RELATED APPLICATIONS [0001] This application relates to and claims priority to U.S. Provisional Patent Application

No. 61/336,834, which was filed January 27, 2010, U.S. Provisional Patent Application No. 61/268,652, which was filed June 10, 2009; U.S. Provisional Patent Application No. 61/268,651, which was filed June 9, 2009; U.S. Provisional Patent Application No. 61/268,653, which was filed June 9, 2009; and U.S. Provisional Patent Application No. 61/268,654, which was also filed June 9, 2009. All of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

A. Field of the Invention

[0002] The present invention relates to 8-pentafluorosulfanyl analogs of mefloquine. The present invention also discloses new quinoline methanol derivatives of mefloquine, including compounds wherein the trifluoromethyl group found at the 8-position of the quinoline ring has been replaced with a pentafluorosulfanyl group at the same position and the piperidine ring has been replaced by non-piperidine functional groups at the 4-position.

[0003] Further disclosed by the present invention are novel intermediate compounds used for making the 8-pentafluorosulfanyl analogs of mefloquine and 8-position pentafluorosulfanyl quinoline methanol derivatives. Methods of making and using these compounds in the treatment or prevention of malaria, microbial, parasitic, protozoan, bacterial, and fungal diseases and conditions, as well as, methods of making and using the intermediate compounds are also disclosed.

B. Description of the Related Art [0004] Commercially available quinoline methanols, such as mefloquine, have considerable clinical utility as antimalarials due to their potency against chloroquine-resistant parasites (i.e. Plasmodium, falciparum), oral bioavailability, and long plasma half-lives. Mefloquine has also shown effectiveness as an antimicrobial, antiparasitic, antiprotozoan, antibacterial, and antifungal agent. But, mefloquine is not without its adverse side effects. [0005] Among subjects who received mefloquine for treatment, the most frequently observed adverse experiences included: dizziness, myalgia, nausea, fever, headache, vomiting, chills, diarrhea, skin rash, abdominal pain, fatigue, loss of appetite, and tinnitus. Those side effects occurring in less than 1% included bradycardia, hair loss, emotional problems, pruritus, asthenia, transient emotional disturbances and telogen effluvium (loss of resting hair). Seizures have also been reported.

[0006] Among subjects who received mefloquine for prophylaxis of malaria, the most frequently observed adverse experience was vomiting (3%). Dizziness, syncope, extrasystoles and other complaints affecting less than 1 % were also reported. But, because these experiences are reported voluntarily from a population of uncertain size, it is likely that their frequency is under reported.

[0007] Mefloquine is associated with severe depression, anxiety, paranoia, aggression, nightmares, insomnia, seizures, birth defects, peripheral motor-sensory neuropathy, vestibular (balance) damage, and various central nervous system problems. Effects to the central nervous system (CNS) are permanent.

[0008] The most frequently observed laboratory alterations possibly attributable to administration of mefloquine were decreased hematocrit, transient elevation of transaminases, leukopenia and thrombocytopenia. These alterations were observed in patients with acute malaria who received treatment doses of the drug and were attributed to the disease itself. During prophylactic administration of mefloquine to indigenous populations in malaria-endemic areas, the following occasional alterations in laboratory values were observed: transient elevation of transaminases, leukocytosis or thrombocytopenia.

[0009] Mefloquine is known to cross the blood-brain barrier and accumulate as much as

30-fold in the CNS. It acts as a blood schizonticide, but the exact mechanism(s) of action of mefloquine is unknown. The adverse effects of mefloquine presumably occur because it crosses the blood-brain barrier and accumulates in the CNS where it is known to interact with numerous neurological targets. Therefore, a potential way to eliminate the poor CNS tolerability of mefloquine is to limit its passage across the blood-brain barrier and its accumulation in the brain. [0010] In addition to the aforementioned adverse effects of mefloquine, resistance by

Plasmodium spp., the parasites responsible for malaria, to mefloquine is becoming more prevalent. Further, mefloquine is relatively expensive compared to other antimalarials. As a result, the clinical utility of mefloquine is limited. New compounds are. needed. [0011] The present invention describes 8-pentafluorosulfanyl analogs of mefloquine, as well as quinoline methanol derivatives, including 8-pentafluorosulfanyl quinoline methanol derivatives, which compounds offer an improved therapeutic index relative to mefloquine. It has especially been observed that placement of a pentafluorosulfanyl moiety at the 8-position of the quinoline ring results in compounds that penetrate the blood-brain barrier at reduced rate yet still retain the same, or even improved, therapeutic efficacy as mefloquine. Accordingly, these new analogs and derivatives of mefloquine will be more clinically useful than mefloquine because they have the suitable structures and physiochemical properties that maintain or improve their therapeutic activity, but limit their exposure to the CNS.

SUMMARY OF THE INVENTION [0012] The present invention provides therapeutic compositions that comprise new pentafluorosulfanyl analogs of mefloquine, as well as, therapeutic compositions that comprise new quinoline methanol derivatives derived from modification of the mefloquine skeleton that have a pentafluorosulfanyl moiety. As compared to mefloquine, these new analogs and derivatives are more useful pharmacological agents, alone or in combination, for the prevention or treatment of malaria, or other microbial, parasitic, protozoan, bacterial and fungal diseases, because they are less able to cross the blood-brain barrier yet have equal or better therapeutic activity.

[0013] The invention relates to 8-pentafluorosulfanyl analogs of mefloquine, methods of making the analogs, and methods of using them. The invention also provides a modification of the mefloquine scaffold through the switching of the 8-position trifluoromethyl moiety (CF ₃ ) to a novel pentafluorosulfanyl moiety (SF ₅ ) at the 8-position of the quinoline ring. This modification results in improved activity as compared to mefloquine. These new derivative analogs are more potent and efficacious than similar CF ₃ substituted quinoline analogs as described herein. It is expected that the combination of this SF5 moiety, or use of a similar large electron withdrawing group, at the 8-position in a mefloquine derivative will impart greater intrinsic potency and efficacy as compared to mefloquine when combined with other substituents elsewhere on the molecule.

[0014] The present invention also discloses therapeutic compositions that comprise new quinoline methanol derivatives derived from modification of the mefloquine skeleton that have a pentafluorosulfanyl moiety (SF5) at the 8-position of the quinoline ring rather than a trifluoromethyl moiety (CF3), and a non-piperidine functional group at the 4-position rather than a piperidine ring. These new derivatives are generically referred to herein as either 8-position pentafluorosulfanyl quinoline methanol derivatives or 8-pentafluorosulfanyl quinoline methanol derivatives. As compared to mefloquine, the combination of the 8-position pentafluorosulfanyl moiety when combined with other substituents elsewhere on the molecule (i.e. the 4-position) will impart greater intrinsic potency and efficacy with improved tolerability. The 8- pentafluorosulfanyl analog of mefloquine and the 8-pentafluorosulfanyl quinoline methanol derivatives identified herein are more useful pharmacological agents, alone or in combination, for the prevention and/or treatment of malaria, or other microbial, parasitic, protozoan, bacterial and fungal diseases than mefloquine because they are less able to cross the blood-brain barrier yet have equal or better therapeutic activity. Other possible applications include, but are not limited to, preventing and/or reducing the severity of certain immunological indications. Preferably, the severity of at least one indication is reduced by at least 10%, more preferably by 20%, 30%, 40%, 50%, or even more preferably by 60%, 70%, 80%, 90%, or more as compared to an untreated, similarly infected subject.

[0015] The novel compounds described herein may be employed in pharmaceutical compositions. The compositions may comprise an effective amount of one or more of these compounds, and optionally a pharmaceutically acceptable carrier known in the art. The effective amount of these compounds will vary based upon the use for which the composition is intended. The pharmaceutical compositions within the scope of the present invention may be administered to a patient via any suitable, conventional route of administration known in the art - i.e. oral, intravenous, etc. [0016] The quinoline methanol derivatives of the present invention are represented by

Formula I

Formula I wherein, X is an oxygen atom, a sulfur atom, a carbon atom or a nitrogen atom. R is a hydrogen atom, a side chain containing heterocycle, a straight chain alkyl group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, a cyclic alkyl group containing a nitrogen atom, a cyclic amine, a cyclic chain alkyl group containing one or more heteroatoms, an aryl group, or a straight chain alkyl group containing one or more heteroatoms. Alternatively, R may represent two substituents, Ri and R ₂ . Ri is a hydrogen atom, a side chain containing heterocycle, a straight chain alkyl group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, a cyclic alkyl group containing a nitrogen atom, a cyclic amine, an imidazole, or a triazole; R ₂ is a hydrogen atom, a straight chain group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, a cyclic alkyl group containing a nitrogen atom, a cyclic amine, an imidazole, or a triazole. Ri and R ₂ may or may not be the same and may or may not be joined to each other to form a cyclic amine, aryl group, or heterocycle. [0017] Exemplary pentafluorosulfanyl analogs or and associated derivatives of the invention (including enantiomers, diastereomers, racemates, or pharmaceutically acceptable salts thereof) are represented in FIGs. 25, 26, 30, and 34. Exemplary quinoline methanol compounds of the invention that can be combined to include a pentafluorosulfanyl moiety are presented in Tables 1-3 herein. It will be understood in the art that the invention is not limited to the exemplary compounds herein but includes other compounds that are represented by Formula I and are not previously known in the art as having a therapeutic use as described herein.

[0018] In certain quinoline methanol compounds of the invention, the Ri and R ₂ groups are joined directly or through linking atoms to form a substituted imidazole ring, unsubstituted imidazole ring, substituted triazole ring, or unsubstituted triazole ring. In other quinoline methanol compounds of the invention, the Ri and R ₂ groups are joined directly or through linking atoms to form a substituted or unsubstituted cyclic amine.

[0019] The therapeutic compositions of the invention comprise a pharmaceutically- acceptable carrier, adjuvant, or combination thereof, and at least one quinoline methanol compound as represented by Formula I and having a calculated log ratio of brain:blood concentration (cLogBB) that is less than the cLogBB of mefloquine as determined by cLogBB =

(0.205*LogP) - (0.0094*PSA) - (0.055*FRBs) + 0.18 in a similarly treated subject. LogP is the partition coefficient reflecting the relative solubility in octanol versus water; PSA is the polar surface area of a molecule; and FRB is the number of freely rotatable bonds in a molecule.

[0020] A quinoline methanol compound of the invention exhibits an in vitro permeability across the blood-brain barrier that is less than 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or even 50% of the relative rate of mefloquine under similar conditions in vitro. Preferably, the quinoline methanol compounds exhibits an in vitro permeability across the blood- brain barrier that is less than 80% of the relative rate of mefloquine.

[0021] In another aspect, a quinoline methanol compound of the invention exhibits an in vivo total or free brain concentration that is less than 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or even 50% of the relative concentration of mefloquine under similar conditions in vivo. Preferably, the quinoline methanol compounds exhibits an in vivo total or free brain [0022] The present invention further discloses quinoline methanol derivatives represented by Formula II.

Formula II In Formula II, ( )„ represents one, two, or more carbon atoms; Ri is a hydrogen atom, a straight chain alkyl group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, or a cyclic alkyl group containing a nitrogen atom; R ₂ is a hydrogen atom, a straight chain group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, or a cyclic alkyl group containing a nitrogen atom; and R ₃ represents at least one substitution at the 8-position of the quinoline ring, wherein the substitution is selected from the group consisting of a trifluoromethyl group, an OH group, an oxygen atom, a hydrogen atom, or a combination thereof. Preferably, a trifluoromethyl group is at position 8. Optionally, a trifluoromethyl group is at position 8 and position 6 or 7; or a trifluoromethyl group is present at positions 6, 7, and 8. [0023] Notably, when ( ) _n represents one carbon atom then neither Ri nor R ₂ are selected from the group consisting of hydrogen, methyl, ethyl, propel, butyl, hydroxyl, cyclopropyl, CH ₂ - CHOH-CH ₂ -CH ₃ , CH ₂ -CH ₂ -CHOH-CH ₃ , CH ₂ -CH ₂ -CH ₂ -CH ₂ OH, CH ₂ OH, and CH ₂ -CH ₂ - COOH. In quinoline methanol compounds where ( )„ represents two or more carbon atoms either Ri or R ₂ may be selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, hydroxy, cyclopropyl, CH ₂ -CHOH-CH ₂ -CH ₃ , CH ₂ -CH ₂ -CHOH-CH ₃ , CH ₂ -CH ₂ -CH ₂ - CH ₂ OH, CH ₂ OH, CH ₂ -CH ₂ -COOH, other straight chain alkyl groups, cyclic alkyl groups, straight chain alkyl groups containing a nitrogen atom, or cyclic alkyl groups containing a nitrogen atom.

