-14, H-10', H-14'), 6.43 (1H, t, J= 2.2 Hz, H-12'), 6.77 (2H, d, J=8.8 Hz, H-3', H- 5'), 6.82 (1H, d, .7=16.5 Hz, H-8), 6.90 (1H, d, J=8.3 Hz, H-5), 6.97 (1H, d, .7=16.5 Hz, H-7), 7.20 (2H, d, J=8.8 Hz, H2', H-6'), 7.21 (1H, d, .7=1.4 Hz, H-2), 7.43 (1H, dd, .7=8.3, 1.4 Hz, H- 6); ¹³ C NMR (DMSO-d ₆ , 126 MHz) d 55.0 (OCH ₃ - 11', OCH ₃ -13'), 55.7 (C-8'), 91.9 (C-7'), 98.5 (C-12'), 101.9 (C-12), 104.4 (C-10, C-14), 106.1 (C-10', C-14'), 109.4 (C-5), 115.4 (C-3', C-5'), 122.7 (C-2), 126.3 (C-8), 127.7 (C-6), 127.8 (C-7, C-2', C-6'), 130.1 (C-1'), 130.4 (C-1), 131.2 (C-5), 139.0 (C-9), 143.8 (C-9'), 157.5 (C-4'), 158.4 (C-11, C-13), 158.7 (C-4), 160.7 (C- 11', C-13'). HRESIMS m/z 481.1629 [M-H]- (calcd for C30H25O6, 481.1651, D= -4.5 ppm).

7'-O-methylisoresveptero open dimer (12)

Amorphous solid; [α] ²³ D -1.0° ( c 0.1, MeCN); UV (MeOH) λ _max (log ε) 223 (sh) (4.24), 305 (3.80), 322 (3.79) , 285 (3.74) nm; ¾ NMR (DMSO-d ₆ , 600 MHz) d 9.31 (1H, s, 4ΌH), 9.05 (2H, s, 11'OH, 13ΌH), 7.41 (2H, d, J=8.9 Hz, H-2, 6), 7.13 (1H, d, J=16.4 Hz, H-7), 7.00 (2H, d, J= 8.5 Hz, H-2', 6'), 6.95 (1H, d, .7=16.4 Hz, H-8), 6.86 (2H, d, J= 8.9 Hz, H-3, 5), 6.70 (2H, d, J=23 Hz, H-10, 14), 6.62 (2H, d, J= 8.5 Hz, H-3', 5'), 6.36 (1H, t, J=23 Hz, H-12), 6.05 (2H, d, J= 2.2 Hz, H-14', 10'), 5.97 (1H, t, J= 2.2 Hz, H-12'), 5.17 (1H, d, J= 6.6 Hz, H-8'), 4.35 (1H, d, J=6.6 Hz, H-7'), 3.75 (6H, s, OCH ₃ -11, OCH ₃ -13), 3.13 (3H, s, OCH ₃ -7'); ¹³ C NMR (DMSO- d ₆ , 151 MHz) d 160.6 (C-11, 13), 157.7 (C-4), 157.7 (C-11', 13'), 156.7 (C-4'), 140.1 (C-9'), 139.4 (C-9), 129.4 (C-1), 129.1 (C-2', 6'), 128.5 (C-7), 128.0 (C-1'), 127.6 (C-2, 6), 126.1 (C- 8), 115.9 (C-3, 5), 114.6 (C-3', 5'), 105.7 (C-10', 14'), 104.1 (C-10, 14), 101.8 (C-12'), 99.5 (C- 12), 86.0 (C-7'), 82.4 (C-8'), 56.4 (OCH ₃ -7'), 55.2 (OCH ₃ -11, OCH ₃ -13); HRESIMS m/z 559.1973 [M+FA-H] ^' (calcd for C ₃₂ H ₃₁ 0 ₉ , 559.1968, D = 0.9 ppm).

7-O-methyl-11,11'13,13'-tetramethoxyleachianol F (13)

Amorphous solid; [α] ²³ _D -0.3° (c 0.27, MeCN); UV (MeOH) X _max (log e) 223 (sh) (4.06), 283 (3.32) nm; ECD (c = 9.2 x 10-5 M, MeCN) [θ]214 +0.8, [θ]232 -0.1, [q]255 +0.1; ¾ NMR (DMSO-d ₆ , 600 MHz) d 6.70 (2H, m, H-2, 6), 6.69 (1H, d, J=22 Hz, H-14), 6.62 (6H, m, H-3, 5, 2', 3', 5', 6'), 6.46 (1H, d, J=2.2 Hz, H-12), 6.21 (1H, t, J=2.3 Hz, H-12'), 5.72 (2H, d, J=2.3 Hz, H-10 ¹ , 14'), 4.09 (1H, d, J= 3.9 Hz, H-7'), 3.90 (1H, d, J= 8.9 Hz, H-7), 3.78 (3H, s, OCH ₃ - 13), 3.58 (6H, s, OCH ₃ -13', 11'), 3.56 (3H, s, OCH ₃ -I I), 3.26 (1H, dd, J=8.9, 3.9 Hz, H-8), 3.00 (3H, s, OCH ₃ -7), 2.74 (1H, t, J= 3.9 Hz, 8'); ¹³ C NMR (DMSO-d ₆ , 151 MHz) d 160.4 (C-11), 160.1 (C- 11', 13'), 156.9 (C-4), 156.3 (C-13), 155.3 (C-4'), 148.9 (C-9'), 146.9 (C-9), 135.7 (C- 1), 130.0 (C-1), 128.7 (C-2, 6), 127.9 (C-2', 6'), 123.9 (C-10), 114.8 (C-3, 5), 114.8 (C-3', 5'), 104.5 (C-10', 14'), 102.9 (C-14), 97.5 (C-12), 97.3 (C-12'), 86.3 (C-7), 59.6 (C-8), 57.8 (C-8'), 56.0 (OCH ₃ -7), 55.2 (OCH ₃ -13), 55.1 (OCH ₃ -I I), 54.8 (OCH ₃ -11', OCH ₃ -13'), 54.6 (C-7'); HRESIMS m/z 587.2258 [M+FA-H] ^' (calcd for C ₃₄ H ₃₅ O ₉ , 587.2281, Δ = -3.9 ppm).

11 , 13-dimethoxy-trans-δ-viniferin (14)

Amorphous solid; [α] ²⁵ _{D -} 4(c 0.05, MeOH); UV λmax (MeOH) (log e) 227 (sh) (3.51), 301 (3.24) nm; ¾ NMR (DMSO-d ₆ , 500 MHz) d 3.75 (6H, s, OCH ₃ -11, OCH ₃ -13), 4.46 (1H, d, J=8.3 Hz, H-8'), 5.41 (1H, d, J=8.3 Hz, H-7'), 6.05 (2H, d, J=2.2 Hz, H-10', H-14'), 6.11 (1H, t, J=22 Hz, H-12'), 6.35 (1H, t, J=22 Hz, H-12), 6.73 (2H, d, J= 2.3 Hz, H-10, H-14), 6.76 (2H, d, J=8.8 Hz, H-3', H-5'), 6.90 (1H, d, J=8.3 Hz, H-5), 6.96 (1H, d, J=16.4 Hz, H-8), 7.19 (1H, d, J=8.8 Hz, H-2', H-6'), 7.22 (1H, d, J=16.4 Hz, H-7), 7.23 (1H, d, J= 2.0 Hz, H-2), 7.44 (1H, dd, J= 8.3, 2.0 Hz, H-6); ¹³ C NMR (DMSO-d ₆ , 126 MHz) d 55.1 (OCH ₃ -11, OCH ₃ -13), 55.7 (C-8'), 92.6 (C-7'), 99.5 (C-12), 101.3 (C-12'), 104.1 (C-10, C-14), 106.0 (C-10', C-14'), 109.3 (C-5), 115.3 (C-3', C-5'), 123.0 (C-2), 125.7 (C-8), 127.6 (C-6), 127.9 (C-2', C-6'), 128.7 (C- 7), 130.2 (C-E), 130.3 (C-1), 131.4 (C-3), 139.5 (C-9), 143.5 (C-9'), 157.6 (C-4'), 158.6 (C- 11', C-13'), 159.0 (C-4), 160.6 (C-11, C-13). HRESIMS m/z 481.1658 [M-H] ^' (calcd for C ₃₀ H ₂₅ O ₆ , 481.1651, Δ = 1.4 ppm). pterostilbene trans-dehydromer (15) ¹ H NMR (DMSO-d ₆ , 500 MHz) d 3.70 (6H, s, OCH ₃ - 11', OCH ₃ -13'), 3.75 (6H, s, OCH ₃ - 11, OCH ₃ -13), 4.61 (1H, d, J= 8.5 Hz, H-8'), 5.59 (1H, d, J= 8.5 Hz, H-7'), 6.35 (1H, t, J=22 Hz, H-12), 6.38 (2H, d, J= 2.3 Hz, H-10', H-14'), 6.43 (1H, t, J= 2.3 Hz, H-12'), 6.72 (2H, d, J=2.2 Hz, H-10, H-14), 6.76 (2H, d, J=8.4 Hz, H-3', H-5'), 6.92 (1H, d, J=8.3 Hz, H-5), 6.95 (1H, d, J=16.5 Hz, H-8), 7.20 (3H, m, H-2, H-2', H-6'), 7.21 (1H, d, J=16.5 Hz, H-7), 7.45 (1H, dd, J= 8.3, 1.8 Hz, H-6); ¹³ C NMR (DMSO^, 126 MHz) d 55.1 (OCH ₃ -11, OCH ₃ -13, OCH ₃ -H', OCH ₃ -13'), 55.7 (C-8 ^' ), 92.0 (C-7'), 98.5 (C-12'), 99.5 (C-12), 104.1 (C-10, C-14), 106.3 (C- 10', C-14'), 109.4 (C-5), 115.2 (C-3', C-5'), 122.8 (C-2), 125.7 (C-8), 127.6 (C-6), 127.8 (C-2', C-6'), 128.8 (C-7), 129.9 (C- 1'), 130.3 (C-1), 131.4 (C-3), 139.4 (C-9), 143.6 (C-9'), 157.6 (C- 4'), 158.8 (C-4), 160.5 (C-11, C-13), 160.7 (C- 11', C-13'). HRESIMS m/z 509.1968 [M-H] ^' (calcd for C32H29O6, 509.1964, D= 0.8 ppm).

11, 11', 13, 13'-tetramethoxypallidol (16)

Amorphous solid; [a] ²³ _D -0.3 (c 0.003, MeOH); UV λ _max (MeOH) (log e) 233 (sh)(4.78), 280 (4.53) nm; ¹ H NMR( CD ₃ OD, 500 MHZ) d 3.60 (6H, s, OCH ₃ -13, 13'), 3.84 (6H, s, OCH ₃ -11, 11'), 3.85 (2H, s, H-8, 8'), 4.49 (2H, s, H-7, 7'), 6.30 (2H, d, J= 2.1 Hz, H-12, 12'), 6.65 (4H, d, J= 8.4 Hz, H-3, 5, 3', 5'), 6.69 (2H, d, J= 2.1 Hz, H-14, 14'), 6.90 (4H, d, J= 8.4 Hz, H-2, 6, 2', 6') . ¹³ C NMR (CD3OD, 126 MHz) d 55.3 (OCH ₃ -11, 11'), 55.7 (OCH ₃ -13, 13'), 60.7 (C- 8, 8'), 98.2 (C-12, 12'), 101.0 (C-14, 14'), 115.7 (C-3, 5, 3', 5'), 126.0 (C-10, 10'), 128.8 (C-2, 6, 2', 6'), 137.9 (C-1, G), 149.6 (C-9, 9'), 156.1 (C-4, 4'), 158.0 (C-13, 13'), 162.6 (C-11, 11'). HRESIMS m/z 509.1984 [M-H] ^' (calcd for C32H29O6, 509.1964, D = 3.9 ppm).

11, 11', 13, 13'-tetramethoxyrestrytisol B (17)

Amorphous solid; [a] ²³ D -52 (c 0.02, MeOH); UV λ _max (MeOH) (log e) 248 (3.89), 281 (3.76) nm; ¹ H NMR (DMSO-d ₆ , 500 MHz) d 3.54 (6H, s, OCH ₃ -11, 13), 3.57 (1H, dd, J= 10.8, 9.7 Hz, H-8'), 3.64 (6H, s, OCH ₃ -H', 13'), 4.12 (1H, dd, J= 10.8, 8.9 Hz, H-8), 4.99 (1H, d, J = 9.7 Hz, H-7'), 5.43 (1H, d, J= 8.9 Hz, H-7), 6.04 (1H, t, J= 2.2 Hz, H-12), 6.11 (2H, d, J= 2.2 Hz, H-10, 14), 6.25 (1H, t, J= 2.2 Hz, H-12'), 6.42 (2H, d , J= 2.2 Hz, H-10', 14'), 6.53 (2H, d, J= 8.7 Hz, H-3, 5), 6.74 (2H, d, J= 8.5 Hz, H-3', 5'), 6.96 (2H, d, J= 8.7 Hz, H-2, 6), 7.25 (3H, d , J= 8.5 Hz, H-2', 6'). ¹³ C NMR (DMSO-d ₆ , 126 MHz) d 54.5 (OCH ₃ -11, 13), 54.6 (OCH ₃ - 11', 13'), 56.2 (C-8'), 57.6 (C-8), 82.2 (C-7), 85.4 (C-7'), 97.6 (C-12, 12'), 106.1 (C-10', 14'), 106.8 (C-10, 14), 113.8 (C-3, 5), 114.6 (C-3', 5'), 127.5 (C-2, 6), 127.8 (C-2', 6'), 129.3 (C-1'), 130.6 (C-1), 140.9 (C-9 or 9'), 141.0 (C-9 or 9'), 155.5 (C-4), 156.6 (C-4'), 159.0 (C-11, 13),

159.8 (C-11', 13'). HRESIMS m/z 527.2076 [M-H] ^' (calcd for C ₃₂ H _{3 1} O ₇ , 527.2070, Δ = 1.1 ppm).