[0024] For these therapeutic compounds, a calculated log ratio of brain:blood concentration (cLogBB) of the quinoline methanol compound is less than a cLogBB of mefloquine as determined by cLogBB = (0.205*LogP) - (0.0094*PSA) - (0.055*FRBs) + 0.18, where LogP is the partition coefficient reflecting the relative solubility in octanol versus water; PSA is the polar surface area of a molecule; and FRB is the number of freely rotatable bonds in a molecule, such that the therapeutic composition exhibits in vitro permeability across a blood-brain barrier at less than 90% of the relative rate of mefloquine in vitro, or exhibits in vivo total or free brain concentrations at less than 90% of the relative concentration of mefloquine in vivo.

[0025] The compounds of the present invention alleviate at least one indication of neurotoxicity and improve therapeutic activity, while retaining the desirable properties of a practical and useful pharmacological agent. These principles are broadly applicable to the treatment and prevention of any of a variety of conditions including infectious disease or immunological disease against which mefloquine can be applied. Thus, the present invention provides mefloquine analog compounds and methods for identifying and making these less neurotoxic mefloquine analogs that also retain the properties of useful drug substances for the treatment of a variety of diseases and conditions. [0026] Quinoline methanol compounds and therapeutic compositions of the present invention may be included in a pharmaceutical preparation that is administered to a subject by at least one mode selected from the group consisting of oral, topical, parenteral, subcutaneous, intramuscular, intradermal, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, and transdermal. Preferred routes of administration include oral, topical, parenteral, subcutaneous, or intramuscular. Depending on the desired duration and effectiveness of the therapy, the compositions according to the invention may be administered once or several times, also intermittently, for instance on a daily or weekly basis for several days, weeks, or months in different dosages and by a combination of different routes.

[0027] The present invention further relates to methods of making therapeutic compositions and quinoline methanol compounds that are less neurotoxic than mefloquine as well as being efficacious as antimalarials, antimicrobials, antiparasitics, antiprotozoans, antibacterials, or antifungals. Preferably, these compounds may be utilized as preventative measures against or as treatment for malaria or other diseases, infections, or infectious agents.

The methods of making the quinoline methanol compounds employ novel intermediate compounds. While the intermediate compounds described in the present invention are useful in making compounds for preventing and/or treating malaria, other infectious diseases or immunological conditions, one of skill in the art will recognize that these novel intermediates may be employed in various other chemical syntheses so as not to be limited to the purpose for which they are employed in the present invention. Methods of making these novel intermediate compounds are further described herein. [0028] The invention further provides methods of using the described therapeutic compositions to treat, reduce, or prevent diseases or conditions associated with infection by microbes, parasites, preferably Plasmodium spp., protozoans, bacteria, or fungi. The therapeutic compositions may be used alone, in combination with one another, or in combination with other therapies or compositions.

[0029] In another aspect, the invention provides a method of treating (e.g. curing, suppressing, ameliorating, delaying or preventing the onset of, or preventing recurrence or relapse of) or preventing a microbial, parasitic, protozoan, bacterial, or fungal associated disease or condition in a subject. The method includes: administering to a subject a quinoline methanol compound of the invention in an effective amount sufficient to reduce the severity of at least one indication of disease or condition as compared to an untreated, similarly infected subject or prevent the disease or condition. The quinoline methanol compound or derivative can be administered to the subject alone or in combination with other therapeutic modalities.

[0030] The invention provides a method of reducing the incidence of or severity of a clinical sign associated with a microbial, parasitic (preferably malaria, more preferably a

Plasmodium falciparum infection), protozoan, bacterial, or fungal associated disease or condition, comprising the step of administering a therapeutic composition of the invention such that the incidence of or the severity of a clinical sign of malaria is reduced by at least 10%, preferably by 15%, 20%, 25%, 30%, 35%, 40% 45%, 50% or more, relative to a similarly infected, untreated subject. Such clinical signs include fever, chills, sweats, headaches, muscle pains, nausea, vomiting, elevated temperature, perspiration, tiredness, confusion, coma, neurologic focal signs, severe anemia, and respiratory difficulties.

[0031] The invention also provides kits for administering a therapeutic composition of the invention comprising a set of printed instructions; a dispenser capable of administering a therapeutic composition to a subject; and at least one quinoline methanol compound of the invention that is therapeutically effective against at least one clinical sign associated with a microbial, parasitic (preferably malaria, more preferably a Plasmodium falciparum infection), protozoan, bacterial, or fungal associated disease or condition. Kits of the invention may further comprise a physiologically acceptable vehicle, carrier molecule, adjuvant, or combination thereof. A quinoline methanol compound of the invention and a physiologically acceptable vehicle, carrier molecule, adjuvant, or combination may be supplied in the kit either separately or in a premixed combination.

[0032] In another aspect, the invention provides novel intermediate compounds discovered during the synthesis of the 8-pentafluorosulfanyl analogs of the present invention, which compounds are represented in FIG. 31 (i.e. compounds 7, 12, 12a, 13, and 13a). Specifically, compound 7 is represented by Formula III:

Formula III [0033] Specifically, compound 12 is represented by Formula IV:

Formula FV

[0034] Specifically, compound 12a is represented by Formula V:

Formula V

[0035] Specifically, compound 13 is represented by Formula VI:

Formula VI

[0036] Specifically, compound 13a is represented by Formula VII:

[0037] The method for making the novel intermediate compounds of Formula III- VII is further detailed herein.

[0038] As used herein, the term "effective amount" refers to the amount of a therapy which is sufficient to reduce or ameliorate the severity or duration of a disease or disorder, or one or more symptoms thereof, prevent the advancement of a disease or disorder, cause the regression of a disease or disorder, prevent the recurrence, development, onset, or progression of one or more symptoms associated with a disease or disorder, or enhance or improve the prophylaxis or treatment of another therapy or therapeutic agent.

[0039] Herein, a "subject" is a mammal, preferably a human, in need of either prophylactic or treatment for a microbial, parasitic, protozoan, bacterial, or fungal associated infection, disease, or condition, or disease associated with prions. [0040] Herein, a "combination" may include one or more of the quinoline methanol derivatives of the present invention provided together or separately to a subject. Such combinations may also include other known therapeutic compounds and/or therapies.

[0041] "Protection against disease" and similar phrases, mean a response against a disease or condition generated by administration of one or more therapeutic compositions of the invention, or a combination thereof, that results in fewer deleterious effects than would be expected in a non-immunized subject that has been exposed to disease or infection. That is, the severity of the deleterious effects of the infection is lessened in a vaccinated subject. Infection may be reduced, slowed, or possibly fully prevented, in a vaccinated subject. Herein, where complete prevention of infection is meant, it is specifically stated. If complete prevention is not stated then the term includes partial prevention. Protection and similar phrases includes a reduction in severity of at least one clinical indication of disease or infection by at least 10%, preferably 20%, 30%, 40%, 50%, more preferably by 60%, 70%, 80%, or even more preferably by 90% or more as compared to an untreated, infected or diseased subject. [0042] Herein, "reduction of the incidence and/or severity of clinical signs" or "reduction of clinical symptoms" means, but is not limited to, reducing the number of infected subjects in a group, reducing or eliminating the number of subjects exhibiting clinical signs of infection, or reducing the severity of any clinical signs that are present in one or more subjects, in comparison to wild-type infection. For example, it should refer to any reduction of pathogen load, pathogen shedding, reduction in pathogen transmission, or reduction of any clinical sign symptomatic of malaria. Preferably these clinical signs are reduced in one or more subjects receiving the therapeutic composition of the present invention by at least 10% in comparison to subjects not receiving the composition and that become infected. More preferably clinical signs are reduced in subjects receiving a composition of the present invention by at least 20%, preferably by at least 30%, more preferably by at least 40%, and even more preferably by at least 50%.

[0043] The term "increased protection" herein means, but is not limited to, a statistically significant reduction of one or more clinical symptoms which are associated with infection by an infectious agent, preferably a Plasmodium spp. , respectively, in a vaccinated group of subjects vs. a non-vaccinated control group of subjects. The term "statistically significant reduction of clinical symptoms" means, but is not limited to, the frequency in the incidence of at least one clinical symptom in the vaccinated group of subjects is at least 10%, preferably 20%, more preferably 30%, even more preferably 50%, and even more preferably 70% lower than in the non- vaccinated control group after the challenge the infectious agent. [0044] Those of skill in the art will understand that the compositions used herein may incorporate known injectable, physiologically acceptable sterile solutions. For preparing a ready-to-use solution for parenteral injection or infusion, aqueous isotonic solutions, e.g. saline or plasma protein solutions, are readily available. In addition, the immunogenic and vaccine compositions of the present invention can include pharmaceutical- or veterinary-acceptable carriers, diluents, isotonic agents, stabilizers, or adjuvants.

[0045] As used herein, "a pharmaceutical- or veterinary-acceptable carrier" includes any and all solvents, dispersion media, coatings, adjuvants, stabilizing agents, diluents, preservatives, antibacterial and antifungal agents, isotonic agents, adsorption delaying agents, and the like. In some preferred embodiments, and especially those that include lyophilized immunogenic compositions, stabilizing agents for use in the present invention include stabilizers for lyophilization or freeze-drying.

[0046] "Diluents" can include water, saline, dextrose, ethanol, glycerol, and the like.

Isotonic agents can include sodium chloride, dextrose, mannitol, sorbitol, and lactose, among others. Stabilizers include albumin and alkali salts of ethylendiamintetracetic acid, among others.

[0047] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0049] FIG. 1. General structure motifs of derivatives.

[0050] FTG. 2. Synthesis of 4-position library.

[0051] FIG. 3. Exemplary active compounds that embody the diamine motif.

[0052] FIG. 4. Compounds WR318973 and WR 177000. [0053] FIG. 5. Diamine quinoline methanols with reduced brain penetration as compared to mefloquine.

[0054] FIG. 6. Diamines with additional lipophilicity.

[0055] FTG. 7. Putative active metabolites of WR318973.

[0056] FIG. 8. Generic Diamine Quinoline Methanols of Interest. [0057] FIG. 9. Proposed synthetic route to construct N-oxide amine derivatives of

WR318973.

[0058] FTG. 10. Proposed synthetic route to construct N-hydroxyl amine analogs of

WR318973.

[0059] FIG. 11. Structures of straight chain ethylene diamines. [0060] FIG. 12. Synthetic scheme for straight chain ethylene diamines.

[0061] FTG. 13. Structure of pyrrolidine ethylene diamines.

[0062] FTG. 14. Synthetic schemes for pyrrolidine ethylene diamines.

[0063] FTG. 15. Structure of bicyclic ethylene diamines.

[0064] FIG. 16. Synthetic schemes for bicyclic ethylene diamine 37. [0065] FTG. 17. Synthetic schemes for bicyclic ethylene diamine 41. [0066] FTG. 18. Synthetic schemes for bicyclic ethylene diamine 50.

[0067] FIG. 19. Generic bicyclic compounds of interest.

[0068] FIG. 20. Epoxide opening scheme [EtOH, uw, 30min, 13O ⁰ C, 25Ow].