11, 11', 13, 13'-tetramethoxyleachianol F (18)

Amorphous solid; [α] ²³ D -38 (c 0.012, MeOH); UV λ _ma ( _x MeOH) (log e) 228 (sh) (4.72), 279 (4.24) nm; ECD (c = 3.0 x 10 ^-4 M, MeCN) [θ] ₁₉₁ -3114, [q]i ₉₈ +3702, [q] ₂ 08 +4131, [θ] ₂₂₈ - 1485, [q] ₂₄ i +691; ¹ H NMR (DMSO-d ₆ , 500 MHz) d 2.88 (1H, dd, J= 4.4, 4.0 Hz, H-8'), 3.22 (1H, dd, J= 8.0, 4.4 Hz, H-8), 3.55 (3H, s, OCH ₃ -13), 3.60 (6H, s, OOE-I T, 13'), 3.74 (3H, s, OCH ₃ -11), 4.11 (1H, d, J= 4.0 Hz, H-7'), 4.29 (1H, dd, J= 8.0, 4.8 Hz, H-7), 5.19 (1H, d, J =

4.8 Hz, OH-7), 5.83 (2H, d, J= 2.3 Hz, H-10’, 14’), 6.23 (1H, t, J= 2.3 Hz, H-12’), 6.42 (1H, d, J= 2.2 Hz, H-12), 6.60 (1H, d, J= 2.2 Hz, H-14), 6.61 (2H, d, J= 8.6 Hz, H-3’, 5’), 6.61 (2H, d, J= 8.5 Hz, H-3, 5), 6.66 (2H, d, J= 8.6 Hz, H-2’, 6’), 6.78 (2H, d, J= 8.5 Hz, H-2, 6), 9.11 (1H, s, OH), 9.23 (1H, s, OH). ¹³ C NMR (DMSO-d ₆ , 126 MHz) d 54.3 (C-7'), 54.9 (OCH ₃ -H', 13’), 55.1 (OCH ₃ -11, 13), 58.0 (C-8 ^' ), 61.1 (C-8), 75.0 (C-7), 97.3 (C-12 ¹ ), 97.4 (C-12), 103.2 (C-10), 104.7 (C-10 ^' , 14’), 114.7 (C-3, 5, 3’, 5’), 124.1 (C-14), 127.8 (C-2, 6), 128.0 (C-2 ¹ , 6’), 134.9 (C- 1'), 135.9 (C-1), 155.2 (C-4 ^' ), 156.3 (C-4, 11), 160.1 (C-13), 160.2 (C-11', 13'). HRESIMS m/z 527.2069 [M-H] ^' (calcd for C ₃₂ H ₃₁ O ₇ , 527.2070, D = -0.1 ppm).

11, 11', 13, 13'-tetramethoxyleachianol G (19)

Amorphous solid; [a] ²³ D -24 (c 0.01, MeOH); LTV λ _ma ( _x MeOH) (log e) 230 (sh) (4.63), 279 (4.23) nm; ECD (c = 3.0 x 10 ^-4 M, MeCN) [θ]i _9i +2389, [θ]i ₉₉ -5619, [θ] ₂₀₇ +636, [θ] ₂₁₁ -1131, [Q] ₂₁₇ +1331; ¾ NMR (DMSO-d ₆ , 500 MHz) d 3.23 (1H, dd, J= 8.0, 3.3 Hz, H-8), 3.43 (1H, t , J= 3.3 Hz, H-8'), 3.52 (3H, s, OCH ₃ -13), 3.52 (3H, s, OCH ₃ -11), 3.65 (6H, s, OCH ₃ -H', 13'), 4.09 (1H, d, J= 3.3 Hz, H-7'), 4.32 (1H, dd, J= 8.0, 4.0 Hz, H-7), 5.15 (1H, d, J= 4.0 Hz, OH- 7), 5.59 (1H, d, J= 2.0 Hz, H-14), 6.10 (2H, d, J= 2.2 Hz, H-10', 14'), 6.29 (1H, t, J= 2.2 Hz, H-12’), 6.32 (1H, d, J= 2.0 Hz, H-12), 6.62 (2H, d, J= 8.7 Hz, H-3’, 5’), 6.66 (2H, d , J= 8.4 Hz, H-3, 5), 6.73 (2H, d, J= 8.7 Hz, H-2', 6'), 6.96 (2H, d, J= 8.4 Hz, H-2, 6), 9.11 (1H, brs, OH), 9.25 (1H, brs, OH). ¹³ C NMR (DMSO-d ₆ , 126 MHz) d 54.4 (OCH ₃ -l 1), 54.6 (OCH ₃ - 11', 13’, 13), 54.7 (C-7 ^' ), 57.1 (C-8 ^' ), 61.5 (C-8), 75.1 (C-7), 96.7 (C-12 ^' ), 97.1 (C-12), 101.6 (C- 14), 104.5 (C-10 ^' , 14’), 114.0 (C-3, 5), 114.4 (C-3 ^' , 5’), 124.1 (C-10), 127.6 (C-2 ^' , 6’), 127.9 (C- 2, 6), 133.9 (C-1), 135.9 (C- ^1' ), 145.3 (C-9), 149.8 (C-9 ^' ), 154.8 (C-4 ^' ), 155.9 (C-11), 156.0 (C- 4), 159.3 (C-13), 159.9 (C-11', 13'). HRESIMS m/z 527.2068 [M-H]- (calcd for C ₃₂ H ₃₁ O ₇ , 527.2070, D = -0.4 ppm). Pterostilbene open dimer (20)

Amorphous solid; ¹ H NMR (DMSO-d ₆ , 500 MHz) d 7.41 (2H, d , J = 8.7 Hz, H-2, H-6), 7.13 (1H, d, J= 16.2 Hz, H-7), 7.01 (2H, d, J= 8.5 Hz, H-2', H-6'), 6.95 (1H, d, J= 16.2 Hz, H-8), 6.89 (2H, d , J= 8.7 Hz, H-3, H-5), 6.69 (2H, d, J= 2.3 Hz, H-10, H-14), 6.60 (2H, d , J= 8.5 Hz, H-3', H-5'), 6.37 (1H, t, J= 2.3 Hz, H-12), 6.29 (2H, d, J= 2.3 Hz, H-10', H-14'), 6.26 (1H, t, J= 2.3 Hz, H-12'), 5.47 (1H, s, OH-7'), 5.20 (1H, d, J= 6.2 Hz, H-8'), 4.73 (1H, d, J= 6.2 Hz, H-7'), 3.76 (6H, s, OCH ₃ -13, OCH ₃ -11), 3.60 (6H, s, OCH ₃ -13', OCH ₃ -11'); ¹³ C NMR (DMSO-d ₆ , 500 MHz) d 160.3 (C-11), 159.5 (C-11', C-13'), 157.5 (C-4), 156.1 (C-4'), 139.1 (C-9), 131.5 (C-1'), 129.3 (C-1), 128.1 (C-7), 128.0 (C-2 ¹ , C-6'), 127.2 (C-2, C-6), 125.8 (C-8), 115.7 (C-3, C-5), 113.9 (C-3', C-5'), 105.3 (C-10', C-14'), 103.8 (C-10, C-14), 99.1 (C-12), 98.5 (C-12'), 83.5 (C-8 ^' ), 75.7 (C-7 ^' ), 54.8 (OCH ₃ -11, OCH ₃ -13), 54.6 (OCH ₃ -11', OCH ₃ -13'). HRESIMS m/z 527.2078 [M-H] ^‘ (calcd for C ₃₂ H ₃₁ O ₇ , 527.2070, D= 1.5 ppm).

14-bromtre- trans-δ-viniferin (21)

UV (MeOH) λ _max c (log ε) 229 (sh) (4.52), 288 (sh) (4.09), 313 (4.26), 332 (4.24) nm; ¹ HNMR (DMSO, 600 MHz) d 4.47 (1H, d , J= 7.8 Hz, H-8'), 5.41 (1H, d , J= 7.8 Hz, H-7'), 6.04 (2H, d, J= 2.0 Hz, H-10', H-14'), 6.10 (1H, t, J= 2.0 Hz, H-12'), 6.38 (1H, d, J= 2.6 Hz, H-12), 6.61 (1H, d , J= 2.6 Hz, H-10), 6.76 (2H, d , J= 8.5 Hz, H-3', H-5'), 6.92 (1H, d , J= 8.3 Hz, H-5), 7.01 (1H, d , J= 16.2 Hz, H-7), 7.14 (1H, d, J= 16.2 Hz, H-8), 7.18 (2H, d , J= 8.5 Hz, H-2', H-6'), 7.20 (1H, s, H-2), 7.43 (1H, d , J= 8.3 Hz, H-6), 9.22 (2H, s, 11'OH), 9.45 (1H, s, 11 OH), 9.53 (1H, s, 4ΌH), 10.00 (1H, s, 130H); ¹³ C NMR (DMSO, 151 MHz) d 55.5 (C-8 ¹ ), 100.9 (C- 14), 101.3 (C-12 ^' ), 102.5 (C-12), 104.2 (C-10), 105.9 (C-10 ¹ , C-14'), 109.5 (C-5), 115.3 (C-3', C-5'), 123.1 (C-2), 124.7 (C-8), 127.8 (C-2', C-6'), 128.0 (C-6), 130.0 (C-1), 130.3 (C-1'), 130.8 (C-7), 131.4 (C-3), 137.9 (C-9), 143.7 (C-9'), 154.9 (C-13), 157.1 (C-11), 157.5 (C-4'), 158.6 (C-11', C-13'), 159.3 (C-4); HR-ESI/MS analysis: m/z 531 ,0446[M - H]-, (calcd for C ₂₈ H ₂₀ BrO ₆ , 531.0443, Δ = 0.4 ppm).

14, 14’ -dibromo- trans-δ-viniferin (22)

UV (MeOH) λmax (log e) 230 (sh) (4.59), 288 (sh) (4.10), 313 (4.25) nm; ¾ NMR (DMSO, 600 MHz) d 5.05 (1H, brs, H-8'), 5.46 (1H, brs, H-7'), 5.96 (1H, d, J= 2.7 Hz, H-10'), 6.36 (1H, d, J= 2.7 Hz, H-12'), 6.38 (1H, d, J= 2.7 Hz, H-12), 6.61 (1H, d, J= 2.7 Hz, H-10), 6.73 (2H, d, J= 8.4 Hz, H-3', H-5'), 6.95 (1H, d, J= 8.3 Hz, H-5), 7.00 (1H, d, J= 16.0 Hz, H-7), 7.15 (1H, d, J= 16.0 Hz, H-8), 7.18 (2H, d, J= 8.4 Hz, H-2', H-6'), 7.27 (1H, s, H-2), 7.46 (2H, d, J = 8.3 Hz, H-6), 9.45 (2H, s, 110H), 9.46 (1H, s, 11'OH), 9.51 (1H, s, 4ΌH), 10.00 (1H, s, 13 OH), 10.12 (1H, s, 13'OH); ¹³ C NMR (DMSO, 151 MHz) d 54.2 (C-8'), 91.9 (C-7'), 100.8 (C-14'), 100.9 (C-14), 102.3 (C-12'), 102.5 (C-12), 104.2 (C-10), 106.7 (C-10'), 109.7 (C-5), 115.2 (C-3', C-5'), 123.1 (C-2), 124.9 (C-8), 127.6 (C-2', C-6'), 128.1 (C-6), 130.7 (C-7), 130.8 (C-1'), 130.9 (C-1), 138.0 (C-9), 154.9 (C-13), 157.0 (C-11), 157.5 (C-11'), 157.5 (C-4'), 159.4 (C-4); HR-ESI/MS analysis: m/z 608.9565 [M - H] ^' , (calcd for C ₁₈ HigBr ₂ O ₆ , 608.9548, Δ = 2.8 ppm).

14-chloro-trans-δ-viniferin (23)

UV (MeOH) Xmax (log e) 229 (sh) (4.52), 289 (sh) (4.10), 314 (4.29), 333 (4.28) nm; ¾NMR (DMSO, 600 MHz) d 4.46 (1H, d, J= 7.8 Hz, H-8'), 5.41 (1H, d , J= 7.8 Hz, H-7'), 6.04 (2H, d , J= 2.2 Hz, H-10', H-14'), 6.10 (1H, d, J= 2.2 Hz, H-12'), 6.38 (1H, d, J= 2.7 Hz, H-12), 6.61 (1H, d, J= 2.7 Hz, H-10), 6.76 (2H, d , J= 8.4 Hz, H-3', H-5'), 6.91 (1H, d, J= 8.2 Hz, H-

5), 7.05 (1H, d , J= 16.4 Hz, H-7), 7.16 (1H, d, J= 16.4 Hz, H-8), 7.18 (2H, d, J= 8.4 Hz, H- 2', H-6'), 7.22 (1H, s, H-2), 7.44 (1H, dd, J= 8.2, 1.8 Hz, H-6), 9.22 (2H, s, 11'OH, 13'OH), 9.41 (1H, s, 110H), 9.54 (1H, s, 4ΌH), 9.91 (1H, s, 130H); ¹³ C NMR (DMSO, 151 MHz) d 55.5 (C-8 ^' ), 92.6 (C-7 ^' ), 101.3 (C-12 ^' ), 102.7 (C-12), 103.6 (C-10), 105.9 (C-10', C-14'), 109.5 (C-5), 109.6 (C-14), 115.3 (C-3 ^' , C-5'), 121.9 (C-8), 123.1 (C-2), 127.8 (C-2 ¹ , C-6'), 128.0 (C-

6), 130.0 (C-1), 130.3 (C- 1'), 130.7 (C-7), 131.4 (C-3), 136.2 (C-9), 143.7 (C-9'), 153.9 (C-13), 156.3 (C-11), 157.5 (C-4'), 158.6 (C- 11', C-13'), 159.3 (C-4); HR-ESI/MS analysis: m/z 487.0949 [M - H] ^' , (calcd for C ₁₈ H ₂₀ C1O ₆ , 487.0948, Δ = 0.1 ppm).

14,14’-dichloro-trans-δ-viniferin (24)

UV (MeOH) λmax (log e) 229 (sh) (4.51), 287 (sh) (4.09), 313 (4.22), 332 (4.19) nm; ¹ H NMR (DMSO, 600 MHz) d 5.00 (1H, d , J= 5.9 Hz, H-8'), 5.47 (1H, d , J= 5.9 Hz, H-7'), 5.94 (1H, d, J= 2.7 Hz, H-10'), 6.36 (1H, d, J= 2.7 Hz, H-12'), 6.38 (1H, d, J= 2.7 Hz, H-12), 6.61 (1H, d , J= 2.7 Hz, H-10), 6.74 (2H, d , J= 8.6 Hz, H-3', H-5'), 6.94 (1H, d , J= 8.3 Hz, H-5), 7.05 (1H, d, J= 16.2 Hz, H-7), 7.18 (3H, m, H-2', H-6', H-8), 7.28 (1H, s, H-2), 7.47 (1H, dd, J = 8.3, 1.9 Hz, H-6), 9.41 (1H, s, 110H), 9.42 (1H, s, 11'OH), 9.51 (1H, s, 4ΌH), 9.91 (1H, s, 13 OH), 10.03 (1H, s, 13'OH); ¹³ C NMR (DMSO, 151 MHz) d 91.6 (C-7 ^' ), 102.4 (C-12 ^' ), 102.7 (C-12), 103.6 (C-10), 109.6 (C-5), 109.7 (C-14), 109.9 (C-14 ^' ), 115.2 (C-3 ^' , C-5'), 122.1 (C-8), 123.3 (C-2), 127.6 (C-2', C-6'), 128.2 (C-6), 130.2 (C-1), 130.5 (C-3), 130.7 (C-7), 130.8 (C- 9'), 136.3 (C-9), 153.9 (C-13), 154.0 (C-13'), 156.3 (C-11), 156.7 (C-11'), 157.5 (C-4'), 159.5 (C-4); HR-ESI/MS analysis: m/z 521.0564 [M - H]-, (calcd for C ₂₈ H ₁₉ Cl ₂ O6 ₂ 521.0559, Δ = 1.0 ppm).

14-iodo-trans-δ-viniferin (25 )

UV (MeOH) λmax (log e) 229 (sh) (4.96), 288 (sh) (4.53), 313 (4.68), 332 (4.65) nm; ¹ H NMR (DMSO, 600 MHz) d 4.48 (1H, d , J= 7.8 Hz, H-8'), 5.41 (1H, d , J= 7.8 Hz, H-7'), 6.04 (2H, d, J= 2.2 Hz, H-10', H-14'), 6.10 (1H, t, J= 2.2 Hz, H-12'), 6.35 (1H, d, J= 2.6 Hz, H-12), 6.60 (1H, d, J= 2.6 Hz, H-10), 6.76 (2H, d, J= 8.5 Hz, H-3', H-5'), 6.92 (1H, d, J= 16.0 Hz, H-7), 6.93 (1H, d, J= 8.1 Hz, H-5), 7.07 (1H, d, J= 16.0 Hz, H-8), 7.18 (3H, m, H-2, H-2', H-6'), 7.43 (1H, dd, J = 8.1, 1.9 Hz, H-6), 9.21 (1H, s), 9.21 (2H, s, 11'OH, 13ΌH), 9.47 (1H, s, 110H), 9.53 (1H, s, 4ΌH), 10.14 (1H, s, 130H); ¹³ C NMR (DMSO, 151 MHz) d 55.5 (C-8'), 78.4 (C-14), 92.5 (C-7'), 101.2 (C-12'), 101.3 (C-12), 104.4 (C-10), 105.8 (C-10', C-14'), 109.4 (C-5), 115.1 (C-3 ^' , C-5'), 123.0 (C-2), 127.8 (C-6, C-2', C-6'), 129.8 (C-1, C-8), 130.3 (C- 1'), 130.6 (C-7), 131.2 (C-3), 141.1 (C-9), 143.5 (C-9'), 157.5 (C-4'), 158.2 (C-11), 158.6 (C- 11', C-13'), 159.3 (C-4); HR-ESI/MS analysis: m/z 579.0314 [M - H] ^' , (calcd for C ₁₈ HioIOe, 579.0305, D = 1.6 ppm).

12-iodo-trans-δ-viniferin (26 )

UV (MeOH) λmax (log e) 229 (sh) (4.56), 288 (sh) (4.08), 313 (4.27), 336 (4.29), 353 (sh) (4.05) nm; ¹ HNMR (DMSO, 600 MHz) d 4.44 (1H, d , J= 7.7 Hz, H-8'), 5.39 (1H, d , J= 7.7 Hz, H-7'), 6.03 (2H, d, J= 2.2 Hz, H-10', H-14'), 6.10 (1H, t, J= 2.2 Hz, H-12'), 6.51 (2H, s, H-10, H-14), 6.76 (3H, d, J= 8.6 Hz, H-3', H-5'), 6.86 (1H, d, J= 16.3 Hz, H-8), 6.90 (1H, d, J= 8.3 Hz, H-5), 6.96 (1H, d, J= 16.3 Hz, H-7), 7.18 (2H, d, J= 8.6 Hz, H-2', H-6'), 7.27 (1H, s, H-2), 7.44 (1H, dd, J= 8.3, 1.9 Hz, H-6), 9.21 (2H, s, 11'OH, 13ΌH), 9.53 (2H, s, 4ΌH), 10.06 (2H, s, 110H, 130H); ¹³ C NMR (DMSO, 151 MHz) d 55.7 (C-8'), 74.1 (C-12), 92.6 (C- 7'), 101.3 (C-12'), 103.7 (C-10, C-14), 105.9 (C-10', C-14'), 109.4 (C-5), 115.3 (C-3', C-5'), 123.1 (C-2), 125.6 (C-8), 127.8 (C-2', C-6'), 128.0 (C-6), 128.4 (C-7), 130.1 (C-1), 130.4 (C- 1'), 131.1 (C-3), 138.6 (C-9), 143.7 (C-9'), 157.5 (C-4'), 158.0 (C-11, C-13), 158.7 (C-1 E, C- 13'), 159.1 (C-4); HR-ESI/MS analysis: m/z 579.0315 [M - H] ^‘ , (calcd for C ₁₈ H ₂₀ IO ₆ , 579.0305, Δ = 1.8 ppm). 14-bromo-11'13’-dimethoxy-rans-δ-viniferin (27)

UV (MeOH) Xmax (log e) 229 (sh) (4.49), 285 (sh) (4.07), 313 (4.28), 332 (4.26) nm; ¾NMR (DMSO, 600 MHz) d 3.70 (6H, s, CH ₃ O- 11', CH ₃ O-13'), 4.62 (1H, d, J= 8.0 Hz, H-8'), 5.58 (1H, d , J= 8.0 Hz, H-7'), 6.37 (3H, m, H-10', H-12, 14'), 6.43 (1H, t, J= 2.3 Hz, H-12'), 6.61 (1H, d , J= 2.6 Hz, H-10), 6.76 (2H, d , J= 8.5 Hz, H-3', H-5'), 6.93 (1H, d , J= 8.3 Hz, H-5), 7.00 (1H, d, J= 16.1 Hz, H-7), 7.13 (1H, d, J= 16.1 Hz, H-8), 7.20 (3H, m, H-2, H-2', H-6'), 7.44 (1H, dd, J = 8.3, 1.9 Hz, H-6), 9.45 (1H, s, 11 OH), 9.53 (1H, s, 4ΌΗ), 10.00 (1H, s, 13 OH); ¹³ C NMR (DMSO, 151 MHz) δ 55.2 (CH ₃ 0-11', CH ₃ O-13'), 55.5 (C-8'), 92.0 (C-7'),

98.6 (C-12'), 100.8 (C-14), 102.5 (C-12), 104.2 (C-10), 106.1 (C-10', C-14'), 109.6 (C-5), 115.3 (C-3', C-5'), 123.0 (C-2), 124.7 (C-8), 127.9 (C-2', C-6'), 128.0 (C-6), 130.1 (C-l, C-l'), 130.8 (C-7), 131.4 (C-3), 137.9 (C-9), 143.7 (C-9'), 154.9 (C-13), 157.1 (C-l l), 157.6 (C-4'), 159.1 (C-4), 160.7 (C-l l', C-13'); HR-ESI/MS analysis: m/z 559.0764 [M - H] ^" , (calcd fo C ₃₀ H ₂₄ BrO ₆ , 559.0756, Δ = 1.4 ppm).

10,14-dibromo-ll’,13’-dimethoxy-trans-δ-viniferin (28)

UV (MeOH) λmax (log ε) 229 (sh) (4.62), 288 (4.23), 309 (4.20) nm; ¹ H NMR (DMSO, 600 MHz) δ 3.70 (6H, s, CH ₃ O-11', CH ₃ 0-13'), 4.60 (1H, d, J= 7.8 Hz, H-8'), 5.60 (1H, d, J= 7.8 Hz, H-7'), 6.38 (2H, d, J= 2.3 Hz, H-10', H-14'), 6.42 (1H, t, J= 2.3 Hz, H-12'), 6.63 (1H, s, H-12), 6.68 (1H, d, J= 16.5 Hz, H-7), 6.76 (2H, d ,J= 8.6 Hz, H-3', H-5'), 6.76 (1H, d, J= 16.5 Hz, H-8), 6.93 (1H, d, J= 8.2 Hz, H-5), 7.18 (1H, s, H-2), 7.20 (2H, d, J= 8.6 Hz, H-2', H-6'), 7.44 (1H, dd, J= 8.2, 1.9 Hz, H-6), 9.53 (1H, s, 4ΌΗ), 10.26 (2H, s, 11 OH, 13 OH); ¹³ C NMR (DMSO, 151 MHz) δ 55.0 (CH ₃ 0-11', CH ₃ 0-13'), 55.5 (C-8'), 91.9 (C-7'), 98.4 (C-12'), 100.6 (C-10, C-14), 102.0 (C-12), 106.0 (C-10', C-14'), 109.5 (C-5), 115.1 (C-3', C-5'), 122.9 (C-2), 125.2 (C-8), 127.6 (C-6), 127.8 (C-2', C-6'), 129.6 (C-l), 130.1 (C-1'), 131.2 (C-3), 135.5 (C- 7), 138.8 (C-9), 143.8 (C-9'), 153.9 (C-l l, C-13), 157.5 (C-4'), 159.1 (C-4), 160.6 (C-l l', C- 13'); HR-ESI/MS analysis: m/z 636.9877 [M - H] ^" , (calcd for C ₃ oH ₂₃ Br ₂ 0 ₆ , 636.9861, Δ = 2.4 ppm).

14-chloro-ll’,13’-dimethoxy-trans-δ-viniferin (29)

UV (MeOH) Xmax (log ε) 228 (sh) (4.58), 286 (sh) (4.16), 314 (4.39), 330 (4.37) nm; ¹ H NMR (DMSO, 600 MHz) δ 3.70 (6H, s, CH ₃ 0-11', CH ₃ 0-13'), 4.61 (1H, d, J= 8.1 Hz, H-8'), 5.59 (1H, d, J= 8.1 Hz, H-7'), 6.37 (3H, m, H-10', H-12, H-14'), 6.43 (1H, t, J= 2.3 Hz, H-12'), 6.61 (1H, d , J= 2.6 Hz, H-10), 6.76 (2H, d , J= 8.6 Hz, H-3', H-5'), 6.93 (1H, d , J= 8.3 Hz, H-5), 7.04 (1H, d, J= 16.2 Hz, H-7), 7.15 (1H, d, J= 16.2 Hz, H-8), 7.20 (3H, m, H-2, H-2', H-6'), 7.45 (1H, dd, J = 8.3, 1.9 Hz, H-6), 9.41 (1H, s, 11 OH), 9.53 (1H, s, 4' OH), 9.91 (1H, s, 13 OH); ¹³ C NMR (DMSO, 151 MHz) δ 55.1 (CH ₃ 0-11', CH ₃ 0-13'), 55.5 (C-8'), 92.0 (C-7'), 98.6 (C- 12'), 102.7 (C-12), 103.6 (C-10), 106.1 (C-10', C-14'), 109.6 (C-5), 109.6 (C-14), 115.3 (C-3', C-5'), 121.9 (C-8), 123.0 (C-2), 127.8 (C-2', C-6'), 128.0 (C-6), 130.1 (C-1', C-3), 130.7 (C-7), 131.4 (C-1), 136.3 (C-9), 143.8 (C-9'), 153.9 (C-13), 156.3 (C-11), 157.6 (C-4'), 159.1 (C-4), 160.7 (C-11', C-13'); HR-ESI/MS analysis: m/z 515.1262 [M - H] ^’ , (calcd for C ₃₀ H ₂₄ CIO ₆ , 515.1261, D = 0.1 ppm). 12-chloro-11'13’-dimethoxy-trans-δ-viniferin (30)

UV (MeOH) λmaxc (log ε) 228 (sh) (4.46), 286 (sh) (4.03), 313 (4.29), 333 (4.27), 350 (sh) (4.04) nm; ¹ H NMR (DMSO, 600 MHz) d 3.70 (6H, s, CH ₃ O- 11', CH ₃ O-13'), 4.58 (1H, d, J = 8.0 Hz, H-8'), 5.56 (1H, d , J= 8.0 Hz, H-7'), 6.36 (2H, d, J= 2.3 Hz, H-10', H-14'), 6.43 (1H, t, J= 2.3 Hz, H-12'), 6.58 (2H, s, H-10, H-14), 6.76 (2H, d , J= 8.6 Hz, H-3', H-5'), 6.84 (1H, d, J= 16.4 Hz, H-8), 6.91 (1H, d, J= 8.3 Hz, H-5), 6.93 (1H, d, J= 15.4 Hz, H-7), 7.19 (2H, d, J= 8.6 Hz, H-2', H-6'), 7.24 (1H, d, J= 1.3 Hz, H-2), 7.44 (1H, dd, J= 8.3, 1.3 Hz, H-6), 9.53 (1H, s, 4ΌH), 9.87 (2H, s, 110H, 130H); ¹³ C NMR (DMSO, 151 MHz) d 55.0 (CTHO-I T, CH ₃ O-I3'), 55.5 (C-8 ¹ ), 91.9 (C-7'), 98.4 (C-12'), 104.8 (C-10, C-14), 106.2 (C-12, C-10', C- 14'), 109.4 (C-5), 115.1 (C-3', C-5'), 122.7 (C-2), 125.5 (C-8), 127.8 (C-2', C-6'), 128.0 (C-6), 128.1 (C-7), 130.1 (C-1'), 131.0 (C-3), 136.4 (C-9), 143.8 (C-9'), 154.1 (C-11, C-13), 157.5 (C- 4'), 158.8 (C-4), 160.6 (C-11', C-13'); HR-ESI/MS analysis: m/z 515.1263 [M - H] ^' , (calcd for C30H24CIO6, 515.1261, D = 0.3 ppm).