[0069] FIG. 21. Remaining diamine quinoline methanols of interest. [0070] FTG. 22. Structures and IC ₉₀ S of the most potent quinoline methanols. IC90S are against the mefloquine resistant Pf C2A strain.

[0071] HG. 23. Reagents and conditions: (a) 1. POBr ₃ , 75°C - 150 ⁰ C (91 %) (b) n-BuLi,

N,N-dimethylformamide,THF, -78°C (64%) (c) NaH, Me ₃ SO, DMSO, THF (82%) (d) NaH, ROH, THF, 0 ⁰ C to rt (72-89%) (e) NaH, RSH, THF, 0 ⁰ C to rt (81-84%) (f) RMgBr, ether or THF, -78°C to rt (88-93%) (g) amine, 200 proof EtOH, microwaves, 25Ow, 130 ⁰ C, 15-30 min (18-97%).

[0072] FTG. 24. Actual versus calculated LogBB Values for Structurally Diverse Quinoline

Methanols.

[0073] FTG. 25. Modification of mefloquine scaffold to generate preferred mefloquine analog hybrids.

[0074] FTG. 26. Exemplary preferred derivatives of the invention.

[0075] FIG. 27. Synthesis of 4-, 6-, 7-, 8-position quinoline 6 and enantiopure 6". This synthesis and the R groupings are intended to be generic and applicable to any combination of preferred substituents at the 4-, 6-, 7-, or 8-positions. The R group designations herein are intended for this figure only and do not refer specifically to other R grouping or substituents described elsewhere herein.

[0076] FTG. 28. Synthesis of mefloquine analogs 2 and 3.

[0077] FIG. 29. Structures of additional quinoline methanols 10 and 11 evaluated in biological assays. [0078] FIG. 30. Structures of racemic mefloquine 1 and racemic 8-position SF ₅ mefloquine 6 from novel building-block compound 7. Other 6- and 7-position CF ₃ or SF ₅ analogs of mefloquine 2, 3, 4, and 5. The four possible isomers of compound 6 are also illustrated (compounds 6a, 6b, 6c, and 6d)

[0079] FIG. 31. Stereoselective synthesis of compound 6a-b and synthesis and structures of intermediate compounds 7, 12, 12a, 13 and 13a. [0080] FIG. 32. Plasma concentrations of mefloquine and 8-SF ₅ mefloquine 6 in mice over time.

[0081] FIG. 33. Utility of Compound 12a in the proposed synthesis of other 8-SF ₅ quinoline methanol derivatives.

[0082] FIG. 34. Structures of Exemplary Compounds 20, 21, 23, and 24. DETAILED DESCRIPTION

[0083] The present invention provides new quinoline methanol compounds that penetrate the blood-brain barrier at reduced concentrations as compared to mefloquine and have the same, or even improved, therapeutic efficacy as mefloquine. These new compounds are expected to be useful pharmacological agents for the prevention or treatment of malaria, and other microbial, parasitic, protozoan, bacterial and fungal diseases and potentially of Parkinson's disease or diseases associated with prions.

[0084] The present invention relates to 8-pentafluorosulfanyl analogs of mefloquine, new quinoline methanol derivative compounds, and pharmaceutical compositions containing one or more analog or derivative compounds. The present invention further relates to enantiomers, diastereomers, racemates, or pharmaceutically acceptable salts of the 8-pentafluorosulfanyl analogs. The invention embodies a series of new antimalarial compounds in which the quinoline methanol scaffold has been optimized in terms of the structure modifications and physiochemical properties required for excellent oral bioavailability, equivalent and/or improved potency as compared to mefloquine and reduced potential for blood brain barrier penetrability/brain uptake than mefloquine. First, these properties were mediated by the incorporation of 8-position pentafluorosulfanyl groups and 4-position side chains imparting lower lipophilicity and higher polar surface area to the compounds. The general structure of these new compounds is provided in Formula I

Formula I wherein, X is an oxygen atom, a sulfur atom, a carbon atom or a nitrogen atom. R is a hydrogen atom, a side chain containing heterocycle, a straight chain alkyl group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, a cyclic alkyl group containing a nitrogen atom, a cyclic amine, a cyclic chain alkyl group containing one or more heteroatoms, or a straight chain alkyl group containing one or more heteroatoms. In addition, R may represent two substituents, Ri and R ₂ . Ri is a hydrogen atom, a side chain containing heterocycle, a straight chain alkyl group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, a cyclic alkyl group containing a nitrogen atom, a cyclic amine, an imidazole, or a triazole; R ₂ is a hydrogen atom, a straight chain group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, a cyclic alkyl group containing a nitrogen atom, a cyclic amine, an imidazole, or a triazole. Ri and R ₂ may or may not be the same and may or may not be joined to each other to form a cyclic amine, aryl group, or heterocycle.

[0085] Compounds within the scope of the present invention, including enantiomers, diastereomers, racemates, or pharmaceutically acceptable salts thereof, are generally represented by Formula I. Subsets of compounds of Formula I are further described by the formulas set forth as compounds 6, 6a, 6b, 6c, and 6d in FIG. 30. In certain embodiments, a mefloquine derivative of the present invention is selected from the group consisting of:

, or combinations thereof.

[0086] Additional subsets of compounds of Formula I are further described by the formulas set forth as compounds 16-19 in F ⁷ IG. 33. In certain embodiments, the mefloquine derivative is selected from the group consisting of:

, or combinations thereof.

In other embodiments, the mefloquine derivative is selected from the group consisting of: , or combinations thereof.

[0087] It has also been observed that the physiochemical properties of mefloquine were mediated by the incorporation of 4-position side chains imparting lower lipophilicity and higher polar surface area to the compounds. The general structure of these 4-position compounds, including enantiomers, diastereomers, racemates, or pharmaceutically acceptable salts thereof, is provided in Formula I.

Formula II

In Formula II, ( )„ represents one, two, or more carbon atoms; Ri is a hydrogen atom, a straight chain alkyl group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, or a cyclic alkyl group containing a nitrogen atom; R ₂ is a hydrogen atom, a straight chain group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, or a cyclic alkyl group containing a nitrogen atom; and R3 represents at least one substitution at the 6- or 7- or 8- position of the quinoline ring, preferably a substitution only at the 8-position, wherein the substitution is selected from the group consisting of a pentafluorosulfanyl group, a trifluoromethyl group, a OH group, an oxygen atom, a hydrogen atom, or a combination thereof. Preferably, a pentafluorosulfanyl group is at position 8, optionally a trifluoromethyl group is at position 6 or 7.

[0088] Notably, when ( )„ represents one carbon atom then neither Ri nor R ₂ are selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, hydroxy, cyclopropyl, CH ₂ - CHOH-CH ₂ -CH ₃ , CH ₂ -CH ₂ -CHOH-CH ₃ , CH ₂ -CH ₂ -CH ₂ -CH ₂ OH, CH ₂ OH, and CH ₂ -CH ₂ - COOH. In quinoline methanol compounds where ( ) _n represents two or more carbon atoms either Ri or R ₂ may be selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, hydroxy, cyclopropyl, CH ₂ -CHOH-CH ₂ -CH ₃ , CH ₂ -CH ₂ -CHOH-CH ₃ , CH ₂ -CH ₂ -CH ₂ - CH ₂ OH, CH ₂ OH, CH ₂ -CH ₂ -COOH, other straight chain alkyl groups, cyclic alkyl groups, straight chain alkyl groups containing a nitrogen atom, and cyclic alkyl groups containing a nitrogen atom.

[0089] These new compounds have physiochemical properties, such as Log P (water- octanol partition coefficient) values, polar surface area (PSA) and/or freely rotatable bonds (FRBs), which limit the ability of this compound to penetrate the blood brain barrier and enter the central nervous system (CNS). These new compounds have equivalent and/or improved activity under comparable conditions over mefloquine.

[0090] Conventional quinoline methanols, such as mefloquine, penetrate the CNS and cause adverse CNS effects. The 8-pentafluorosulfanyl mefloquine analogs of the present invention have been engineered to avoid or limit penetration of the CNS, and thereby reduce, or possibly prevent, CNS adverse events. It, therefore, offers a potential advantage over existing drugs.

[0091] The novelty of this compound is found in its biological and chemical properties.

There are no drugs presently available from this general class of compounds (quinoline methanols) with the same pharmaceutical activity that also exhibit a propensity to not cross the blood-brain barrier. In addition, the chemical structure of this compound is different from those compounds within the class that are available commercially or that might be reported elsewhere.

[0092] The compounds within the scope of the invention and described in more detail below may be employed in pharmaceutical compositions, wherein said compositions may comprise an effective amount of one or more of these compounds, alone or in combination together or separately, and optionally a pharmaceutically acceptable carrier. The effective amount of these compounds will vary based upon the use for which the composition is intended and the subject (e.g. species, gender, age, etc.).

[0093] The compounds and compositions within the scope of the present invention may be administered to a subject via any conventional route of administration. Selection of a suitable, pharmaceutically acceptable carrier is well within the ordinary skill of the art depending on the method of administration sought to be employed - i.e. oral, intravenous, etc.

[0094] These compounds and compositions containing them may be used in methods for preventing and/or treating malaria, methods for preventing and/or treating other infectious diseases, or methods for preventing and/or treating certain immunological conditions. In addition, compounds and compositions within the scope of the present invention may be used in the intermittent preventive treatment of malaria. Reference to treatment herein includes intermittent preventive treatment. [0095] The invention is suitable for use against all species of malaria (i.e. blood stages of all malaria parasites). In addition, the invention is suitable for use against diseases caused by bacteria, protozoa, parasites, and fungi, and against some autoimmune diseases (e.g. rheumatoid arthritis). [0096] Compounds within the scope of the present invention are generally represented by

Formulas I and II. Subsets of compounds of Formula II are further described by the formulas set forth as Series A, Series B, Series C, and Series D in FIG. 1. In general, R ¹ , R ³ , R ⁴ , and R ⁵ in these formulas represent substituents that render a quinoline methanol less able to cross the blood-brain barrier than mefloquine (see, for example, Tables 1-3 for illustrative substituents). This reduction is because quinoline methanols represented by these formulas exhibit lower LogP, or higher polar surface area (PSA), or have a greater number of freely rotatable bonds (FRBs), or a combination of all three of these properties as compared to mefloquine. These changes in physiochemical properties are known to correlate with lower blood-brain barrier permeability. (In Tables 1 and 2 the combined effects of different PSA, LogP and FRBs for each analog is expressed as the parameter cLogBB or the calculated log ratio of brain:blood concentration.) Use of cLogBB is one method available to assess the sought after properties herein. The individual values of LogP, PSA and FRBs can be derived from the chemical structures using standard physiochemical prediction software (e.g. ACD). Furthermore, this reduced penetration of the blood-brain barrier is achieved without loss of functionality critical to maintaining intrinsic activity, which is essential for their utility as potential drugs. R ³ and R ⁴ (see FIG. 1, Series B) may include cyclic and alkyl tertiary amines. They may also join one to the other to form a substituted or unsubstituted heterocyclic ring. R ⁵ (see FIG. 1, Series C and D) represents a substitution at one or more of the 2-, 3-, 4-, or 5-positions of the imidazole ring or triazole ring.

[0097] R ₂ denotes any substituent at the 8-position and optionally at the 6- or 7 -positions of the quinoline ring, including but not limited to SF ₅ in the 8-position.

[0098] The notation ( ) _n indicates that the structures represented by Series A, Series B,

Series C, and Series D contain one or more carbon atoms positioned between the C-OH and the N atoms of the 4-position side chain as shown in FIG. 1. Analogues wherein n=l or 2 were found to be of particular interest; however, the invention is not so limited. Any suitable value for "n" wherein the compounds illustrate the desirable properties described herein is within the scope of the present invention.