10,14-dichloro-ll ^, ,13 ^, -dimethoxy-trans-δ-viniferin (31)

UV (MeOH) λmax (log e) 229 (sh) (4.49), 285 (sh) (4.13), 300 (4.19) nm; ¹ H NMR (DMSO, 600 MHz) d 3.70 (6H, s, CH ₃ O- 11', CH ₃ 0-13'), 4.60 (1H, d , J= 7.8 Hz, H-8'), 5.60 (1H, d, J =

7.8 Hz, H-7'), 6.38 (2H, d, J= 2.3 Hz, H-10', H-14'), 6.42 (1H, t, J= 2.3 Hz, H-12'), 6.61 (1H, s, H-12), 6.76 (2H, d, J= 8.5 Hz, H-3', H-5'), 6.83 (1H, d , J= 16.6 Hz, H-8), 6.90 (1H, d , J = 16.6 Hz, H-7), 6.94 (1H, d , J= 8.3 Hz, H-5), 7.19 (3H, m, H-2, H-2', H-6'), 7.45 (1H, dd, J = 8.3, 1.9 Hz, H-6), 9.53 (1H, s, 4ΌH), 10.15 (2H, s, 110H, 130H); ¹³ C NMR (DMSO, 151 MHz) d 55.1 (CH ₃ O- 11', CH ₃ O-13'), 55.6 (C-8'), 91.9 (C-7'), 98.6 (C-12'), 102.5 (C-12), 106.1 (C-10', C-14'), 109.6 (C-5), 110.2 (C-10, C-14), 115.3 (C-3', C-5'), 120.8 (C-8), 123.0 (C-2),

127.8 (C-2', C-6'), 127.8 (C-6), 129.7 (C-1), 130.2 (C-1'), 131.4 (C-3), 135.4 (C-9), 135.9 (C- 7), 143.9 (C-9'), 152.4 (C-11, C-13), 157.6 (C-4'), 159.2 (C-4), 160.7 (C-11', C-13'); HR- ESI/MS analysis: m/z 549.0877 [M - H] ^' , (calcd for C30H23CI2O6, 549.0872, D = 1.0 ppm). 14-iodo-ll ^, ,13 ^, -dimethoxy-trans-δ-viniferin (32)

UV (MeOH) λ _max (log e) 229 (sh) (4.63), 287 (sh) (4.15), 313 (4.31), 335 (4.28) nm; ¹ H NMR (DMSO, 600 MHz) d 3.70 (6H, s, CH ₃ 0-11', CH ₃ 0-13'), 4.63 (1H, d, J= 8.1 Hz, H-8'), 5.58 (1H, d, J= 8.1 Hz, H-7'), 6.35 (1H, d, J= 2.6 Hz, H-12), 6.37 (2H, d, J= 2.3 Hz, H-10', H-14'), 6.43 (1H, t, J= 2.3 Hz, H-12'), 6.59 (1H, d, J= 2.6 Hz, H-10), 6.76 (2H, d, J= 8.6 Hz, H-3', H- 5'), 6.92 (1H, d , J= 16.0 Hz, H-7), 6.94 (1H, d, J= 8.3 Hz, H-5), 7.06 (1H, d , J= 16.0 Hz, H- 8), 7.18 (1H, d, J= 1.9 Hz, H-2), 7.20 (2H, d, J= 8.6 Hz, H-2', H-6'), 7.44 (1H, dd, J= 8.3, 1.9 Hz, H-6), 9.47 (1H, s, 11 OH), 9.53 (1H, s, 4ΌH), 10.14 (1H, s, 130H); ¹³ C NMR (DMSO, 151 MHz) d 55.0 (CH ₃ O- 11', CH ₃ O-13'), 55.5 (C-8'), 78.4 (C-14), 91.9 (C-7'), 98.6 (C-12'), 101.3 (C-12), 104.4 (C-10), 106.0 (C-10', C-14'), 109.5 (C-5), 115.1 (C-3', C-5'), 122.9 (C-2), 127.8 (C-6, C-2', C-6'), 129.9 (C-8), 130.1 (C-1), 130.6 (C-7), 131.2 (C-3), 141.1 (C-9), 143.5 (C-9'), 157.3 (C-13), 157.5 (C-4 ¹ ), 158.2 (C-11), 159.1 (C-4), 160.6 (C- 11', C-13'); HR-ESI/MS analysis: m/z 607.0632 [M - H]-, (calcd for C ₃₀ H ₂₄ lO ₆ , 607.0618, Δ = 2.4 ppm). 12 -iodo-11'13’-dimethoxy-trans-δ-viniferin (33)

UV (MeOH) λ _max (log e) 229 (sh) (4.54), 287 (sh) (4.10), 313 (4.40), 337 (4.43), 352 (sh) (4.23) nm; ¹ H NMR (DMSO, 600 MHz) d 3.70 (6H, s, CH ₃ O- 11', CH ₃ O-13'), 4.58 (1H, d, J = 8.0 Hz, H-7'), 5.56 (1H, d , J= 8.0 Hz, H-8'), 6.36 (2H, d, J= 2.2 Hz, H-10', H-14'), 6.43 (1H, t, J= 2.2 Hz, H-12'), 6.50 (2H, s, H-10, H-14), 6.76 (2H, d , J= 8.6 Hz, H-3', H-5'), 6.85 (1H, d, J= 16.2 Hz, H-8), 6.91 (1H, d, J= 8.3 Hz, H-5), 6.95 (1H, d, J= 16.2 Hz, H-7), 7.19 (2H, d, J = 8.6 Hz, H-2', H-6'), 7.25 (1H, s, H-2), 7.45 (1H, dd, J = 8.3, 1.9 Hz, H-6), 9.53 (1H, s, 4ΌH), 10.06 (2H, s, 110H, 130H); ¹³ C NMR (DMSO, 151 MHz) d 55.1 (CH ₃ 0-11', CH ₃ 0- 13'), 55.7 (C-8 ¹ ), 74.1 (C-12), 92.0 (C-7'), 98.5 (C-12'), 103.7 (C-10, C-14), 106.1 (C-10', C- 14'), 109.5 (C-5), 115.3 (C-3', C-5'), 122.9 (C-2), 125.6 (C-8), 127.8 (C-2', C-6'), 128.0 (C-6), 128.3 (C-7), 130.2 (C-1, C-1'), 131.2 (C-3), 138.6 (C-9), 143.8 (C-9'), 157.6 (C-4'), 158.0 (C- 11, C-13), 158.9 (C-4), 160.7 (C- 11', C-13'); HR-ESI/MS analysis: m/z 607.0626 [M - H] ^' , (calcd for C ₃₀ H ₂₄ lO ₆ , 607.0618, Δ = 1.4 ppm).

14,14 ^, -dibromo-ll,13-dimethoxy-trans-δ-viniferin (34)

UV (MeOH) λ _max (log e) 229 (sh) (4.62), 288 (sh) (4.23), 314 (4.39), 332 (4.36) nm; ¹ H NMR (DMSO, 600 MHz) d 3.82 (3H, s, CH ₃ O-11), 3.83 (3H, s, CH ₃ 0-13), 5.08 (1H, brs, H-8'), 5.49 (1H, brs, H-7'), 5.99 (1H, brs, H-10'), 6.37 (1H, d, J= 2.7 Hz, H-12'), 6.57 (1H, d, J= 2.7 Hz, H-12), 6.74 (2H, d, J= 8.5 Hz, H-3', H-5'), 6.95 (1H, d, J= 2.7 Hz, H-10), 6.97 (1H, d, J= 8.4 Hz, H-5), 7.19 (2H, d, J= 8.5 Hz, H-2', H-6'), 7.24 (2H, m, H-7, H-8), 7.26 (1H, d, J= 1.9 Hz, H-2), 7.52 (1H, dd, J= 8.4, 1.9 Hz, H-6), 9.47 (1H, s, 11'OH), 9.52 (1H, s, 4'OH), 10.13 (1H, s, 13'OH); ¹³ C NMR (DMSO, 151 MHz) d 54.1 (C-8'), 55.5 (CH ₃ O-11) 56.2 (CH ₃ 0-13), 91.9 (C-7'), 98.9 (C-12), 101.1 (C-14'), 102.3 (C-12'), 103.6 (C-14), 106.7 (C-10') 109.7 (C-5, C- 10), 115.1 (C-3', C-5'), 123.7 (C-2), 123.9 (C-8), 127.6 (C-2', C-6'), 127.8 (C-6), 130.3 (C-1), 130.5 (C-1'), 130.9 (C-3), 131.9 (C-7), 155.0 (C-13'), 156.4 (C-13), 157.3 (C-11'), 157.5 (C-4'), 159.3 (C-11), 159.5 (C-4); HR-ESI/MS analysis: m/z 636.9877 [M - H] ^' , (calcd for C ₃ oH ₂₃ Br ₂ 0 ₆ , 636.9861, D = 2.4 ppm).

14 ^, -chloro-ll,13-dimethoxy-trans-δ-viniferin (35)

UV (MeOH) λ _max (log e) 228 (sh) (4.46), 288 (sh) (4.10), 313 (4.29), 332 (4.24) nm; ¾NMR (DMSO, 600 MHz) d 3.75 (6H, s, CH ₃ O-11, CH ₃ 0-13), 5.01 (1H, brs, H-8'), 5.48 (1H, brs, H- 7'), 5.99 (1H, d, J= 2.7 Hz, H-10'), 6.35 (1H, t, J= 2.2 Hz, H-12), 6.37 (1H, d, J= 2.7 Hz, H- 12'), 6.72 (2H, d, J= 2.2 Hz, H-10, H-14), 6.74 (2H, d, J= 8.6 Hz, H-3', H-5'), 6.93 (1H, d, J = 8.3 Hz, H-5), 6.98 (1H, d, J= 16.4 Hz, H-8), 7.18 (2H, d, J= 8.6 Hz, H-2', H-6'), 7.22 (1H, d, J= 16.4 Hz, H-7), 7.27 (1H, s, H-2), 7.46 (1H, dd, J= 8.3, 1.9 Hz, H-6), 9.43 (1H, s, 11'OH), 9.51 (1H, s, 4ΌH), 10.02 (1H, s, 13'OH); ¹³ C NMR (DMSO, 151 MHz) d 55.1 (CH ₃ O-11, CH ₃ O-I3), 91.8 (C-7'), 99.5 (C-12), 102.5 (C-12'), 104.1 (C-10, C-14), 106.8 (C-10'), 109.5 (C- 5), 110.1 (C-14 ^' ), 115.2 (C-3', C-5'), 122.9 (C-2), 125.9 (C-8), 127.6 (C-2', C-6'), 127.9 (C-6),

128.7 (C-7), 130.4 (C-3), 130.6 (C-1), 130.7 (C-1'), 139.5 (C-9), 153.9 (C-13'), 156.7 (C-11'), 157.5 (C-4 ^' ), 159.2 (C-4), 160.6 (C-11, C-13); HR-ESI/MS analysis: m/z 515.1268 [M - H] ^' , (calcd for C ₃₀ H ₂₄ CIO ₆ , 515.1261, Δ = 1.3 ppm).

14-chloro- 11 , 13-dimethoxy-trans-δ-viniferin (36)

UV (MeOH) λ _max (log e) 229 (sh) (4.71), 287 (sh) (4.31), 313 (4.53), 332 (4.51) nm; ¹ HNMR (DMSO, 600 MHz) d 3.82 (3H, s, CH ₃ O-11), 3.83 (3H, s, CH ₃ 0-13), 4.48 (1H, d, J= 8.0 Hz, H-8'), 5.43 (1H, d, J= 8.0 Hz, H-7'), 6.05 (2H, d, J= 2.2 Hz, H-10', H-14'), 6.10 (1H, t, J= 2.2 Hz, H-12'), 6.60 (1H, d, J= 2.6 Hz, H-12), 6.76 (2H, d , J= 8.6 Hz, H-3', H-5'), 6.93 (1H, d, J = 8.3 Hz, H-5), 6.96 (1H, d, J= 2.6 Hz, H-10), 7.19 (2H, d, J= 8.6 Hz, H-2', H-6'), 7.22 (1H, d, J= 16.2 Hz, H-8), 7.23 (1H, s, H-2), 7.31 (1H, d, J= 16.2 Hz, H-7), 7.50 (1H, dd, J= 8.3, 1.9 Hz, H-6), 9.22 (2H, s, 11'OH, 13'OH), 9.54 (1H, s, 4'OH); ¹³ C NMR (DMSO, 151 MHz) d 55.6 (C-8', CH ₃ O-11), 56.2 (CH ₃ O-13), 92.7 (C-7'), 99.1 (C-12), 101.3 (C-12'), 101.8 (C-10), 106.0 (C-10', C-14'), 109.6 (C-5), 112.3 (C-14), 115.3 (C-3', C-5'), 121.0 (C-8), 123.7 (C-2),

127.7 (C-6), 127.9 (C-2', C-6'), 129.9 (C-1), 130.2 (C-1'), 131.5 (C-3), 132.0 (C-7), 136.4 (C- 9), 143.6 (C-9'), 155.6 (C-13), 157.6 (C-4'), 158.7 (C-11, C-11', C-13'), 159.4 (C-4); HR- ESI/MS analysis: m/z 515.1263 [M - H] ^' , (calcd for C30H24CIO6, 515.1261, D = 0.3 ppm).

12-chloro-ll,13-dimethoxy-trans-δ-viniferin (37)

UV (MeOH) λ _max (log e) 227 (sh) (4.78), 288 (sh) (4.29), 313 (4.53), 335 (4.52), 352 (sh) (4.27) nm; ¹ HNMR (DMSO, 600 MHz) d 3.86 (6H, s, CH ₃ O-11, CH ₃ 0-13), 4.48 (1H, d, J = 8.5 Hz, H-8'), 5.42 (1H, d , J= 8.5 Hz, H-7'), 6.05 (2H, d, 7= 2.1 Hz, H-10', H-14'), 6.11 (1H, t, J= 2.1 Hz, H-12'), 6.76 (2H, d , J= 8.6 Hz, H-3', H-5'), 6.92 (1H, d , J= 8.2 Hz, H-5), 6.98 (2H, s, H-10, H-14), 7.02 (1H, d, J= 16.4 Hz, H-8), 7.20 (2H, d , J= 8.6 Hz, H-2', H-6'), 7.24 (1H, s, H-2), 7.33 (1H, d, J= 16.4 Hz, H-7), 7.45 (1H, dd, J= 8.2, 1.9 Hz, H-6), 9.22 (2H, s, 1 GOH, 13ΌH), 9.54 (1H, s, 4'OH); ¹³ C NMR (DMSO, 151 MHz) d 55.5 (C-8'), 56.1 (CH ₃ O- 11, CH ₃ O-13), 92.6 (C-7'), 101.3 (C-12'), 102.8 (C-10, C-14), 106.0 (C-10', C-14'), 107.6 (C-

12), 109.3 (C-5), 115.1 (C-3', C-5'), 122.8 (C-2), 125.2 (C-8), 127.6 (C-6), 128.0 (C-2', C-6'), 129.4 (C-7), 129.8 (C-1H), 130.1 (C-1), 131.4 (C-3), 137.3 (C-9), 143.3 (C-9'), 155.5 (C-11, C-

13), 157.7 (C-4 ^' ), 158.6 (C-11', C-13'), 159.1 (C-4); HR-ESI/MS analysis: m/z 515.1265 [M - H]-, (calcd for C ₃₀ H ₂₄ CIO ₆ , 515.1261, D = 0.7 ppm).