[0099] Compounds within the scope of the present invention that are of particular interest are set forth as general structures in FTG.1 and specific exemplary compounds are described in Table 1 , Table 2 and Table 3. Herein, compounds of particular interest are referred to as diamine quinoline methanols (see FIG. 1). These compounds are illustrative of the types of compounds within the scope of the invention. The present invention, however, is not intended to be limited to the compounds identified in these tables. One having ordinary skill in the art, and equipped with the description set forth herein, would know or be able to identify what substituents would be suitable for attaining the sought after properties of interest herein. As set forth above, for example, with reference to R ¹ , R ³ , R ⁴ , and R ⁵ suitable substituents are those that render quinoline methanols less able to cross the blood-brain barrier relative to mefloquine without imparting a loss of potency.

[00100] The analogs and compounds described herein were made in a single step nucleophilic substitution using heat or microwave radiation. They were made from a commercially available epoxide, 2-[2,8-bis(trifluromethyl)-4-quinolyl]oxirane (obtained from BioBlocks, San Diego, California) and commercially available nucleophiles (mostly amines obtained from Maybridge, Cornwall, United Kingdom). See FIG. 2.

[00101] In another aspect, the invention also discloses five key intermediate compounds that were discovered during the synthesis of the 8-pentafluorosulfanyl analogs of the present invention. These novel compounds are represented in FIG. 31 as compounds 7, 12, 12a, 13, and 13a. Methods of making these intermediates are detailed herein below.

[00102] Compounds within the scope of the invention may be made using any suitable method. One skilled in the art would be able to identify and determine other methods of making the compounds within the scope of the present invention. The method of making the compounds herein is not intended to be so limited. A. Pharmacological Properties of Diamine Quinoline Methanol Compounds

[00103] A series of in vitro and in vivo permeability/brain uptake and susceptibility/efficacy and in vivo PK studies were executed. These studies, which are outlined below and detailed in the Examples herein, reduce to practice, the utility of diamine quinoline methanols, since they are less penetrant than non-diamine comparators and maintain useful potency and efficacy and plasma levels relative to mefloquine.

[00104] Specific diamines such as WR318973 cross the blood-brain barrier to a lesser extent than similar compounds that do not contain a second nitrogen atom (FIG. 4). For example, 5 min after an intravenous (i.v.) dose of 5 mg/kg administered to FVB mice, brain concentrations of WR318973 were 129 ng/g compared to 881 1 ng/g for WR 177000.

[00105] More generically, the presence of a second nitrogen atom on the side chain makes such analogs less able to penetrate the blood-brain barrier. For example, diamine analogs such as WR318746, WR318744 and WR319535 exhibit lower brain concentrations 5 min after i.v. dosing than mefloquine (FIG. 5). Brain concentrations were 100, 243, 199 and 550 ng/g respectively for WR319535, WR318744 and WR318744 and mefloquine respectively. As a consequence, they are likely to be better tolerated than mefloquine due to lower exposure of multiple vulnerable CNS targets to the drugs. More generally, quinoline methanols with the requisite diamine motif are more likely to exhibit less blood-brain barrier penetrability than non- diamines and be better tolerated as a consequence. [00106] The reduction in lipophilicity associated with the second nitrogen is also associated with improved pharmacokinetic properties. For example, the clearance of WR177000 is 2681 ml/hr/kg versus 912 ml/hr/kg for WR318973. This means that the plasma concentration of WR318973, 24 h after dosing are still measurable at 83 ng/ml, whereas this is not the case for WR177000. In some diamines the proportion of compound remaining 24 h after an i.v. 5 mg/kg dose is comparable to mefloquine. For example 26% of WR308621 in plasma remained at 24 h versus 26-31% for the mefloquine isomers, meaning that, generically, diamine quinoline methanols may be potentially applicable for treatment indications such as intermittent preventive treatment of malaria or malaria prophylaxis where maintenance of adequate plasma concentrations over substantial periods of time is essential. [00107] The utility of diamine quinoline methanols as antimalarials is partially dependent on- their potency. Potency against malaria parasites is assessed by measuring an IC ₅₀ against well- characterized laboratory strains of P. falciparum such as W2 and C2A. Diamine quinoline methanols are unique in that the reduction in lipophilicity generated does not compromise the utility of the compounds by reducing potency to the point of inactivity. Furthermore, the potency of diamines is dependent on restricting access to the second amine, the positioning of the two nitrogen atoms relative to each other and cyclization of the side chain. For example, WR318972 (FIG. 6) and WR318746 have IC ₉₀ S of 30 and 69 ng/ml respectively against Pf W2 versus 490 ng/ml for WR318973 because access to the second amine is restricted. This trend is even more prominent when one considers an analog such as WR308396, with an IC ₉₀ of 6 ng/ml, in which a large lipophilic group is added to the terminal portion of the side chain. Also, analogs in which the second amine is three atoms from the first nitrogen are more potent. For example, the IC ₉₀ of WR308782 (FTG. 6) is 69 ng/ml compared to 6 ng/ml for WR308396. Finally, cyclization of the side chain improves potency. As an example, WR308621 has an IC ₉₀ of 46 ng/ml versus 490 ng/ml for WR318973. Thus diamines in which access to the second amine is restricted, in which the terminal nitrogen is cyclized and/or in which the second nitrogen is three atoms from the first, are particularly favored.

[00108] The utility of a quinoline methanol derivative for malaria or other indications is dependent on oral bioavailability. The bioavailability of diamines is acceptable, as exemplified by WR318973, for which bioavailability was 70%. This means that a diamine motif in the 4- position side chain is consistent with good oral bioavailability.

[00109] Based on the biological data, diamines of the generic structure outlined below as Series C, D and E (FIG. 8) are embodiments of the present invention. Generally R groups 1 through 6 represent any functionality that improves the intrinsic properties of the diamine scaffold including but not limited to aliphatic or aromatic or heterocyclic or cyclic substituents. They could be methyl groups that block access to the second amine or the second nitrogen could be incorporated into a cyclic structure in order to improve potency. The substituents might increase the molecular weight of the compound in order to render them PGP substrates and thus less penetrant of the blood-brain barrier. The substituents could result in additional increases in polar surface area and or decreases in lipophilicity in order to further decrease permeability. Alternatively, blocking groups could be added to sterically hinder sites of metabolic attack. The symbol ( )„ indicates that there are 1 or more carbon atoms in the side chain either between the hydroxyl and first nitrogen and/or between the first and second nitrogen atoms. Compounds with two carbon atoms between the nitrogen atoms are favored. R ₈ denotes any substituent attached to the 8-position, optionally at the 6- or 7-positions, of the quinoline ring, including but not limited to SF ₅ at the 8-position. R7 is intended to be a substituent that renders the compound a tertiary amine, including, but not limited to compounds in which the substituent at R ₇ is joined to another Ri _-6 substituent to create a cyclic species. Substituents at Ri, R ₂ and R ₇ might be O or OH groups in order that the compounds be mono- or di-hydroxyl amines or N-oxides. B. Construction of Quinoline Methanol Compounds

[00110] FIG. 2 outlines the strategy used to synthesize a 4-position library of methanol quinoline compounds. The structure of mefloquine is indicated at 1. The intermediate scaffold 4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline 3 was synthesized from bis(trifluoromethyl)quinolin-4-ol 2 by the addition Of POBr ₃ at 75°C to 150 ⁰ C for 2 hours with 91 % yield. The resulting 4-bromo-2,8-bis(trifluoromethyl)quinoline was dissolved in tetrahydrofuran, cooled to -78°C and subjected to a n-butyllithium. N,N,-dimethylformamide was subsequently added to afford 2,8-bis(trifluoromethyl)quinoline-4-carbaldehyde. Utilization of Corey's dimethylsulfonium methylide provided racemic epoxide 3. The epoxide 3 can also be purchased commercially from Bioblocks (San Diego, California). The quinoline scaffold 3 was diversified at the 4-position in a single step with commercially available nucleophiles.

[00111] Over two hundred quinoline methanols were synthesized in 20 mg quantities and submitted for in vitro screening. Compounds exhibiting IC90S < 250 nM (approximately equivalent to the upper limit of mefloquine) against Pf C2A and an LC50 against mammalian cells no worse than mefloquine were considered for in vivo studies. The structures of these compounds were examined and ten interesting compounds were selected for further in vivo, ADME and CΝS screens. Based on these data, a single compound was selected as a lead around which to synthesize a new series of compounds.

[00112] Compounds can be constructed using the methodologies outlined below. In order to construct the Ν-oxide compounds 3 and 4 from WR318973 1, the benzylic alcohol and the first amine on the side chain must be protected (FIG. 9). Mixed acetal 2 will be constructed from isobutyraldehyde utilizing the standard protocol in dichloromethane, which allows the second amine to be oxidized with a variety of oxidants. As shown in FIG. 9, t-butyl peroxide promoted oxidation is of interest since it was shown to not oxidize heterocyclic nitrogen atoms (see J. D. Fields and P. J. Kropp, Journal of Organic Chemistry, 2000, 65, 5937-5941). Another possibility will entail the use of 2-sulfonyloxaziridines (Davis' reagents) for the transformation to N-oxides (see W. W. Zajac, T. R. Walters, and M. G. Darcy, Journal of Organic Chemistry, 1988, 53, 5856-5860). Alternatively, there are a variety of procedures to form N-oxide 3 or its tautomer 4. In order to de-protect the mixed acetal, trimethylsilyl iodide in acetonitrile can be utilized. To form dioxide 6, the benzylic alcohol can be protected as the silyl ether. Similar oxidation conditions can be tested followed by tetrabutylammonium fluoride or some other mild deprotection in order to remove the triethyl silane. To form mono-oxide tautomers 9 and 10, a similar sequence can be employed starting with epoxide 7. Utilizing a microwave-assisted nucleophilic epoxide opening, which has been optimized, followed by selective protection of the benzylic alcohol.

[00113] The synthetic routes utilized to construct the putative metabolites are illustrated in FIG. 10. In order to form the N-hydroxyl amine, a procedure reported by Fields and Kropp (J. D. Fields and P. J. Kropp, Journal of Organic Chemistry, 2000, 65, 5937-5941, incorporated herein by reference) can be used. Despite excess oxidant, only the N-hydroxyl amine was isolated when utilizing OXONE on silica. Trimethylsilyl iodide and acetonitrile (G. A. Olah and S. C. Narang, Tetrahedron, 1982, 38, 2225, incorporated herein by reference), can be utilized as a mild deprotection strategy for the mixed acetal and t-butyl carbamate, respectfully.

[00114] The so-called straight chain ethylene diamines depicted in FIG. 1 1 are embodiments of the invention. These can be made by a three-component- 1 -pot synthesis as outlined in FIG. 12. First, the desired tosyl-protected aziridine 13, with various R substitution patterns, is constructed from the corresponding amino alcohol (Loethar W. Bieber and Mariea C. F. de Araujo. Molecules, 2002, 7, 902-906 incorporated herein by reference) or commercially available aziridines. The tosyl group protects the secondary amine, activates the aziridine to nucleophilic attack (SN2), and is an ultraviolet tag to monitor the reaction. Tosyl-protected aziridine 13 (l .Oeq) is dissolved in ethanol (200 proof, 0.25M), amine 14 (l . leq) is added, and the reaction mixture is subjected to microwaves (13O ⁰ C, -250 watts) for 30 minutes. In order to remove the tosyl group, 1.25M HCI/EtOH (1.5eq) is added and the reaction mixture is further subjected to microwaves (130°C, 250 watts) for 30 minutes. 2,2,6,6-Tetramethylpiperidine (3.0eq) is added to increase the pH - 9, followed by the addition of epoxide 7, and the reaction mixture is further subjected to microwaves (130 ⁰ C, 250 watts) for 30 minutes. The ethanol is removed in vacuo and the reaction mixture is purified via normal phase preparative thin layer chromatography in 95:5 dichlo methane: methanol to yield 28-43% yield over three steps. The conditions can be optimized to increase yields.