14,14 ^, -dichloro-ll,13-dimethoxy-trans-δ-viniferin (38)

UV (MeOH) λ _max (log e) 229 (sh) (4.59), 313 (4.40), 333 (4.38) nm; ¾ NMR (DMSO, 600 MHz) d 3.82 (3H, s, CH ₃ O-11), 3.83 (3H, s, CH ₃ 0-13), 5.02 (1H, brs, H-8'), 5.50 (1H, brs, H- 7'), 5.97 (1H, d, J= 2.7 Hz, H-10'), 6.37 (1H, d, J= 2.7 Hz, H-12'), 6.60 (1H, d, J= 2.7 Hz, H-

12), 6.74 (2H, d, J= 8.5 Hz, H-3', H-5'), 6.96 (2H, m, H-5, H-10), 7.19 (2H, d, J= 8.5 Hz, H- 2', H-6'), 7.24 (1H, d, J= 16.3 Hz, H-8), 7.28 (2H, m, H-2, H-7), 7.53 (1H, dd, J= 8.4, 1.9 Hz, H-6), 9.43 (1H, s, 11'OH), 9.52 (1H, s, 4'OH), 10.03 (1H, s, 13'OH); ¹³ C NMR (DMSO, 151 MHz) d 55.6 (CH ₃ O-11), 56.2 (CH ₃ O-13), 99.1 (C-12), 101.9 (C-10), 102.5 (C-12'), 109.7 (C- 5), 110.0 (C-14'), 112.3 (C-14), 115.2 (C-3', C-5'), 121.2 (C-8), 123.8 (C-2), 127.6 (C-2', C-6'), 127.9 (C-6), 130.1 (C-1), 130.7 (C-1', C-3), 131.9 (C-7), 136.4 (C-9), 154.0 (C-13'), 155.6 (C-

13), 156.7 (C-11'), 157.5 (C-4'), 158.7 (C-11), 159.6 (C-4); HR-ESI/MS analysis: m/z 549.0881 [M - H]-, (calcd for C ₃₀ H ₂₃ CI ₂ O ₆ , 549.0872, Δ = 1.7 ppm).

14 ^, -iodo-ll,13-dimethoxy-trans-δ-viniferin (39)

UV (MeOH) λ _max (log e) 230 (sh) (4.45), 288 (sh) (4.07), 313 (4.24), 334 (4.18) nm; ¹ H NMR (DMSO, 600 MHz) d 3.75 (6H, s, CH ₃ O-11, CH ₃ O-13), 5.10 (1H, d, J= 6.7 Hz, H-8'), 5.44 (1H, d , J= 6.7 Hz, H-7'), 6.02 (1H, d, J= 2.6 Hz, H-12' or H-14'), 6.34 (1H, d, J= 2.6 Hz, H- 14' or H-12'), 6.35 (1H, t, J= 2.3 Hz, H-12), 6.73 (2H, d, J= 2.3 Hz, H-10, H-14), 6.74 (2H, d, J= 8.6 Hz, H-3', H-5'), 6.94 (1H, d, J= 8.2 Hz, H-5), 6.96 (1H, d, J= 16.4 Hz, H-8), 7.18 (2H, d, J= 8.6 Hz, H-2', H-6'), 7.21 (1H, d, J= 16.4 Hz, H-7), 7.23 (1H, s, H-2), 7.47 (1H, d, J= 8.2 Hz, H-6), 9.47 (1H, s, 11'OH), 9.50 (1H, s, 4ΌH), 10.24 (1H, s, 13'OH); ¹³ C NMR (DMSO, 151 MHz) d 55.0 (CH ₃ 0-11, CH ₃ 0-13), 58.9 (C-8'), 79.3 (C-14'), 92.5 (C-7'), 99.5 (C-12),

101.3 (C-10' or C-12'), 104.1 (C-10, C-14), 106.9 (C-12' or C-10'), 109.5 (C-5), 115.1 (C-3', C- 5'), 122.7 (C-2), 125.9 (C-8), 127.6 (C-6, C-2', C-6'), 128.7 (C-7), 130.3 (C- 1 '),' 139.5 (C-9), 157.5 (C-4', C-13'), 158.6 (C 11G' ), 158.8 (C-4), 160.4 (C-11, C-13); HR-ESI/MS analysis: m/z 607.0627 [M - H] ^' , (calcd for C ₃ oH ₂₄ l0 ₆ , 607.0618, D = 1.5 ppm).

12’-iodo-11,13-dimethoxy-trans-δ-viniferin (40)

UV (MeOH) λ _max (log e) 218 (sh) (4.74), 310 (4.45), 332 (4.41) nm; ¾ NMR (DMSO, 600 MHz) d 3.75 (6H, s, CH ₃ 0-11, CH ₃ 0-13), 4.49 (1H, d, J= 8.5 Hz, H-8'), 5.35 (1H, d, J= 8.5 Hz, H-7'), 6.19 (2H, s, H-10', H-14'), 6.35 (1H, t, J= 2.2 Hz, H-12), 6.73 (2H, d, J= 2.2 Hz, H- 10, H-14), 6.77 (2H, d , J= 8.6 Hz, H-3', H-5'), 6.92 (1H, d , J= 8.3 Hz, H-5), 6.98 (1H, d, J =

16.4 Hz, H-8), 7.20 (2H, d, J= 8.6 Hz, H-2', H-6'), 7.23 (1H, d , J= 16.4 Hz, H-7), 7.27 (1H, s, H-2), 7.45 (1H, dd, J= 8.3, 1.8 Hz, H-6), 9.55 (1H, s, 4ΌH), 10.07 (2H, s, 11'OH, 13'OH); ¹³ C NMR (DMSO, 151 MHz) d 55.1 (CH ₃ 0-11, CH ₃ 0-13), 55.6 (C-8 ¹ ), 73.6 (C-12 ¹ ), 92.9 (C-7 ¹ ),

99.5 (C-12), 104.1 (C-10, C-14), 105.6 (C-10 ¹ , C-14'), 109.4 (C-5), 115.3 (C-3', C-5'), 123.0 (C-2), 125.8 (C-8), 127.8 (C-6), 128.0 (C-2', C-6'), 128.7 (C-7), 129.9 (C-1'), 130.4 (C-1), 131.0 (C-3), 139.5 (C-9), 143.0 (C-9'), 157.6 (C-4'), 158.1 (C-11', C-13'), 159.1 (C-4), 160.6 (C-11, C-13); HR-ESI/MS analysis: m/z 607.0627 [M - H]-, (calcd for C ₃₀ H ₂₄ lO ₆ , 607.0618, D = 1.5 ppm).

12-bromo-11,11',13,13'tetramethoxy-trans-δ-viniferin (41)

UV (MeOH) λ _max (log e) 229 (sh) (4.50), 286 (sh) (4.06), 313 (4.35), 336 (4.38), 354 (sh) (4.12) nm; ¾ NMR (DMSO, 600 MHz) d 3.70 (6H, s, CH ₃ O- 11', CH ₃ O-13'), 3.86 (6H, s, CH ₃ O-11, CH ₃ O-13), 4.62 (1H, d, J= 8.8 Hz, H-8'), 5.60 (1H, d, J= 8.8 Hz, H-7'), 6.39 (2H, d , J= 2.3 Hz, H-10', H-14'), 6.44 (1H, t , J= 2.3 Hz, H-12'), 6.76 (2H, d , J= 8.7 Hz, H-3', H- 5'), 6.94 (2H, s, H-10, H-14), 6.94 (1H, d, J= 8.3 Hz, H-5), 7.01 (1H, d, J= 16.4 Hz, H-8), 7.21 (3H, m, H-2, H-2', H-6'), 7.35 (1H, d , J = 16.4 Hz, H-7), 7.47 (1H, dd, J= 8.3, 1.9 Hz, H-6), 9.54 (1H, s, 4'OH); ¹³ C NMR (DMSO, 151 MHz) d 55.2 (CH ₃ O- 11', CH ₃ O-13'), 55.7 (C-8'),

56.3 (CH ₃ O-11, CH ₃ O-13), 92.1 (C-7'), 98.2 (C-12), 98.5 (C-12'), 102.9 (C-10, C-14), 106.4 (C-10', C-14'), 109.6 (C-5), 115.3 (C-3', C-5'), 122.9 (C-2), 125.2 (C-8), 127.7 (C-6), 128.0 (C- 2', C-6'), 129.4 (C-7), 129.9 (C-G), 130.2 (C-1), 131.6 (C-3), 138.3 (C-9), 143.5 (C-9'), 156.5 (C-11, C-13), 157.6 (C-4 ¹ ), 158.9 (C-4), 160.7 (C- 11', C-13'); HR-ESI/MS analysis: m/z 587.1072 [M - H] ^' , (calcd for C ₃₂ H ₂₈ Br0 ₆ , 587.1069, Δ = 0.6 ppm).

14-bromo-11,11'13,13 ^, -tetramethoxy-trans-δ-viniferin (42)

UV (MeOH) λ _max (log e) 229 (sh) (4.47), 285 (sh) (4.00), 312 (4.24), 332 (4.23) nm; ¾NMR (DMSO, 600 MHz) d 3.70 (6H, s, CH ₃ - 11', CH ₃ 0-13'), 3.81 (3H, s, CH ₃ O-11), 3.82 (3H, s, CH ₃ O-I3), 4.63 (1H, d, J= 8.3 Hz, H-8'), 5.61 (1H, d , J= 8.3 Hz, H-7'), 6.38 (2H, d , J= 2.3 Hz, H-10', H-14'), 6.43 (1H, t, J= 2.3 Hz, H-12'), 6.57 (1H, d, J= 2.6 Hz, H-12), 6.76 (2H, d, J= 8.5 Hz, H-3', H-5'), 6.95 (2H, m, H-5, H-10), 7.20 (4H, m, H-2, H-2', H-6', H-8), 7.26 (1H, d, J= 16.2 Hz, H-7), 7.50 (1H, dd, J= 8.4, 1.9 Hz, H-6), 9.54 (1H, s, 4'OH); ¹³ C NMR (DMSO, 151 MHz) d 55.2 (CH ₃ O-111, ' CH ₃ O-13'), 55.5 (C-8'), 55.6 (CH ₃ O-11), 56.4 (CH ₃ O-13), 92.1 (C-7 ¹ ), 98.6 (C-12'), 99.1 (C-12), 102.5 (C-10), 103.6 (C-14), 106.2 (C-10', C-14'), 109.7 (C-5), 115.3 (C-3', C-5'), 123.5 (C-2), 123.9 (C-8), 127.6 (C-6), 127.9 (C-2', C-6'), 129.9 (C-1'), 130.0 (C-1), 131.5 (C-3), 132.0 (C-7), 138.1 (C-9), 143.6 (C-9'), 156.4 (C-13), 157.6 (C-4'), 159.2 (C-4), 159.4 (C-11), 160.7 (C-11', C-13'); HR-ESI/MS analysis: m/z 587.1069 [M - H] ^" , (calcd for C ₃₂ H ₂₈ Br0 ₆ , 587.1069, D = 0 ppm).

14-chloro-11,11'13,13 ^, -tetramethoxy-trans-δ-viniferin (43)

UV (MeOH) λ _max (log e) 229 (sh) (4.63), 286 (sh) (4.20), 313 (4.45), 332 (4.44) nm; ¹ H NMR (DMSO, 600 MHz) d 3.70 (6H, s, CH ₃ O-H', CH ₃ O-13'), 3.81 (3H, s, CH ₃ O-11), 3.83 (3H, s, CH ₃ O-I3), 4.62 (1H, d , J= 8.3 Hz, H-8'), 5.61 (1H, d , J= 8.3 Hz, H-7'), 6.38 (2H, d , J= 2.3 Hz, H-10', H-14'), 6.43 (1H, t, J= 2.3 Hz, H-12'), 6.59 (1H, d, J= 2.6 Hz, H-12), 6.76 (2H, d, J= 8.5 Hz, H-3', H-5'), 6.95 (2H, m, H-5, H-10), 7.21 (4H, m, H-2, H-2', H-6', H-8), 7.30 (1H, d, J= 16.3 Hz, H-7), 7.51 (1H, dd, J= 8.4, 1.9 Hz, H-6), 9.54 (1H, s, 4'OH); ¹³ C NMR (DMSO, 151 MHz) δ 55.2 (CH ₃ O- 11', CH ₃ O-13'), 55.5 (C-8'), 55.6 (CH ₃ O-11), 56.2 (CH ₃ 0-13), 92.1 (C-7'), 98.6 (C-12'), 99.2 (C-12), 101.8 (C-10), 106.2 (C-10', C-14'), 109.7 (C-5), 112.3 (C-14), 115.3 (C-3', C-5'), 121.1 (C-8), 123.6 (C-2), 127.7 (C-6), 127.9 (C-2', C-6'), 130.0 (C-1), 130.0 (C-1'), 131.5 (C-3), 132.0 (C-7), 136.3 (C-9), 143.7 (C-9'), 155.6 (C-13), 157.6 (C-4'), 158.6 (C-11), 159.2 (C-4), 160.7 (C-11', C-13'); HR-ESI/MS analysis: m/z 543.1568 [M - H] ^" , (calcd for C ₃₂ H ₂₈ C10 ₆ , 543.1574, D = 1.2 ppm). 14-iodo-11,11'13,13’-tetramethoxy-trans-δ-viniferin (44)

UV (MeOH) λ _max (log e) 287 (sh) (3.96), 312 (4.17), 335 (4.15) nm; ¾ NMR (DMSO, 600 MHz) d 3.70 (6H, s, CH ₃ O-11', CH ₃ 0-13'), 3.81 (6H, s, CH ₃ O-11, CH ₃ 0-13), 4.64 (1H, d, J = 8.4 Hz, H-8 ¹ ), 5.61 (1H, d , J= 8.4 Hz, H-7'), 6.39 (2H, d, J= 2.3 Hz, H-10', H-14'), 6.43 (1H, t, J= 2.3 Hz, H-12'), 6.50 (1H, d, J= 2.6 Hz, H-12), 6.76 (2H, d, J= 8.5 Hz, H-3', H-5'), 6.92 (1H, d, J = 2.6 Hz, H-10), 6.96 (1H, d, J= 8.3 Hz, H-5), 7.15 (2H, m, H-7, H-8), 7.18 (1H, s, H-2), 7.21 (2H, d, J = 8.5 Hz, H-2', H-6'), 7.49 (1H, dd, J = 8.3, 1.9 Hz, H-6), 9.54 (1H, s, 4'OH); ¹³ C NMR (DMSO, 151 MHz) d 55.2 (CH3 _O -11', CH ₃ 0-13'), 55.5 (C-8'), 56.5 (CH ₃ O- 11, CH ₃ O-I3), 81.9 (C-14), 92.0 (C-7'), 98.2 (C-12), 98.6 (C-12'), 103.0 (C-10), 106.2 (C-10', C-14'), 109.7 (C-5), 115.3 (C-3 ¹ , C-5'), 123.5 (C-2), 127.4 (C-6), 127.9 (C-2 ¹ , C-6'), 129.4 (C- 8), 129.9 (C-1), 130.0 (C-G), 131.5 (C-3), 131.9 (C-7), 141.4 (C-9), 143.6 (C-9'), 157.6 (C-4'), 158.6 (C-13), 159.2 (C-4), 160.7 (C-11), 160.7 (C- 11', C-13'); HR-ESI/MS analysis: m/z 635.0920 [M - H] ^' , (calcd for C ₃₂ H ₂₈ IO ₆ , 635.0931, Δ = 1.7 ppm). 12-iodo-11,11',13,13'tetramethoxy-trans-δ-viniferin (45)

UV (MeOH) λ _max (log e) 229 (sh) (4.56), 287 (sh) (4.10), 315 (4.45), 340 (4.52), 358 (sh) (4.28) nm; ¹ H NMR (DMSO, 600 MHz) d 3.70 (6H, s, CH ₃ O-H', CH ₃ 0-13'), 3.84 (6H, s, CH ₃ O-11, CH ₃ O-I3), 4.62 (1H, d, J= 8.8 Hz, H-8'), 5.60 (1H, d, J= 8.8 Hz, H-7'), 6.39 (2H, d , J= 2.3 Hz, H-10', H-14'), 6.44 (1H, t , J= 2.3 Hz, H-12'), 6.76 (2H, d , J= 8.5 Hz, H-3', H- 5'), 6.85 (2H, s, H-10, H-14), 6.94 (1H, d, J= 8.3 Hz, H-5), 7.02 (1H, d, J= 16.4 Hz, H-8), 7.21 (1H, d, J= 1.9 Hz, H-2), 7.21 (2H, d, J= 8.5 Hz, H-2', H-6'), 7.37 (1H, d, J= 16.4 Hz, H-7), 7.47 (1H, dd, J= 8.3, 1.9 Hz, H-6), 9.53 (1H, s, 4'OH); ¹³ C NMR (DMSO, 151 MHz) d 55.1 (CH ₃ O- 11', CH ₃ O-I3'), 55.7 (C-8 ¹ ), 56.5 (CH ₃ O-11, CH ₃ 0-13), 75.6 (C-12), 92.1 (C-7 ¹ ), 98.5 (C-12 ¹ ), 102.4 (C-10, C-14), 106.4 (C-10 ¹ , C-14'), 109.5 (C-5), 115.2 (C-3', C-5'), 122.9 (C-2), 125.2 (C-8), 127.7 (C-6), 127.9 (C-2 ¹ , C-6'), 129.4 (C-7), 129.9 (C-1'), 130.2 (C-1), 131.6 (C- 3), 139.7 (C-9), 143.5 (C-9'), 157.6 (C-4'), 158.9 (C-4), 159.0 (C-11, C-13), 160.7 (C-11', C- 13'); HR-ESI/MS analysis: m/z 635.0923 [M - H] ^' , (calcd for C ₃₂ H ₂₈ II ₆ , 635.0931, D = 1.2 ppm). EXAMPLES

Example 1:

Biotransformation reactions were performed with resveratrol, pterostilbene and the mixture of both at the concentration of 0.5 mg/mL using the secretome of B. cinerea. The reactions were performed in water solutions containing 2%, 10%, 30%, 50%, 70%, 90% and 98% of an organic solvent (acetone or methanol). At concentrations of 2 and 10% of organic solvents, the compounds were not completely soluble, resulting in a "bleached" solution, while at concentrations of 30-98%, the compounds were fully soluble. In a second step, resveratrol and pterostilbene (concentration of 0.5 mg/mL; 0.25 mg/mL each compound) were diluted in those ratios of acetone or methanol and water before incubation with the secretome of B. cinerea during 24 hours. Each reaction was monitored by UHPLC-PDA-ELSD-MS. Based on the semi- quantitative ELSD response the increase in the percentage of acetone (2 to 50%) seemed to improve the yield of the reaction. With 70, 90 and 98% of acetone the reactions did not occur suggesting the enzyme denaturation.

The same patterns were observed using increasing amounts of methanol while at of 90 and 98% of methanol the reactions did not occur. However, starting from 10% methanol, peaks that were not observed in the previous study ⁷ appeared clearly after 24 hours and became very intense at 50 and 70%. In comparison with previous results ⁷ new MS features at m/z 559 [M+FA-H] ^" and m/z 587 [M+FA-H]- were detected, suggesting the presence of new dimeric analogs.

In order to isolate these compounds, the biotransformation reaction was scaled up using the solution with 50% of methanol and 50 mg of each substrate was used (see Material & Method section). After 24 hours, the reaction was monitored by UHPLC-PDA-ELSD-MS. The resveratrol and pterostilbene substrates were totally consumed demonstrating a good enzymatic activity in such optimized conditions.

For an efficient direct targeted isolation of the biotransformed NPs, the analytical conditions used for monitoring were transposed to high-resolution semi-preparative HPLC-UV system hyphenated to an evaporative light scattering detector (ELSD) and to a single quadrupole ESI-MS detector. A geometrical transfer of the analytical HPLC conditions to the semi-preparative HPLC was performed, using the same reversed-phase column chemistry to obtain same chromatographic selectivity. The method takes advantage of HPLC modelling based on generic linear gradients at the analytica11evel to maximize the separation of the compounds of interest in a given reaction mixture. With the objective to avoid loss of resolution caused by the organic solvent during the sample injection, a sample dry load was used instead of a conventional loop injection, following a protocol recently developed in Applicants’ laboratory. ⁹ Using this approach, the separations obtained at the semi-preparative HPLC scale perfectly matched those obtained at analytical scale, demonstrating the efficiency of the gradient transfer method. The use of the ELSD detector gave precious information about the relative amount of each compound in the crude reaction mixture. Finally, MS detection enabled an easy localisation of the minor compounds (e.g. 7 and 13) within the fractions obtained. This is illustrated by the extracted-ion chromatogram (XIC) obtained at the semi-preparative scale.

Using this approach, the reaction performed with the mixture of resveratrol and pterostilbene using the secretome of B. cinerea and 50% of methanol as a solvent afforded fifteen compounds. These compounds were isolated and identified by spectroscopic methods such as nuclear magnetic resonance (NMR) and high-resolution mass spectrometry FIRMS) as pallidol (1), parthenostilbenin A/B (2) resvepterol A/B (3), resvepterodimer A (4), 7-0- methylresvepterol B (5), trans-δ-n iniferin (6), 7-O-m ethyl i sores vepterol B (7), 7-0- methylresvepterol A (8), pterodimer C (9), 7'-O-methylresveptero open dimer (10), 11', 13'- di methoxy-trans-δ-viniferin (11), 7'-O-methylisoresveptero open dimer (12), 7-O-methyl - 11, 11',13,13'-tetramethoxyleachianol F (13), 1 1 , 13-dimethoxy-trans-δ-viniferin (14) and pterostilbene-trans-dehydromer (15).

Using the same approach the biotransformation reaction of pterostilbene using the secretome of B. cinerea and 2% of acetone as a solvent afforded was scale-up and 100 mg of pterostilbene was used. After 24 hours the reaction was stopped, dried and purified affording five compounds identified as 11,11’,13,13’-tetramethoxypallidol (16), 11,11’, 13,13’- tetramethoxyrestrytisol B (17), 11,11’, 13,13 ’-tetramethoxyleachianol F (18), 11,11’, 13,13’- tetramethoxyleachianol G (19) and pterostilbene open dimer (20). Structures were showed in Figure 1.

Example 2:

All derivatives obtained (1-20) were tested against the Gram-negative microorganism Pseudomonas aeruginosa (ATCC 27853) and Gram-positive methicillin-resistant strains of Staphylococcus aureus (MRSA, ATCC 33591) (see Table 1). The antibacterial activity of the initial compound used for the biotransformation, resveratrol (MIC > 128 μg/mL), was considered as not active while pterostilbene presented a moderate activity against the wild strain of S. aureus (MIC of 8 μg/mL). Table 1. Minimum inhibitory concentration (MIC) of the derivatives against Staphylococcus aureus (MRS A 33591) and Staphylococcus aureus (VRSA 510). Compounds 11, 12 and 14 presented significant antibacterial activities against & aureus MRSA strain with a minimum inhibitory concentration (MIC) of 2, 4 and 1 μg/mL, respectively. It was also interesting to observe that 6, 9, 13 and 16 also presented interesting antibacterial activities against the MRSA strain with MIC of 8 to 16 μg/mL, while compounds 10, 17, 18 and 19 presented moderate activity against both strains with MIC between 32 to 64 μg/mL.

The three most active compounds (11, 12 and 14) against MRSA were selected and tested against vancomycin-resistant strains of S. aureus (VRSA 510). All compounds presented remarkable activities with MIC of 2, 2 and 1 μg/mL, respectively.

Example 3:

Applicants have firmly established Dictyostelium discoideum as a powerful alternative host model system to study interactions with pathogenic Mycobacterium marinum and identify anti -infective compounds from natural and synthetic sources as well as their molecular targets. ^{8, 12, 13} Applicants used three bioassays to determine the anti-M marinum activity of the four compounds listed below, one in vitro assay to monitor the antibiotic activity, and two different in cellulo assays to monitor the anti-infective activity of these compounds.

14. 11 ,13-dimethoxy-trans-δ-viniferin 15. pterostilbene trans-dehydromer

To monitor the antibacterial/antibiotic activity of the four compounds, applicants tested them at 20 mM, a concentration similar to the one used in previous publications. ^{8, 14} The growth kinetics clearly show that three compounds exert an anti -M marinum activity ranging from 25% (6) to 50% (14 and 15) growth inhibition. The compound 11 did not show significant antibacterial activity compared to the vehicle control (Figure 2).

To determine the effect of the four compounds on intracellular M marinum growth, applicants used a plate reader-based assay (Figure 3A) and time-lapse imaging with a high-content fluorescence microscope (Figure 3B). Results of one representative experiment is presented. All four compounds exerted an inhibition on M marinum intracellular growth at least in one of the two assays. Interestingly compounds 11 (triangle) and 14 (diamond) showed more than 80% inhibition compared to the vehicle control (black dots) in both assays. The compound 6 showed a moderate anti-infective activity leading to a reduction ofM marinum growth by 50%, whereas 15 showed a similar inhibition to 6 only in the HCM assay. Although no direct cytotoxicity test was performed, a visual inspection of HCM images shows clearly that none of the four compounds exerted any cytotoxic effect (Figure 4).

IC 50 determination: In order to determine the IC50 of compounds 11 and 14, the same infection procedure as mentioned above (anti -infective assay) was used. 5 ^c 10 ⁴ infected cells were transferred to each well of a 96-well plate (Cell Carrier, black, transparent bottom from Perkin Elmer) and a two-fold serial dilution was employed to obtain decreasing compound concentrations from 20 μM to 0.625 μM. The course of infection at 25°C was monitored by measuring bacteria11uminescence in a plate reader (Synergy HI, BioTek) for 72 h with time points taken every 1 h. Rifabutin was used at 10 mM as a positive control. The values of the data points at 3 days post-infection were used to build dose response curves in Graph Pad Prism to determine the IC ₅₀ . A mean value from at least two biological replicates is given for each compound. The absolute IC50 was calculated using a 4PL curve fitting analysis. Compound 11 showed an IC50 ranging from 12 to 19 mM, whereas compound 14 had a lower IC50 ranging from 7 to 13 mM (Figure 5).

Structure-Activity Relationship: In order to further explore the anti-infective activity of the compounds 11 and 14, a variety of halogenations reactions (chlorination, bromination, iodination) were performed at various positions. The resulting derivatives (Figure 6) were tested at 20 mM in both the in vitro assay (Table 2) and the in cellulo D. discoideum - M. marinum infection assay (Table 3), as described above, and luminescence was used as a proxy for intracellular bacterial growth. The results showed that the majority of the halogenated compounds exerted anti -bacterial and anti -infective activities similar to compounds 11 and 14. Table 1 summarizes the anti -bacterial activities of compounds 11 and 14 and their derivatives, calculated as the area under the curve (AUC). The derivative of compound 11, 32 showed improved anti -bacterial activity by reducing M marinum growth to 73% of the vehicle control, compared to 99% for compound 11. Concerning the derivatives of compound 14, 3 compounds (34, 38, and 40) exerted an anti -bacterial activity similar to 14 (Table 2).

The anti-infective activity of the derivatives was assayed on infected D. discoideum and the results are represented as the normalized residual intracellular growth of M marinum compared to the vehicle control (100%). Rifabutin serves as a positive control that leads to 0% growth (Table 3). The compound 27 and 33, two derivatives of compound 11, exerted a more potent anti -infective activity with a residual percentage of growth of 7% and 6% respectively, compared to 18% for compound 11. On the other hand, derivatives of compound 14 showed similar anti-infective activity as the parent compound except for compounds 36 and 37, which reduced the intracellular growth of M marinum to 0% and 2%, respectively.