[00115] Pyrrolidine ethylene diamines as depicted in FIG. 13 are also embodiments of the present invention. These can be synthesized using the following described methods or variations thereof as illustrated in FIG. 14. By utilizing chiral enolates of pseudoephedrine amides 18 and azirides such as 13, substituted pyrrolidin-2-ones 20 can be prepared in >99% enantiomeric excess (see Jose L. Vicario, Dolores Badia, and Luisa Carrillo, J. Org. Chem. 2001 , 66, 5801- 5807, incorporated herein by reference). Treating pyrrolidin-2-one 20 with Swartz' reagent (Cp ₂ ZrHCl) and cyanotrimethylsilane (TMSCN) affords the corresponding α-aminonitrile 21 (see Q. Xia and B. Ganem. Tetrahedron Letters, 2002, 43, 1597-1598, incorporated herein by reference). Subsequent protection of the amine will afford 22, followed by either direct reduction to 23 or treatment with Grignard reagent to yield gem-dimethyl substituted pyrrolidine 24. In order to install a methyl group alpha to the amine, a three-step sequence will be employed to transform pyrrolidin-2-one 20 to α-methylaminonitrile 25, which can be reduced directly to amine 26 or treated with Grignard reagent to afford substituted pyrrolidine 27. With substituted pyrrolidine 27 (23, 24, or 26) in hand, utilization of our microwave-assisted epoxide opening and subsequent deprotection will be utilized to afford HCl salt 28.

[00116] Bicyclic ethylene diamines are also embodiments of the present invention (FIG. 15). These can be synthesized as follows or similar methods thereof as outlined in FIGs. 16-20. FIG. 16 illustrates the proposed synthesis of bicyclic amines such as 37. Utilizing similar strategies employed in the synthesis of the pyrrolidines (FIG. 14), carboxyglutamic acid derivatives such as 31 can be subjected to Swartz' reagent (Cp ₂ ZrHCl) and cyanotrimethylsilane (TMSCN) to afford the corresponding α-aminonitrile 32 (Q. Xia and B. Ganem. Tetrahedron Letters, 2002, 43, 1597-1598, incorporated herein by reference). Subsequent protecting and ring closing metathesis utilized Grubb's catalyst (see Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003, incorporated herein by reference) should afford 34. Reduction to the primary amine should yield 35, while treatment with Grignard and reduction of the olefin should yield 36. The bicyclic diamine can be utilized in microwave-assisted epoxide opening to yield 37.

[00117] The synthesis of compound 41 will proceed in a similar manner as outlined in FIG. 12, where aziridine 13 and commercially available amine 38 will be subjected to microwaves to yield 39 as shown in FIG. 17. Deprotection under acidic conditions and microwaves should yield 40. After adjustment of the pH with 2,2,6,6-tetramethylpiperidine and subsequent microwave-assisted epoxide opening should yield 41.

[00118] Some specific bicyclic compounds of interest are presented in FIG.19. As an example, compounds such as Compound 50 can be made as outlined in FIG 18. Methyl-4- hydroxybenzoate 40 (FIG. 17) was reduced to the corresponding aliphatic cyclohexane and oxidized to ketone 43. A Bucherer-Bergs reaction was utilized to establish the amine and carboxylic acid group in a cis configuration with spirohydantoinic compound 44. Subsequent saponification, formation of the acid chloride, and cyclization led to lactam 46. Protection as the benzylamine provided 47, which was reduced utilizing diphenylsilane and rhodium catalysts provided bicyclic compound 48 (D. Casabona and C. Cativiela. Tetrahedron, 2006, 62, 10000- 10004, incorporated herein by reference). From this point, the amide should be formed upon treatment with ammonia followed by reduction to primary amine 49, which will be subjected to microwave-assisted epoxide opening and subsequent reduction to yield compound 50.

[00119] Other diamines of interest, depicted in FIG. 21, may also be synthesized by epoxide opening as depicted in FIG. 20. The diamine can be purchased commercially or constructed in house and utilized in microwave-assisted epoxide opening.

C. Pentafluorosulfanyl Analogs of Mefloquine

[00120] Introduction of a pentafluorosulfanyl (SF ₅ ) group into an organic compound has been of interest in material, pharmaceutical and agrochemical applications. Compared to the trifluoromethyl (CF ₃ ) group, the SF ₅ group has a higher electronegativity, a substantially larger steric effect, more pronounced hydrophobicity, and slightly higher chemical resistance.

[00121] The physicochemical and pharmacological properties of small organic molecules are often significantly modified by the incorporation of fluorine atoms. As such, the replacement of the trifluoromethyl (CF3) groups in mefloquine with the sterically more demanding, highly fluorinated and yet rigid octahedral pentafluorosulfanyl (SF ₅ ) group was identified as having the potential to reduce the ability of a mefloquine derivative to cross the blood:brain barrier.

[00122] The relative volume of the SF ₅ group is slightly less than that of a tert-buty\ group, but it is considerably larger than a CF ₃ group. The electronegativity of the SF ₅ function has been proposed to be as high as 3.65, vs. 3.36 for the CF3 group. In electrophilic aromatic substitutions, the SF ₅ group was found to have a Hammet σp value of 0.68 vs. σp = 0.54 for CF3. In agreement with these differences, the electron-density surface encoded with the electrostatic potential for 4-methyl-8-pentafluoro-sulfanyl-2-(trifluoromethyl)quinoline vs. 4-methyl-2,8- bis(trifluoromethyl)quinoline shows considerably higher steric crowding around the quinoline nitrogen, a slightly decreased electron density in the benzene ring, and a more positive nitrogen electrostatic charge (-0.64 vs. -0.66). In both cases, the nitrogen atom is completely buried between the two substituents.

[00123] Other noteworthy features of the SF ₅ group include its remarkable chemical stability. Aromatic SF ₅ groups tolerate even harsh acidic conditions their hydrolytic stability equals or exceeds that of the CF ₃ group. As such, the SF ₅ group has the potential to yield desirable effects in a mefloquine derivative.

[00124] Example 4 describes an efficient synthesis of the 6-SF ₅ and 7-SF ₅ analogs of mefloquine (see FIG. 27), as well as, their biological activities against malaria parasites. Exemplary derivatives are provided in FIG. 26. [00125] The racemic 8-pentafluorosulfanyl analog 6 of mefloquine depicted in HG. 30 may offer benefits over its 6- and 7- pentafluorosulfanyl cogeners 2 and 3, since it is less permeable through MDRl-transfected MDCK cell monolayers than compounds 2 and 3 and is more potent (i.e. has lower in vitro IC ₉₀ S) against some strains of P. falciparum with a greater selectivity index than compound 3 (as shown in Table 16). In efficacy tests in mice, 8-pentafluorosulfanyl mefloquine 6 was more efficacious than mefloquine when administered at a dose of 40 mg/kg PO (Table 17). 8-pentafluorosulfanyl mefloquine 6 also exhibited a longer half-life (68 h) than mefloquine (23 h) after intravenous administration to mice at a dose of 5 mg/kg (plasma levels for the two compounds are shown in FTG. C).

Table 16: Antimalarial activity, toxicity, permeability, plasma protein and brain tissue binding of mefloquine and its SFs-analogs.

Analog Pf Pf Pf Pf RAW Sl ^c Papp Fu ^e Fu ^e Fu ^e W2 D6 C235 C2A LC ₉₀ " A-B Mouse Mouse Human MDCK Brain PlasmaPlasma

IC ₉₀ or LC90 for Mefloquine 1°

16 I 92 1 182 1 183 |8934 559 9.4 0.002 0.01630.0305

IC ₉₀ Or LC ₉₀ Analog/IC ₉₀ or LC ₉₀ Mefloquine l '

1.2 0.6 0.5 0.6 6.0 2795 13.8 NT NT NT 1.7 1.0 0.8 0.9 0.7 230 9.7 NT NT NT 0.6 0.8 0.5 0.9 1.0 932 5.0 0.00081 0.004 0.0072

Table 17: Efficacy of 8-pentafluorosulfanyl mefloquine vs. mefloquine in P. berghei- infected mice after administration of both compounds at a dose of 40 mg/kg orally (PO).

[00126] A method of making the anti isomers of 8-pentafluorosulfanyl analog of mefloquine 6a-b is depicted in FTG. 31. The method of making the 8-pentafluorosulfanyl analog of mefloquine involves the use of four intermediates 12, 12a, 13, and 13a in which the SF5 moiety is installed in the 8-position of the quinoline ring. These intermediate compounds are constructed from intermediate ortho-SFs aniline 7 as shown in FTG. 31, which is also a novel compound. The synthesis of ortho-SFs aniline 7 is not published in the literature and this compound is not commercially available.

[00127] As depicted in FIG. 31, aniline 7 was synthesized in four steps from 3-SF ₅ -phenol 8 in a novel sequence. This is the first instance of the substitution of a pentafluorosulfanyl ortho to an aniline substituent on the aromatic ring. This translates to the first 8-pentafluorosulfanyl quinoline as well. In addition, the route from 3-SFs-phenol 8 to ortho-SFs aniline 7 utilizes commercially available (as indicated above and below the reaction arrows in FIG. 31), inexpensive reagents and could be applicable to large-scale synthesis of 8-pentafluorosulfanyl mefloquine or 8-pentafluorosulfanyl quinoline methanol derivatives that is measurably less expensive than conventional technologies.

[00128] As depicted in FIG. 33, intermediate compound 12a may be used as the starting reagent in the synthesis of exemplary 8-pentafluorosulfanyl quinoline methanol derivatives represented by chemical structures 16-19 (see FIG. 33). Compound 12a can be elaborated via the 4-position chloro-substituent to afford vinyl species 14 and transformed into diol 14a. Epoxide 15 should be readily synthesizable from diol 14 as depicted in FIG. 33. Representative compounds 16-19 should then be readily synthesizable from epoxide 15 via a nucleophilic ring opening reaction.

[00129] Again with reference to FIG. 33, compounds represented by chemical structures 16- 19 represent exemplarily 8-pentafluorosulfanyl quinoline methanol derivatives that can be synthesized in one-step from expoxide 15 utilizing commercially available alcohols, thiols, carbon- or metal- substituted aryl groups, and amines to yield ethers 16, thioethers 17, hydrocarbons 18, and amines 19. Alky, aryl and heterocycle, as identified in FTG. 33 in reference to substituent R, may include, but are not intended to be limited to, the following: alkyl may include branched or straight-chain with n<20; aryl may include phenol, thiophenol, aryl Grignards, or anilines; heterocycles may include morpholine, piperazine, piperidine, pyrrolidine, bicyclic compounds such as 2-azabicyclo[2, 2, 2]octane and 2-azabicyclo[2, 1 , l]hexane, imidazoles, tetrazoles, etc. For scaffold 19 it is intended that R may also be represented by, but not be limited to, groups Ri and R ₂ (not illustrated on FIG. 33) which may be H, alkyl, aryl or heterocycles, which may or may not be the same, and which may be joined to each other to form a cyclic amine, aryl group or heterocycle (see FIG. 33). It is intended that all the functional groups represented by 'R' in FIG. 33 may be either substituted or unsubstituted.

[00130] 8-pentafluorosulfanyl quinoline methanol derivatives represented by chemical structures 16-19 in FTG. 33 are set forth merely for exemplary purposes. Other 8- pentafluorosulfanyl quinoline methanol derivatives having different substituents at the 4-position are also within the scope of the present invention. Specific examples of the types of substituents that may suitably be employed at the 4-position of the quinoline ring and are within the scope of the present invention are set forth herein. Included, for example, in the 8-pentafluorosulfanyl quinoline methanol derivatives of the present invention, but not intended to be limited thereto, are quinoline methanol derivatives of mefloquine as represented by or specifically set forth in the Figures and Tables attached hereto, wherein the trifluoromethyl group found at the 8-position of the quinoline ring of these derivatives is replaced with a pentafluorosulfanyl group at that same 8-position. Specific exemplary molecules include Compounds 20-23 outlined in FIG. 34. These compounds will be synthesized from enantiopure epoxide 15. The key intermediate 15 will be synthesized in enantiomeric excess using the Sharpless asymmetric dihydroxylation (see J. Am. Chem. Soc. 1988, 1 10, 1968, which is specifically incorporated herein by reference), then further enriched (>99%ee) if necessary using supercritical chromatography.

[00131] Example 6 describes a detailed synthesis of the 8-SF ₅ analog of mefloquine and the formation of the novel intermediate compounds as set forth in FIG. 31. D. In vivo Screening of Compounds

[00132] Compounds were tested at two different doses in groups of five mice: 160 mg per kilogram of bodyweight per day for three days, and as a single dose of 320 mg/kg. All dosing was oral. Details of tests are provided in the Examples.

[00133] The activity of a compound in this model is reflected as number cures relative to the number of mice experimentally infected (#cures/#tested). Control mice (those administered no drug) died or were humanely euthanized. The control data are not shown. The term #toxic/#infected represents how many of five mice in each treatment group experienced signs of acute toxicity. The results of the tests conducted are set forth in Table 3. E. Table Legends

[00134] Table 1 : Summary of physiochemical properties and biological data for novel quinoline methanols (NGQM - Next Generation Quinoline Methanols). The properties for which data are provided are defined, with a short description of methodology used to derive them, are outlined in the "Definitions" herein.

[00135] Table 2: Summary of physiochemical property and biological data for novel quinoline methanols. The properties for which data are provided, with a short description of methodology used to derive them, are outlined in the "Definitions" herein.

[00136] Table 3: In vitro Plasmodium falciparum (PF) screening and in vivo efficacy and toxicity data for selected compounds of interest. The properties for which data are provided, with a short description of methodology used to derive them, are outlined in the "Definitions" herein.

[00137] Table 4. Physiological properties of the 4-position library. [00138] Table 5. Pharmacological data for compounds selected for further screening. [00139] Table 6. Physiochemical properties of potent, active and inactive compounds.

[00140] Table 7. Properties of different functional groups present in active and inactive amines.

[00141] Table 8. Plasmodium falciparum IC9 ₀ (ng/ml) values resulting from probing hydroxyl utility. [00142] Table 9. Plasmodium falciparum IC ₉₀ (ng/ml) values resulting from probing amine utility.

[00143] Table 10. Plasmodium falciparum IC ₉₀ (ng/ml) values for phenyl, benzyl, and phenethylamino QMs.

[00144] Table 1 1. Plasmodium falciparum IC ₉₀ (ng/ml) values and selectivity of heterocyclic amino quinoline methanols (HAQMs).

[00145] Table 12. Plasmodium falciparum IC ₉₀ (ng/ml) values for alkyl amino quinoline methanols (AAQMs). [00146] Table 13. Plasmodium falciparum IC ₉₀ (ng/ml) values for additional branched alkyl amino quinoline methanols (AAQMs).

[00147] Table 14. Plasmodium falciparum IC ₉₀ (ng/ml) values for alkyl amino quinoline methanols containing additional heteroatoms (AAQMHs). [00148] Table 15. In vivo efficacy of selected quinoline methanols in the P. berghei mouse model and permeability across MDRl-transfected MDCK cell monolayers.

[00149] Table 16. Antimalarial activity and toxicity of selected 50 quinoline methanols. The units are ng/mL for IC50 , IC90 and LC ₅₀ data. The selectivity index is the ratio of the LC ₅₀ against RAW macrophages relative to the PfW2 IC ₅₀ . [00150] Table 17. Antimalarial activity, toxicity, permeability, plasma protein and brain tissue binding of mefloquine and its SFs-analogs.

[00151] Table 18. Efficacy of 8-pentafluorosulfanyl mefloquine vs. mefloquine in P. berghei-inϊected mice after administration of both compounds at a dose of 40 mg/kg orally (PO).

F. Definitions [00152] "LogP" is the partition coefficient reflecting the relative solubility of a drug in octanol versus water. The higher the value, the lower the water solubility. Generally a reduction in the LogP is associated with reduced permeability across the blood brain barrier. LogP can be predicted from the structure of a compound using standard physiochemical prediction software (e.g. ACD). [00153] "PSA" is the polar surface area of a molecule and is a reflection of the polarity of the molecule. Generally, higher PSA is associated with reduced permeability across the blood brain barrier. PSA can be predicted from the structure of a compound using standard physiochemical prediction software (e.g. ACD).

[00154] "FRBs" is the number of freely rotatable bonds a compound has. A greater number of freely rotatable bonds generally correlates with lower blood-brain barrier permeability. FRBs can be determined from the structure of a compound using standard physiochemical prediction software (e.g. ACD). [00155] "cLogBB" is the calculated log ratio of the brain:plasma concentration of a drug calculated using the following formula: cLogBB = (0.205 * LogP) - (0.0094*PSA) - (0.055 * FRBs) + 0.18. This is a composite index that combines the effects of PSA, LogP, and FRBs.

[00156] "PF IC90 (ng/ml)" is the 90% inhibitory concentration in ng/ml of a molecule against P. falciparum in an in vitro cell based growth inhibition assay. Four different strains of drug resistant P. falciparum (W2, D6, C235 and C2A) were used. The lower the value, the more active the molecule.

[00157] "Macrophage IC ₅ 0 (M-M)" is the 50% inhibitory concentration in micromolar units of a molecule in an in vitro cytotoxicity assay against a rodent macrophage cell line. The lower the value, the more toxic the molecule.

[00158] "Lip. Viol." is the number of violations of Lipinski's rule of 5. This index relates the likelihood that a compound will be orally bioavailable based on its physiochemical properties. The fewer Lipinski violations, the greater the likelihood of a compound being orally bioavailable. [00159] "P. berghei-mice" is the animal model that is used to evaluate the potential utility of new antimalarial compounds in a discovery setting. P. berghei, or Plasmodium berghei, is a rodent malaria parasite that induces a lethal infection in mice. For quinoline methanols, all commercially available compounds clinically effective against human malaria parasites are also active in this model. [00160] Herein, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including", as well as other forms such as "includes" and "included" is not limiting.

[00161] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs at the time of filing. The meaning and scope of terms should be clear; however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. All patents and publications referred to herein are incorporated by reference herein.

EXAMPLES

[00162] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventors to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

A. Materials and Methods

1. In Vivo PK Studies

[00163] For selected quinoline methanols brain and plasma concentrations were determined in vivo after intravenous dosing. Groups of 2-4, seven-eight week old male FVB mice were administered a 5 mg/kg dose of quinoline methanol base. The drug was given as a 50 microliter bolus dose in a drug vehicle consisting of 5% w/v glucose, and/or 0-5% dimethylsulfoxide, and/or 0-1 % solutol in 20 μM citrate or acetate buffer at pH 3-4 with the specific buffer characteristics being determined for specific compounds based on solubility. At 5 min, 60 min, 6h and 24h plasma and brain samples were obtained from the mice and frozen at -80 ⁰ C until they were analyzed. On the day of analysis, whole brains were homogenized in 3 parts of aqueous solution containing 0.1 M EDTA and 0.4 g/L KF (inhibitors of hydrolytic enzymes to reduce the potential for ex vivo tissue- mediated degradation of the test compounds). Calibration standards were prepared by spiking blank brain homogenate and blank plasma with the test compound. Both samples and standards were processed by adding acetonitrile (to precipitate proteins) and centrifuging to separate the supernate for analysis. An aliquot of supernatant from each brain homogenate and plasma sample was analyzed to determine quinoline methanol concentrations by liquid chromatography/mass spectrometry. Drug concentration-time data was analyzed using WinNonLin to generate PK parameters using a non-compartmental model. 2. In Vitro Susceptibility Studies

[00164] The 50% and 90% inhibitory concentrations (IC ₅₀ and IC ₉₀ ) of the analogs were determined against four drug resistant strains of Plasmodium falciparum in vitro. These strains were W2, D6, C235 and C2A. W2 is chloroquine-resistant, D6 is mefloquine resistant, and the C235 and C2A strains are resistant to multiple drugs. The IC ₅ 0 and IC ₉₀ values represent the concentrations in ng/ml at which the incorporation of tritiated hypoxanthine is inhibited by 50% or 90% respectively. Since hypoxanthine incorporation is essential for parasite growth, inhibition of its action by drug uptake is a measure of the drug's toxicity to the parasite. Therefore the lower the IC50 or IC90 of a drug, the greater is its potency. 3. In vitro Toxicity Assays

[00165] The LC ₅ 0 of some of the analogs was determined in vitro against a RAW macrophage cell line. The LC ₅₀ is the 50% lethal concentration, and represents the concentration at which colorimetric conversion of a substrate by cell mitochondria is inhibited by 50%. Since mitochondrial activity is indicative of cell viability, the decline substrate conversion is interpreted as the lethal effect of a drug on cells. Thus the lower an LC50, the more potent its toxic effects. Selectivity index relates toxicity to mammalian cells with antimalarial activity by calculation of the ratio of the macrophage LC ₅₀ to the IC50 against a parasite line such as W2. The greater the selectivity index the greater the selectivity of the antimalarial effect.

4. MDCK Permeability Assay [00166] Since mefloquine does have multiple potential targets and the clinically relevant ones are not known, reduced blood-brain barrier penetration is a logical approach to reduce exposure of multiple targets to a next generation quinoline methanol. For this reason, the apparent permeability of selected compounds across MDRl-transfected MDCK cell monolayers was determined. This assay is commonly used in vitro surrogate of the blood-brain barrier. Lower permeability in vitro represents the potential for low brain levels in vivo.

[00167] To determine permeability, MDRI-MDCK monolayers were grown to confluence on collagen-coated, microporous, polycarbonate membranes in 12-well Costar Transwell@ plates. The permeability assay buffer was Hanks Balanced Salt Solution containing 10 μM HEPES and 15 μM glucose at a pH of 7.4. A known p-glycoprotein inhibitor cyclosporin A (CSA) was also added to the assay buffer at 10 μM. Bovine serum albumin (BSA) (1 %) was added to the receiver as well. The dosing solution concentrations of the test compound were 5.0 μM in the assay buffer. All cell monolayers were first pre-incubated for 30 minutes with assay buffer to saturate any p-glycoprotein sites with test compound. After 30 minutes, the buffer was removed, replaced with fresh buffer, and time was recorded as 0. The addition of BSA, preincubation, and longer incubation time were employed to mitigate potential low recovery or permeability that is sometimes observed for lipophilic or "sticky" compounds. Cell monolayers were dosed on the apical side (A-to-B) or basolateral side (B-to-A) and incubated at 37°C with 5% CO ₂ in a humidified incubator. After 2 hours, aliquots were taken from the receiver chambers. Samples were taken from the donor chamber at 0 and 2 hours. Each determination was performed in duplicate. The lucifer yellow flux was also measured for each monolayer to ensure no damage was inflicted to the cell monolayers during the flux period. All samples were assayed by LC/MS/MS using electrospray ionization. The apparent permeability in the apical (A-B direction), Papp _A - _B , is reported in Table 16. Apparent permeability is a measure of the rate of transport across the cell monolayer and was determined as follows:

Papp = (dCr Idi) x Vr/(A x CO) where, dCτ Idi is the slope of the cumulative concentration in the receiver compartment versus time in μM s-1. Vr is the volume of the receiver compartment in cm ³ .