AUC in vitro M. marinum growt Table 2: Anti -bacterial activity of the derivatives of compounds 6, 11, 14 and 15 calculated based on the total Area Under the Curve (AUC). The luminescence values obtained from M marinum in vitro assay were plotted in Prism and the baseline for the AUC calculation was the average of the first 3 time-points. The inhibitory effect is reflected in the normalized residual growth, compared to the vehicle control (100%) and the positive control (Rifa 0%).

AUC in cellulo intracellular M marinum growt

Table 3: The in cellulo anti -infective activity of the derivatives of compounds 6, 11, 14 and 15 was calculated based on the AUC of M marinum intracellular growth. The luminescence values were plotted in Prism and the baseline for the AUC calculation was the average of the first 3 time-points. The inhibitory effect is reflected in the normalized residual growth, compared to the vehicle control (100%) and the positive control (Rifa 0%).

Example 4:

Cells v iability assay

MDCK cells (2xlE4 cells per well) were seeded in a 96-well plate one day before the assay. A dose range of each d-Viniferin (spanning from 1.58 μg/ml to 128 μg/ml) was added on the cells in serum-free DMEM or serum-free DMEM + TPCK-Trypsin 0.2 μg/ml for 24 hours. MTT reagent (Promega) was added on the cells for 3h at 37°C according to manufacturer instructions. Subsequently, the absorbance was read at 570 nm. Percentages of viability were calculated by comparing the absorbance in treated wells and untreated conditions.

It is reported that 15 is the less toxic compound and that the presence of trypsin affects the CC50, except for 6 (Figure 7).

Antiviral activity of δ-Viniferins against influenza A(H1N1)pdm09 virus in pre- incubation

Influenza A virus, at the multiplicity of infection (MOI) of 0.1 PFU/cell, was added to a dose range of 6, 11 or 14, spanning from 175 ng/ml to 14.2 μg/ml, or of 15 spanning from 527 ng/ml to 42.67 μg/ml. The mix virus + compounds was incubated in serum-free DMEM for 1 hour at 37°C and then inoculated for 1 hour at 37°C on a confluent layer of MDCK cells seeded in a 96 multiwell. The inoculum was then removed and the cells were overlaid with serum-free DMEM containing 1% penicillin/streptomycin. 12 hours post infection (hpi) at 37°C the number of infected cells was calculated by immunocytochemistry. Upon fixation in methanol the primary antibody (mouse monoclonal Influenza A anti -body 1:100 dilution, Chemicon®) was added for 1 hour at 37°C. The cells were then washed with DPBS/Tween 0.05% three times and the secondary antibody (Anti -mouse IgG, HRP -linked 1:500 dilution, Cell signaling technology) was added. After 1 hour the cells were washed and the DAB solution was added. Infected cells were counted and percentages of infection were calculated comparing the number of infected cells in treated and untreated conditions.

It is reported that all the molecules display similar antiviral effectiveness against influenza A(HlNl)pdm09 virus, in pre-incubation (Figure 8). Of note, their antiviral activity in dose- response is comparable to that of C11-6’ or CD1, virucidal antivirals able to inactivate extracellular viral particles. ¹⁵ ’ ¹⁶

Post-treatment of the δ-Viniferins against Influenza A pdm09 virus

Confluent layers of MDCK cells seeded in 96 multiwells were infected with a MOI of 0.01 PFU/cell of Influenza A virus in serum-free DMEM for lh at 37°C. One hour post infection the inoculum was removed and two concentrations of each d-Viniferin (1.5 ug/ml and 4.7 ug/ml) were added on the cells for 24h. Then the supernatant was collected and infectious virus yields were determined by Plaque Assay as the number of PFU/ml in MDCK cells.

It is reported that all the molecules display similar antiviral effectiveness against influenza A(HlNl)pdm09 virus, also when administered at 24 post infection (Figure 9).

Example 5:

Background:

The vanDelden/Kohler lab has an established track record in determining antibacterial activity, mode of action as well as elucidation of bacterial resistance mechanisms in Pseudomonas aeruginosa and in other Gram-negative bacteria. ^17-20 The group possesses a large collection of clinical isolates of P. aeruginosa and has access to clinical isolates of both Grampositive and Gram-negative bacteria from the Geneva University Hospitals (HUG, Geneva, Switzerland).

Three different assays were used to assess the anti -bacterial activity of small molecule libraries: (i) a growth inhibition assay based on optical density readings in a plate reader, allowing the screening of a large number of compounds in a microtiter plate format, (ii) determination of the minimal inhibitory concentration (MIC), a clinically relevant value, performed here on compounds showing growth inhibitory activities and (iii) killing assays to assess the bactericidal activity, determined by viable plate counting of the bacterium to be tested (colony forming units = CFU) upon exposure to test compounds.

Antibacterial activities of viniferins and their halogenated derivatives

The MICs of compounds 6, 11, 14 and 15 and their halogenated derivatives were determined. 6 showed anti -bacterial activity as determined by MIC determinations against the Gram positive methicillin-susceptible Staphylococcus aureus (MSS A) Newman strain and the methicillin-resistant (MRS A) COL strain (Table 4). 6 was also active (MIC = 16 mM) against Staphylococcus epidermidis (Table 4). None of the viniferins was active (MIC <= 32 μM) against the tested Gram-negative bacteria (Table 4). The compounds 11 and 14 showed 8-fold decreased MICs compared to 6 for the two S. aureus strains. Hence, the methoxy group containing 11 and 14 were more active than the hydroxyl containing 6.

Twenty-three halogenated viniferin compounds (Figure 8) were also tested by MIC determinations in the S. aureus strain Newman (Table 4). The activities of four halogenated derivatives were improved against this strain compared to the unmodified compound. These corresponded to the three chlorinated 14-derivatives (35, 36, 38) and the iodinated 14-derivative (40). The MICs of these compounds decreased by 2-4 fold, indicating increased activity compared to the unmodified viniferin compound (highlighted in bold in Table 4). Iodination of 6 also improved its activity (MIC of 4 μM for the halogenated compound compared to 32 μM for the original compound 6). However, halogenation did not confer activity on the 15- derivatives (Table 4).

It was concluded that halogenation may improve activity of 6, 11 and 14 depending on the type of halogen atom and its position on the viniferin scaffold.

Table 4. MIC values (mM) for Gram-positive and Gram-negative bacteria

Legend Example 6:

Synthesis of Viniferin Derivatives Synthesis of compound 11:

Key to the synthesis of 11 was a careful consideration of protecting groups. As such, the addition of arene lithium $4 to aldehydes such as $12 did not lead to the desired product if Piv, Ac or TIPS were employed as protecting groups for the phenol, as only decomposition of the starting material was observed in this case. On the other hand, when a MOM protecting group was used, addition to aldehyde $3 was successful and afforded the desired product in 79% yield. Benzylic oxidation was accomplished with Mn0 _2. After condensation with hydrazine, the corresponding hydrazone was oxidized in-situ to the diazo compound, which underwent Rh- catalyzed C-H insertion to afford the syn benzofruan $7. ²¹ ’ ²² At this stage, the MOM ether was readily cleaved by HC1 and the resulting phenol was isomerized to the anti benzofuran by treatment with base. After acylation $8 underwent Pd catalyzed heck coupling with styrene $9. The desired compound was finally obtained by treatment of $11 with KOH.

5-bromo-2-((4-(methoxymethoxy)benzyl)oxy)benzaldehyde ($3):

To a solution of 5-bromo-2-hydroxybenzaldehyde (2.10 g, 10.5 mmol) in DMF (25 mL) was added NaH (501 mg, 12.5 mmol, 1.2 equiv., 60 % in mineral oil) and stirred at rt for 30 min. Then, 1-(bromomethyl)-4-(methoxymethoxy)benzene (2.41 g, 10.5 mmol, 1 equiv.) in DMF (25 mL) was added and the mixture was allowed to stir overnight. The reaction was quenched by the addition of sat. aq. NH ₄ CI (50 ml) and extracted with Et ₂ 0 (3 x 50 mL). the combined organic layers were washed with NH ₄ CI (2 x 50 mL) and brine (50 mL) and dried over MgSO ₄ . The solvent was removed under reduced pressure and the crude residue was purified by column chromatography (SiO ₂ . Hexane:EtOAc = 9:1) to obtain the desired product (2.90 g, 8.26 mmol, 79%). 1H -NMR (400 MHz, CDCl ₃ ) δ 10.42 (s, 1H), 7.93 (d, J= 2.6 Hz, 1H), 7.60 (dd, J= 8.9, 2.6 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.07 (d, J= 8.7 Hz, 1H), 6.96 (d, J= 8.9 Hz, 1H), 5.19 (s, 2H), 5.11 (s, 2H), 3.49 (s, 3H).

¹³ C-NMR (100 MHZ, CDCh) d 188.5, 160.1, 157.6, 138.3, 131.1, 129.2, 128.9, 126.6, 116.6, 115.3, 113.9, 94.5, 70.8, 56.2.

IR (ATR, cm- ¹ ): 2953, 2896, 1682, 1589, 1512, 1478, 1406 1392, 1379, 1310, 1269, 1232, 1199, 1177, 1152, 1122, 1079, 996, 922, 883, 866, 812, 756, 651.

HRMS (ESI+, [M+Na] ⁺ ): m/z calculated for C ₁₆ H ₁₅ BrNa0 ₄ 373.0046; found: 373.0045.

(5-bromo-2-((4-(methoxymethoxy)benzyl)oxy)phenyl)(3,5-dim ethoxyphenyl)methanol

($5)

To a solution of 3,5-dimethoxybromobenzene (1.36 g, 6.26 mmol, 1.1 equiv.) in THF (27 mL) at -78 °C was added n- BuLi (3.74 mL, 5.98 mmol, 1.05 equiv., 1.6 M in hexane) and the resulting mixture was allowed to stir at that temperature for 1 h. Then, aldehyde $3 (2.00 g, 5.69 mmol, 1 equiv.) in THF (27 mL) was added and the mixture was allowed to reach room temperature overnight. The reaction was cooled to 0 °C diluted with Et ₂ 0 and quenched by the addition of ice/aq. sat. NH ₄ CI. The mixture was extracted with Et ₂ 0 (3 x 50 ml), the combined organic layers were washed with brine (50 mL) and dried over MgSCh. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography (S1O2, hexane:EtOAc = 4:1) to afford the pure product (2.38 g, 4.86 mmol, 85%). ¹ H-NMR (400 MHz, CDCh) d 7.51 (dd, J= 2.5, 0.6 Hz, 1H), 7.33 (dd, J= 8.7, 2.5 Hz, 1H), 7.16 - 7.09 (m, 2H), 7.04 - 6.94 (m, 2H), 6.79 (d, J= 8.7 Hz, 1H), 6.49 (dd, J= 2.3, 0.7 Hz, 2H), 6.37 (t, J= 2.3 Hz, 1H), 5.91 (d, J= 4.6 Hz, 1H), 5.17 (s, 2H), 4.92 (s, 2H), 3.71 (s, 6H), 3.48 (s, 3H), 2.81 (d, J= 5.4 Hz, 1H).

¹³ C-NMR (100 MHZ, CDCh) d 160.9, 157.3, 154.8, 145.5, 134.4, 131.4, 130.6, 129.5, 129.3, 116.4, 113.9, 113.6, 104.7, 99.6, 94.5, 71.8, 70.3, 56.1, 55.4.

IR (ATR, cm ^"1 ): 3465,2998, 2936, 2901, 2837, 1607, 1596, 1512, 1481, 1463, 1428, 1405, 1379, 1341, 1310, 1291, 1277, 1232, 1202, 1173, 1151, 1124, 1078, 1067, 999, 923, 830, 759, 749, 705, 691, 649, 617.

HRMS (ESI+, [M+Na] ⁺ ): m/z calculated for C ₂₄ H ₂₅ BrNaO ₆ 511.0727; found: 511.0722.

(5-bromo-2-((4-(methoxymethoxy)benzyl)oxy)phenyl)(3,5-dim ethoxyphenyl)methanone

($6):

To benzylic alcohol $5 (1.10 g, 2.25 mmol) in CH2CI2 (22 mL) was added MnCh (3.91 g, 45 mmol, 20 equiv.) and the resulting suspension was allowed to stir overnight. Then the reaction mixture was filtered trough a pad of Celite®, the solvent was evaporated and the residue was purified by column chromatography (S1O2, hexane:EtOAc = 4:1) to afford the desired product (912 mg, 1.87 mmol, 83%).

Ή-NMR (400 MHz, CDCl ₃ ) δ 7.54 - 7.44 (m, 2H), 6.98 (d, J= 8.6 Hz, 2H), 6.94 - 6.85 (m, 5H), 6.66 (t, J= 2.3 Hz, 1H), 5.14 (s, 2H), 4.93 (s, 2H), 3.79 (s, 7H), 3.46 (s, 3H).

¹³ C-NMR (100 MHZ, CDCh) d 194.8, 160.9, 157.1, 155.5, 139.8, 134.5, 132.1, 131.4, 129.4, 128.6, 116.3, 115.0, 113.3, 107.6, 105.7, 94.5, 70.4, 56.1, 55.7.

IR (ATR, cm- ¹ ): 3000, 2938, 2900, 2838, 1670, 1590, 1512, 1479, 1459, 1426, 1396, 1351, 1318, 1302, 1271, 1233, 1204, 1174, 1154, 1112, 1078, 1065, 996, 924, 846, 825, 774, 717, 672, 639, 620.

HRMS (ESI+, [M+Na] ⁺ ): m/z calculated for C ₂₄ H ₂₃ BrO ₆ : 509.0570; found: 509.0570.

(2S*,3R* )-5-bromo-3-(3,5-dimethoxyphenyl)-2-(4-(methoxymethoxy)pheny l)-2,3- dihydrobenzofuran ($7):

To ketone $6 (1.50 g, 3.08 mmol, 1 equiv.) in EtOH (31 mL) was added hydrazine hydrate (1.49 mL, 30.8 mmol, 10 equiv.) and acetic acid (1.76 ml, 30.8 mmol, 10 equiv.) and the resulting mixture was heated to reflux overnight. Then, the volatiles were removed under reduced pressure and the residue was dissolved in EtOAc. Water was added, the phases were separated and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with 1 M HC1 (2 x 10 mL), aq. sat. NaHC0 ₃ (2 x 10 ml) followed by brine and dried over MgS0 ₄ . The solvent was evaporated under pressure. The residue was dissolved in CH2CI2 (200 L) and the flask was wrapped in aluminum foil. To the stirred solution was added Rh ₂ (OAc) ₄ (13.3 mg, 0.0300 mmol, 1 mol%) followed by Mn0 ₂ (3.91 g, 45.0 mmol, 15 equiv.) and stirring was continued for 16 h at room temperature. The reaction mixture was filtered trough a pad of Celite® and the solvent was removed under reduced pressure. Purification by column chromatograph (S1O2, hexane:CH2Ch:EtOAc = 92:4:4) gave the desired product (750 mg, 1.59 mmol, 53%). 1H NMR (400 MHz, CDCl ₃ ) d 7.34 (ddd, J= 8.5, 2.2, 0.7 Hz, 1H), 7.20 (dd, J= 2.3, 1.0 Hz, 1H), 6.97 - 6.91 (m, 2H), 6.88 (d, J= 8.5 Hz, 1H), 6.83 - 6.74 (m, 2H), 6.15 (t, J= 2.3 Hz, 1H), 5.96 (d, J= 8.9 Hz, 1H), 5.83 (d, J= 2.3 Hz, 2H), 5.08 (s, 2H), 4.75 (d, J= 8.9 Hz, 1H), 3.57 (s, 6H), 3.41 (s, 3H).