Vd is the volume of the donor compartment in cm ³ . A is the area of the cell monolayer (1.13 cm ² for 12- well Transwell®). CO is the measured concentration of the donor chamber at time 0 in μM. 5. Unbound Brain and Plasma Fraction [00168] The unbound fraction of each analog in mouse brain, mouse plasma and human plasma was determined. This unbound fraction may reflect the concentration of drug that is free to interact with non-target receptors or protein in plasma or brain. Thus, all other things being equal, a drug with a lower unbound plasma or brain fraction may have a more favorable adverse event profile. The unbound concentrations in brain and plasma were determined using equilibrium dialysis according to the methods of J. C. Kalvass and T. S. Maurer, Biopharmaceutics and Drug Disp. 2002, 23: 327-338, incorporated herein by reference, with the following modifications: Membranes (12-14kDA cut-off) were conditioned in deionized water for 60 minutes, followed by conditioning in 80:20 deionized wateπethanol for 20 minutes, and then rinsed in isotonic buffer or artificial CSF before use. Brain tissue was diluted 2-fold with artificial cerebral-spinal fluid (CSF). The compound of interest was spiked at a concentration of 10 ug/ml and dialysis was performed for 5 hours. Diluted brain tissue homogenate was dialysed against artificial CSF and plasma was dialysed against isotonic buffer. 6. Assessment of In Vivo Efficacy of Mefloquine and 8-SF ₅ Mefloquine

[00169] The standard Plasmodium berghei-mouse model was used to assess the efficacy of the two drugs. This model is usually predictive of activity against P. falciparum in humans or primate models. Three groups of five mice were inoculated with 1,000,000 asexual blood stage parasites of P. berghei intraperitoneal^ (i.p.). Three days later parasites were detectable on Geimsa-stained blood smears. Three groups of five mice were treated with either the drug vehicle, mefloquine (40 mg/kg orally as a single dose) or 8-SF5 mefloquine (40 mg/kg orally as a single oral dose). The drug vehicle was 5% v/v ethanol, 5% v/v chremophor EL, 0.5% w/v hydroxyethylcellulose in 0.2% v/v Tween 80. Mefloquine and 8-SF ₅ mefloquine were dispersed in the drug vehicle by homogenization. Animals dosed with only the drug vehicle were controls. Animals were monitored daily for clinical signs of malaria, and euthanized humanely parasite burden was high or the animals showed clinical signs of malaria. Typically this occurs in control (vehicle-dosed) animals on Day 6-7. The animals are monitored through Day 30. Animals surviving through Day 30 are considered cured. 7. Measurement of Mefloquine, 8-SF ₅ Mefloquine, and WR318973 Levels After IV and PO Dosing in Mice

[00170] FVB mice were given mefloquine, or 8-SF ₅ mefloquine, or WR318973 intravenously as a single dose of 5 mg/kg. WR318973 was give as a single oral dose of 160 mg/kg. Periodically, groups of 4 mice were euthanized and plasma was collected. Plasma proteins were precipitated using 20% ice-cold acetonitrile followed by microcentrifugation. Drug levels were measured using standard LCMS/MS. A measured plasma drug concentration vs. time curve were produced, in graphic and tabular form, for each subject on both linear/linear and log/linear scales, for the compounds. Mean plasma drug concentration vs. time curves were also presented separately. Summary statistics (i.e. mean, standard deviation, minimum, maximum, n and coefficient of variation) were calculated for plasma concentrations for each time point and each dose level. Pharmacokinetic parameter values were estimated using WinNonlin pharmacokinetic software (version 5.2). A non-compartmental model and/or compartment model were used to generate parameter estimates. The terminal half-life of test drug was determined by regression analysis of the terminal elimination slope. Area under the plasma (AUC) concentration-time curve extrapolated to infinite time was calculated by extrapolation of the elimination slope from t to infinity, thus: AUC(, _n β = AUC( _0- ia _S t) + (Ct/Kel). Where Ct = the plasma drug concentration at time t, and KeI = the elimination rate constant for the drug, determined from the terminal elimination slope. Bioavailability was calculated as follows: Bioavailability (%) = 100 x AUC _I6 O _PO /(AUC _5I V x 32), where AUQeopo is the AUC after an oral dose of 160 mg/kg PO and AUCsiv is the AUC after an IV dose of 5 mg/kg.

EXAMPLE 1 : Physiochemical Properties and Biological Data A. Methods [00171] Over two hundred next generation quinoline methanols were synthesized. All analogs were modified at the 4 position. The synthesis was designed to provide rapid access to a broad range of chemotypes at the 4-position in a single step from the 4-(oxiran-2-yl)-2,8- bis(trifluoromethyl)quinoline scaffold using the general reaction scheme outlined in FIG. 2. A small subset of compounds was synthesized by alternative means (data not shown). Compounds were designed to be rule of 5 (R05) compliant (Lipinski, 2000, J. Pharmacol. Toxicol. Methods 44: 235-49, incorporated herein by reference) and to encompass the widest feasible range of LogD, LogP, freely rotatable bonds (FRBs), polar surface area (PSA), hydrogen bond donors (HBDs) and hydrogen bond acceptors (HBAs, see Table 4). The in vitro IC90 values of the compounds against four different strains of P. falciparum, W2, D6, C235 and C2A, and LC ₅₀ values in a cytotoxicity assay were determined as described herein (Dow et al., 2008a). [00172] Interesting compounds were evaluated in several secondary assays including metabolic stability assessments using in vitro liver microsomes, drug-drug interaction assays, in vivo efficacy in the P. berghei mouse model as single and three day dose regimens and against neurons in vitro as previously described by Dow et al., 2006a and Dow et al., 2008a, incorporated herein by reference. Inhibition of the A2A and Al receptors was determined at 200 nM in duplicate by Caliper Biosciences (Hanover, Maryland). The A2A and Al receptors are suspected to be two of many targets of mefloquine in vivo (Gillespie et al., 2008, Weiss et al., 2003). Permeability across MDRl -transformed MDCK cell monolayers was determined by Absorption Systems (Exton, Pennsylvania) determined as previously described (Wang et al., 2005, incorporated herein by reference) with appropriate modifications to maximize the permeability of mefloquine. These were the incorporation of 1% BSA into recipient wells, co- incubation with the PgP inhibitor cyclosporine A at 10 μM and extension of the normal incubation time to 120 min after an initial 30 min incubation. This screen is a standard in vitro assay for blood-brain barrier permeability. All physiochemical properties were calculated using ACD (Version 10, ACD Labs, Toronto, Canada) except LogD (pH 7.4) which was determined using Pipeline Pilot (Version 6.1 , Accelrys, San Diego California).

B. Results

1. Synthesis and primary screening.

[00173] One hundred ninety eight quinoline methanols were synthesized and subjected to the screening paradigm laid out in FTG.2. The ranges of physiochemical properties represented by the library are outlined in Table 4. The primary screening data and physiochemical properties of all compounds are presented in Tables 1 and 2. Of the original 198 compounds, 24 (12%) exhibited IC9 ₀ S less than 250 nM and cytotoxicity similar or better than mefloquine. The structures of these compounds and their IC ₉₀ S are presented in FIG. 22. Ten of these compounds were selected for screening in various secondary assays based on their chemical structures. WR308278 and WR308396 were selected as they were the only compounds containing heteroatoms in the side chain that were more potent than mefloquine. WR308245, WR308255, WR308257 and WR308266 were selected because they were approximately equivalent or superior to mefloquine in terms of potency, but contained less steric bulk in their side chains. WR308387, WR.308388, WR308413 and WR308446 were selected as they were substantially more potent than mefloquine in vitro.

2. Secondary screening.

[00174] The rank order of mefloquine and selected quinoline methanols in terms of potency against the four strains of Pf were similar in most cases (Table 5). Most of the compounds screened were more metabolically labile than mefloquine (Table 5). The exceptions were those in which the side chain was presumably less susceptible to N-dealkylation (WR308245 and WR308257) and the diamine WR308396. In the in vivo experiments, only WR308245 and WR308257 exhibited similar cure rates to mefloquine after administration of a single dose of 320 mg/kg. There was a significant correlation between the half-life in mouse microsomes to the therapeutic outcomes in mice after administration of a single dose (r ² = 0.51 , P = O 014) of 320 mg/kg but not with the three day regimen. The failure of WR308396 in vivo despite its metabolic stability is an outlier relative to this general trend. All the compounds except WR308245 and WR308255 exhibited more potent inhibitory effects on cP450 2D6 than the other iso forms. All the compounds were less neurotoxic than mefloquine WR308245, WR308257, WR308278 and WR308387 were more permeable across MDCK-MDRI cell monolayers than mefloquine (Table 5). WR308396 exhibited slightly lower permeability than mefloquine and half the permeability of WR308387 (Table 5). The inhibition of the A2A and Al receptors by four of the analogs at 200 nM was evaluated (Table 5). In most cases the level of inhibition observed was lower or comparable to that observed with mefloquine. The exception was WR308245 against the Al receptor.

3. Relationship between activity and physiochemical properties.

[00175] The physiochemical properties amongst inactive compounds, active compounds with ICg ₀ S < 500 ng/ml or 1000 nM and active compounds with IC ₉₀ S < 250 nM were compared. The threshold for inactivity was set at an IC90 > 500 (or the approximate corresponding concentration of 1000 nM) since this was the highest concentration tested in the assay. There were no significant differences amongst these groups in terms of LogD, HBDs and FRBs (Table 6). LogP was significantly higher, PSA significantly lower, and the number of HBAs significantly lower in active compounds (Table 6). The most active compounds exhibited lower molecular weights (MW) than less potent and inactive compounds.

4. Structural characteristics of active and inactive compounds.

[00176] Analogs were categorized arbitrarily as having particular structural motifs. The proportion of active (IC90 < 500 ng/ml or 1000 nM) and inactive compounds containing these functional groups was determined and differences between the groups were tested for significance using Fisher's Exact test (Table 7). The inactive group contained a greater proportion of compounds in which the 4 position amino side chain contained additional heteroatoms, analogs in which the hydroxyl group or amine functionality were replaced, and compounds in which the first nitrogen atom in the side chain was conjugated. The active groups of compounds contained a higher proportion of secondary amines and compounds in which the amino side chain contained no additional heteroatoms. The inactive and active groups contained similar proportions of tertiary and benzyl amines.

C. Discussion [00177] From a structural standpoint several attributes appear to be required for activity in quinoline methanols. The 4-position side chain hydroxyl and amine functionality is essential. Generally, conjugated amines were ineffective so these should be avoided. Lower molecular weight secondary amines with no additional heteroatoms in the side chain were the most potent (e.g. WR177000, WR308446 and WR308387). However, there are two barriers to the utility of these compounds as drugs. First, they exhibit higher relative permeability than mefloquine across MDCK-MDRl cell monolayers. Second, they are metabolically labile and this is reflected in poorer efficacy outcomes in vivo, confirming earlier observations (Dow et al., 2006b). Both of these limitations are likely related to their higher lipophilicity relative to mefloquine. Both could potentially be resolved by the inclusion of appropriate substituents in the side chain to lower lipophilicity.

[00178] Permeability across the blood-brain barrier can be reduced by decreasing lipophilicity (lower LogP and LogD), increasing PSA, and increasing HBDs and HBAs (Kearns and Di, 2008). A priori it was a reasonable expectation that these characteristics might also be associated with higher IC ₉₀ S (and therefore lower potency) as a consequence of lower permeability across parasite membranes. The data suggest this relationship may be more complicated. Significant differences between inactive and active compounds were observed for LogP, HBAs and PSA. This was not the case for HBDs and LogD. It can be rationalized that the first set of data has increasing lipophilicity resulting in increased potency, presumably due to increased permeability. LogD incorporates ionization state at physiological pH whereas LogP does not. Almost all the analogs, active and inactive, contain a basic side chain and thus are likely to be protonated at physiological pH. The HBD trends are more counter-intuitive given that increased HBDs should lower lipophilicity and therefore potency. This may be an artifact imposed by the constraints of R05 compliance, as library contains only seven compounds with greater than three HBDs. Mefloquine has two HBDs. The sample sizes may be insufficient to show a statistical association.