¹³ C-NMR (101 MHz, CDCl ₃ ) d 160.4, 159.5, 156.7, 140.6, 132.6, 131.8, 130.5, 129.1, 127.8, 115.7, 113.2, 111.5, 107.7, 99.1, 94.5, 89.0, 56.0, 55.3, 54.0.

IR (ATR, cm ^_1 ):2998, 2953, 2935, 2899, 2788, 2836, 2788, 1605, 1594, 1511, 1467, 1429, 1346, 1330, 1306, 1291, 1258, 1230, 1202, 1150, 1109, 1066, 990, 970, 921, 859, 811, 784, 760, 731, 691, 669, 656, 613.

HRMS (ESI+, [M+H] ⁺ ): m/z calculated for C ₂₄ H ₂₄ BrO ₅ 471.0802; found: 471.0801. 4-((2R* ,3R* )-5-bromo-3-(3,5-dimethoxyphenyl)-2,3-dihydrobenzofuran-2-yl )phenyl acetate ($8):

To $7 (200 mg, 0.424 mmol, 1 equiv.) in a mixture of MeOH and THF (4 ml, 1:1, v:v) was added HC1 (4 M in dioxane, 530 μL, and the mixture was hated to 60 °C for 10 min. The reaction was quenched by the addition of aq. sat. NaHCCh and extracted with EtOAc (3 x 10 mL). The solvent was removed under reduced pressure. The residue was taken up in MeOH (4 ml), Na ₂ CO ₃ (180 mg, 4 equiv.) was added, and the resulting suspension was stirred room temperature for 2 h. Then, the mixture was acidified with 1 M HC1 and extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine and dried over NaS0 ₄ . The solvent was removed under reduced pressure and the residue was taken up in CH2CI2 (4 mL). DMAP (205 mg, 1.68 mmol, 4 equiv.). followed by AC2O (119 μL, 1.26 mmol, 3 equiv.) was added at 0 °C and the reaction was allowed to stir for 16 h, gradually warming to room temperature. Then, HC1 was added, and the mixture was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were washed with 1 M aq. HC1 (10 mL) followed by brine (10 ml) and dried over MgSO ₄ . The solvent was evaporated and the residue purified by flash column chromatography (S1O2, hexanes:CH ₂ Cl ₂ :EtOAc = 8:1:1) to afford the title compound as a colorless oil (153 mg, 0.326 mmol, 78%). 1H NMR (400 MHz, CDCl) ₃ d 7.38 - 7.28 (m, 3H), 7.14 - 7.03 (m, 3H), 6.84 (d, J = 8.5 Hz, 1H), 6.41 (t, J= 2.3 Hz, 1H), 6.31 (d, J= 2.3 Hz, 2H), 5.60 (d, 7= 8.1 Hz, 1H), 4.44 (dt, J= 8.0, 1.0 Hz, 1H), 3.76 (s, 6H), 2.30 (s, 3H).

¹³ C-NMR (101 MHz, CDCl ₃ ) d 169.4, 161.4, 158.8, 150.7, 143.4, 138.1, 132.4, 131.8, 128.3, 126.9, 121.9, 113.2, 111.3, 106.4, 99.3, 92.5, 58.0, 55.5, 21.2.

IR (ATR, cm ^-1 ): 3000 2938 2904, 2838, 1768, 1735, 1594, 1508, 1468, 1257, 1190, 1155, 1114, 1065, 1052, 1010, 984, 941, 910, 874, 836, 810, 745, 727, 692, 675, 61, 634, 594, 548, 518, 436.

HRMS (ESI+, [M+H] ⁺ ): m/z calculated for C ₂₄ H ₂₁ BrO ₅ : 469.0645; found: 469.0638

5-((E)-2-((2R* ,3R* )-2-(4-acetoxyphenyl)-3-(3,5-dimethoxyphenyl)-2,3- dihydrobenzofuran-5-yl)vinyl)-l,3-phenylene diacetate ($11):

A 10 ml Schlenk tube was charged with bromide $8 (103 mg, 0.219 mmol, 1 equiv.), $9 (97.0 mg, 0.439 mmol, 2 equiv.) and, $10 (10.3 mg, 0.0160 mmol, 10 mol%). DMF (4 mL) was added followed by DIPEA (153 μL, 0.636 mmol, 4 equiv.). The mixture was heated to 140 °C for 16 h. Then, aq. sat. NH ₄ Cl was added and the aqueous phase was extracted with Et ₂ 0 (3 x 10 mL). The combined organic layers were washed with 1 N HC1 (10 mL) and brine (10 mL) and dried over MgSCri. The solvent was removed, and the residue purified by column chromatography (SiO ₂ , hexanes:CH ₂ Cl ₂ :EtOAc ₃ = 6 :2:2) to afford the desired product (84.0 mg, 0.138 mmol, 63%) 1H NMR (400 MHz, CDCl) ₃ d 7.40 - 7.32 (m, 3H), 7.17 (s(br), 1H), 7.12 - 7.07 (m, 2H), 7.09 (d, 7 = 8.6 Hz, 2H), 7.00 (d, 7 = 16.2 Hz, 1H), 6.94 (d, 7 = 8.3 Hz, 1H), 6.82 (d, 7 = 16.2 Hz, 1H), 6.78 (t, 7= 2.1 Hz, 1H), 6.42 (t, 7= 2.3 Hz, 1H), 6.35 (d, 7= 2.3 Hz, 3H), 5.61 (d, 7= 8.0 Hz, 1H), 4.47 (d, 7= 8.0 Hz, 1H), 3.76 (s, 6H), 2.30 (s, 3H), 2.29 (s, 6H).

¹³ C-NMR (101 MHz, CDCl ₃ ) d d 169.5, 169.1, 161.3, 160.0, 151.4, 150.7, 143.9, 140.1, 138.4, 130.8, 130.6, 130.5, 128.4, 127.0, 124.7, 123.4, 121.9, 116.7, 113.9, 109.9,

106.5, 99.3, 92.5, 57.9, 55.5, 21.2, 21.2.

IR (ATR, cm ^"1 ): 3005, 2936, 2840, 1765, 1603, 1593, 1507, 1487, 1462, 1430, 1368, 1298, 1276, 1192, 1154, 1122, 1065, 1020, 1001, 984, 962, 909, 841, 812, 731, 696, 677, 649, 595, 562.

HRMS (ESI+, [M+H] ⁺ ): m/z calculated for C36H33O9: 609.2119; found: 609.2112. 5-((E)-2-((2R* ,3R* )-3-(3,5-dimethoxyphenyl)-2-(4-hydroxyphenyl)-2,3- dihydrobenzofuran-5-yl)vinyl)benzene-l,3-diol (14):

A solution of $11 (40.0 mg, 0.0660 mmol, 1 equiv) in MeOH (6 mL) was cooled to 0 °C, KOH (36.9 mg, 0.657 mmol, 10 equiv.) was added and the solution was allowed to stir for 10 min at

0°C. The cooling bath was removed, and the reaction was allowed to stir for lh at room temperature. The reaction mixture was acidified with 1 M HC1 and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 ml) and dried over NaiSCL and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (SiO ₂ , CH2CI2: acetone = 9:1) to afford the title compound (16.0 mg, 0.0330 mmol. 50%). 1H NMR (500 MHz, DMSO-d ₆ ) d 7.42 (dd, J= 8.5, 1.5 Hz, 1H), 7.25 - 7.13 (m, 3H), 6.97 (d, J= 16.4 Hz, 1H), 6.90 (d, J= 8.3 Hz, 1H), 6.82 (d, J= 16.4 Hz, 1H), 6.76 (d, J= 8.6 Hz, 2H), 6.43 (t, J= 2.3 Hz, 1H), 6.36 (m, 4H), 6.11 (t, 7= 2.1 Hz, 1H), 5.56 (d, 7 = 8.2 Hz, 1H), 4.58 (d, 7= 8.1 Hz, 1H), 3.70 (s, 6H).

¹³ C-NMR (126 MHz, DMSO-7;) d 160.7, 158.7, 158.5, 157.6, 143.8, 139.1, 131.2, 130.4, 130.1, 127.8, 127.8, 127.7, 126.3, 122.7, 115.3, 109.4, 106.2, 104.4, 101.9, 98.5, 92.0, 55.7, 55.1.

IR (ATR, cm ^_1 ):3392, 2938, 1596, 1516, 1487, 1346, 1234, 1204, 1152, 1107, 1065, 989, 960, 832, 689, 542.

HRMS (ESI+, [M+H] ⁺ ): m/z calculated for C ₃₀ H ₂₇ O ₆ : 483.182; found: 483.1798.

Synthesis of 14 Key to the synthesis of 14 was Pd-catalyzed coupling of benzofuran $14. ^[1,2] to styrene $15. Deprotection of $16 with KOH afforded the desired compound.

5-((2R* ,3R* )-2-(4-acetoxyphenyl)-5-((E)-3,5-dimethoxystyryl)-2,3-dihydr obenzofuran-3- yl)-l,3-phenylene diacetate ($16):

A 5 ml vial was charged with $ 14 ^[1 ’ ^2] (200 mg, 0.381 mmol, 1 equiv.), $15 (71.4 mg, 0.761 mmol, 2 equiv.) , $10 (35.7 mg, 0.0381 mmol, 10 mol%) and DMF (7 mL) was added followed by DIPEA (111 μL, 0.636 mmol, 4 equiv). The mixture was heated to 140 °C for 16 h. Then, aq. sat. NH ₄ Cl was added and the aqueous phase was extracted with Et ₂ 0 (3 x 10 mL). The combined organic layers were washed with 1 N HC1 (10 mL), aq. sat. NH ₄ Cl (10 mL) and brine (10 mL) and dried over MgSO ₄ . The solvent was removed, and the residue purified by column chromatography (SiO ₂ , SiO ₂ , hexanes:CH ₂ Cl2EtOAc = 6:2:2) to afford the desired product (168 mg, 0.276 mmol, 72%). 1H NMR (400 MHz, CDCl ₃ ) d 7.45 - 7.38 (m, 1H), 7.35 (d, J= 8.5 Hz, 2H), 7.23 (t, J = 1.5 Hz, 1H), 7.11 (d, J= 8.6 Hz, 2H), 7.03 (d, J= 16.2 Hz, 1H), 6.97 - 6.93 (m, 2H), 6.88 (d, 7= 16.3 Hz, 1H), 6.84 (d, J= 2.0 Hz, 1H), 6.64 (d, J= 2.3 Hz, 2H), 6.37 (t, J= 2.2 Hz, 1H), 5.55 (d, J= 8.0 Hz, 1H), 4.55 (d, J= 7.9 Hz, 1H), 3.81 (s, 6H), 2.30 (s, 3H), 2.27 (s, 6H).

¹³ C-NMR d 169.4, 168.9, 161.0, 159.7, 151.4, 150.7, 143.9, 139.6, 137.8, 131.2, 129.7, 128.7, 128.3, 126.9, 126.7, 123.3, 121.9, 118.9, 114.8, 110.0, 104.3, 99.9, 92.4, 57.4, 55.4, 21.1, 21 1

IR (ATR, cm- ¹ ): 3003, 2938, 2838, 1765, 1589, 1507, 1487, 1455, 1425, 1368, 1323,1299,1283, 1264, 1189, 1164, 1152, 1125, 1054, 1019, 965, 909, 829, 734, 684, 628, 594, 525, 465, 434.

HRMS (ESI+, [M+H] ⁺ ): m/z calculated for C ₃₆ H ₃₃ O ₉ : 609.2119; found: 609.2120.

5-((2R* ,3R* )-5-((E)-3,5-dimethoxystyryl)-2-(4-hydroxyphenyl)-2,3-dihydr obenzofuran- 3-yl)benzene-1,3-diol (14): A solution of $16 (70.0 mg, 0.115 mmol, 1 equiv.) in MeOH (15 mL) was cooled to 0 °C, KOH (38.7 mg, 0.690 mmol, 6 equiv) was added and the solution was allowed to stir for lh at 0°C . The reaction mixture was acidified with 1 N HC1 and extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine and dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (SiO ₂ , CH ₂ CI ₂ : acetone = 9:1) to afford the title compound (52.3 mg, 0.108 mmol, 94%). 1H NMR (500 MHz, DMSO-d ₆ ) d 7.44 (dd, J = 8.1, 1.9 Hz, 1H), 7.25 - 7.20 (m, 2H), 7.18 (d, J= 8.6 Hz, 2H), 6.96 (d, J= 16.4 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.76 - 6.72 (m, 4H), 5.40 (d, J= 8.4 Hz, 1H), 4.45 (d, J= 8.3 Hz, 1H), 3.75 (s, 6H).

¹³ C-NMR (126 MHz, DMSO-d ₆ ) d 160.6, 159.0, 158.8, 157.6, 143.5, 139.5, 131.5, 130.3, 130.2, 128.8, 127.9, 127.6, 125.6, 123.0, 115.4, 109.3, 106.0, 104.1, 101.4, 99.5, 92.7, 55.7, 55.1. IR (ATR, cm- ¹ ): 3381, 3025, 2927, 2852, 1593, 1516, 1487, 1455, 1344, 1300, 1235, 1203, 1150, 1107, 1064, 998, 960, 924, 831, 751, 691, 600, 543, 501, 425, 414. 408.

HRMS (ESI+, [M+H] ⁺ ): m/z calculated for C ₃₀ H ₂₇ O ₆ : 483.1802; found: 483.1792.

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