[00179] From the perspective of synthesizing a next generation of quinoline methanols, these observations indicate that incorporation of HBDs (rather than HBAs) into the side chain may be the most viable way to optimize potency and blood-brain barrier permeability. To this end, WR308396 is probably a more useful starting scaffold than WR308278 because it was less, rather than more, permeable relative to an appropriate comparator (WR308387). However, there may be a limit to how many H-bond donors can be added before decreasing lipophilicity results in decreased potency. It is well known that decreasing lipophilicity increases metabolic stability and decreases clearance in vivo (Kerns and Di, 2008). Therefore these same structural modifications may improve efficacy in vivo. However it is also possible that such changes will have a counteracting effect in terms of reducing volumes of distribution (and therefore half-life).

[00180] The goal is to resolve the CNS tolerability issues of mefloquine by reducing partitioning into the central nervous system. However, this strategy may be counter productive if it results in inadvertent increases in potency against suspected targets of mefloquine in the CNS. Prior studies suggest that mefloquine may exhibit a direct neurotoxic effect in vivo and has potent activity against the A2A receptor (Weiss et at., 2003, Caridha et al., 2008, Gillespie et al., 2008). The most interesting analogs were evaluated against these targets. Most of the analogs tested exhibited lower LC ₅ 0S against neurons or greater inhibition of the A2A receptor than mefloquine. [00181] Generally mefloquine and the compounds evaluated in the in vivo studies showed the same rank order in terms of potency in vitro against the four drug resistant strains of P. falciparum. This may indicate cross-susceptibility to mefloquine. One can speculate that, all other factors being equal, such compounds, where they have equivalent potency to mefloquine, might not be fully effective if used clinically as single agents for malaria treatment in areas where background resistance to mefloquine if used as monotherapy is prevalent (e.g. the Thai borders). Mefloquine is normally used in combination with artesunate in such regions and remains clinically useful when deployed in this manner (Price et al., 2004). The intent would be to use a next generation quinoline methanol with a combination (perhaps non-artemisinin) agent in the same manner if needed. For this reason, lack of cross-susceptibility to mefloquine is a desirable rather than a required property of a next generation quinoline methanol.

EXAMPLE 2: Structure Activity Relationships [00182] In order to efficiently prepare analogs with the 2,8-trifluoromethyl quinoline core, the vast majority of derivatives were constructed according to the procedure outlined in FIG. 23. Large quantities of the 2,8-bis-trifluoromethyl-lH-quinolin-4-one intermediate 8 were prepared following the protocol of the Lutze group (see Ohnmacht et al. 1971. Antimalarials. 7. Bis(trifluoromethyl)-α-(2-piperidyl)-4-quinolinemethanols. J Med Chem VoI 14, No 10: pp 926- 928, incorporated herein by reference). Bis(trifluoromethyl) quinolin-4-ol 8 was melted along with phosphorous oxybromide to provide 4-bromo-2,8-bis(trifluoromethyl) quinoline 9. The resulting white solid was dissolved in tetrahydrofuran, cooled to -78°C and subjected to n- butyllithium. N,N-dimethylformamide was subsequently added to afford 2,8- bis(trifluoromethyl)quinoline-4-carbaldehyde 10. Utilization of Corey's dimethylsulfonium methylide provided racemic epoxide 11, which is also commercially available from Bioblocks (San Diego, Ca).

[00183] Quinoline scaffold 11 was diversified at the 4-position through a regioselective S _N 2 nucleophilic ring opening mechanism. To prepare ethers 12a and thioethers 12b, the requisite alcohol or thiol was added to a suspension of sodium hydride in THF and cooled to 0 ⁰ C prior to adding epoxide 11. After screening a variety of carbon nucleophiles, it was determined that Grignard reagents were clearly superior for constructing 12c. Epoxide 11 was dissolved in ether or THF, depending on the solvent associated with the commercially available Grignard reagent, and cooled to -78°C prior to adding the Grignard reagent and subsequently allowed to warm to 0°C. Generally, the nitrogen-based analogs were prepared via a microwave-assisted epoxide opening. Epoxide 11 was dissolved in ethanol; the requisite amine was added and the solution subjected to microwaves at 13O ⁰ C.

Results and Discussion

[00184] In an effort to systematically explore the 4-position, the utility of the amino alcohol was tested. It appears the benzylic alcohol is essential for activity since the addition of a methyl blocking group results in loss of activity (compare mefloquine WR142490 to WR308038, Table 8). Substitution of hydroxyl with either a thiol or amino group results in a loss of activity relative to mefloquine (compare WR142490 to WR308393 and WR308392, Table 8).

[00185] Once the alcohol was deemed essential, the utility of the amine was explored. As shown in Table 9, while n-butyl amine (WR 177000) was quite efficacious, alternate heteroatoms such as oxygen (WR308633), sulfur (WR308632), and carbon (WR308653) were devoid of activity. Based upon these results, nitrogen-based moieties were explored at the 4-position while generating the remainder of the empirical library. In regards to nitrogen functionalization, the data suggest that the nature of the 4-position amine and the degree of electron density around the nitrogen are most strongly associated with activity. The remainder of the discussion explores the relationship between 4-position amine substituents and antimalarial activity. [00186] Antimalarial and selectivity data for a subset of compounds with benzene side chains are presented in Table 10. In order to maintain consistency with the numbering system of polysubstituted benzenes, nitrogen functionalization is denoted as position 1 on the ring and the R-groups are numbered accordingly beginning with R ₂ . Not surprisingly, the data suggest resonance and inductive effects are influencing efficacy. For example, phenyl amine (WR308251) has a much lower activity then benzyl amine (WR308252) and phenethylamino QM (WR308253). This suggests the reduction of electron density around the amine, due to the adjacent benzene ring, diminishes potency. In addition all of phenyl amines tested were nearly devoid of activity and the addition of electron withdrawing groups further decreased activity. [00187] Utilizing unsubstituted WR308252 as the reference point, a modest trend was observed for benzyl amines. A 4-methyl (WR308375) substitution increased activity, suggesting additional liphophilicity or steric bulk is beneficial. Electron donating and withdrawing groups had little effect on the structure activity relationship. For example, 3,5-fluoro (WR308414) and 3-piperidine (WR308518) analogs were more active than analogs possessing methoxy (WR308395 and WR308506), chloro (WR308400 and WR3O8371), and thiophene (WR308590) substituents.

[00188] It is well known that activation mechanisms of amines may lead to toxicity. Arylamines in particular are known to form N-hydroxyl amines, which produce nitrenium intermediates that subsequently react with nucleophiles such as DNA to cause toxicity. The in vitro assay systems used to generate the data presented in Table 10 would not likely detect such toxicity. At a more generic level, however, it is encouraging that there is no apparent relationship between intrinsic antimalarial activity and selectivity. All of the compounds except WR308251 and WR308253 exhibited improved selectivity indexes relative to mefloquine. [00189] Imidazole and benzo[rf]imidazole derivatives were collectively categorized as heterocyclic amino quinoline methanols (HAQMs). When the ICg ₀ values for the four drug resistant P. falciparum strains are essentially the same order of magnitude, a promising cross- susceptibility IC ₉₀ profile emerges (Table 1 1). WR308437 and WR308623 in particular illustrated this trend. In regards to benzo[cf|imidazole derivates, a similar trend was observed for WR308682, WR308763, and WR308764. In particular, WR308682 has increased potency and a superior selectivity index as compared to mefloquine. The HAQMs exhibited half-lives in the in vitro metabolic stability assays of 4-22 minutes in comparison to > 60 minutes for mefloquine. They are therefore much less metabolically stable than mefloquine. If this translates into shortlived plasma drug concentrations in vivo, it would not bode well for their utility for prophylaxis. [00190] In regards to alkyl amino quinoline methanols (AAQMs), an intricate relationship between steric bulk and liphophilicity of the alkyl groups have emerged and merits further study to determine the discrete contributions to efficacy. Although the mechanism of action for mefloquine is not fully understood, the lipophilic nature of mefloquine (MQ) and quinine are known to correlate with delivery of drug to the parasite. MQ is also known for high-affinity binding to erythrocytes and other cells, which may provide a reservoir of drug and contribute to the long half-life. In general, these compounds were more potent than MQ and displayed a one- log increase in selectivity. Alkyl substitution is paramount. For example, the primary amine WR308314 is nearly devoid of activity, while the addition of methyl, ethyl, propyl, and butyl groups substantially increase efficacy (Table 12). Interestingly, branched alkyl substituents such as J-Pr and j-Bu prove quite active, while f-butyl displays moderate activity. Chain length also appears to affect activity since «-Bu (WR 177000) and /i-hex (WR308442) have different levels of potency, presumably resulting from the addition of two methylene units. In general, the increase in potency coupled with the reduced cost of goods for these analogs as compared to MQ add to their potential utility.

[00191] N-methyl (WR308245), /-Pr (WR308257), and r-butyl (WR 183545) derivatives (Table 12) all displayed favorable metabolic stability profiles presumably due to inhibition of N- dealkylation. In an effort to probe structural modifications to improve stability, it was useful to probe the site of metabolism. Therefore, WR 17700 was chosen as a scaffold, and the initial strategy was to prepare a series of branched alkyl amino quinoline methanols (Table 13). Methyl substitution resulted in half-lives of greater than 60 minutes with human liver microsomes. As for mouse microsomes, the trend in half-life followed Rl > R2 > R3. Overall, most AAQMs demonstrated an increase in potency and a selectivity index superior to MQ, while branching proved to be an efficient strategy for improving metabolic stability. [00192] A variety of alkyl amino quinoline methanols containing additional heteroatoms (AAQMHs) were also constructed (Table 14). In doing so, it became apparent efficacy is reduced by the addition of an alcohol, acid, fluorine, or amide within the side-chain. In particular, when the hydroxyl of WR308258 is transformed into the methyl ether (WR308412) potency increases by nearly an order of magnitude. Ether WR308622 and thioether WR308278 were more potent and demonstrated a superior selectivity index compared to mefloquine. The presence of a benzyl amine (WR308396) was also advantageous. Interestingly, the presence of a primary amine within WR308426 and WR308384 resulted in decreased potency. Of this series, the ethers, thioethers, and secondary amines have proved most promising. A series was also constructed based upon varying the polar surface area of the efficacious dibutyl amine (WR176990; Table 12). Once the corresponding acid, ester, alcohol and amide were prepared (WR308147, WR308320, WR308321 , WR308318; Table 14, respectively), it was apparent that these modifications did not increase potency.

[00193] This next generation quinoline methanol (NGQM) library was constructed based upon a 4-position scaffold, the goal of achieving greater or equivalent potency, improved selectivity and a lack of cross-susceptibility to mefloquine. One or more of the chemotypes investigated here displayed one or all of these characteristics and could potentially be considered early lead compounds. Analogs with phenyl-containing side chains such as WR308375 and WR308253 have equivalent or greater potency and selectivity relative to mefloquine with different cross-susceptibility profiles. The same is also the case for imidazole-containing analogs such as WR308407, WR3O8681, and WR308682. Alkylaminoquinoline methanols with additional heteroatoms such as WR308412, WR308622, WR308378 and WR308396 exhibited equivalent potency to mefloquine but their activity across different parasite strains also tracked with those of mefloquine. However, to be considered a potential lead compound some evidence of efficacy after oral dosing is desired, as well as, the potential for reduced permeability across the blood brain barrier. The latter trait is essential if the adverse neurological effects of mefloquine are to be avoided in a new series of analogs.

[00194] Representative compounds from the mentioned list were evaluated for their efficacy in vivo against P. berghei in mice. The bidirectional permeability of the same compounds was measured across MDRl -transformed MDCK cell monolayers in the presence of the PgP inhibitor cyclosporin A. This screen is normally used as a surrogate of potential permeability across the blood-brain barrier. Here data for compounds (WR308437, WR308412 and WR308622) not previously described is reported. In an earlier study it was shown that the thioether WR308278, the long chain alkyl compound WRl 77000 and the short chain alkyl compound WR308245 were active in vivo after oral dosing but exhibited greater permeability relative to mefloquine across MDCK cell monolayers (Table 15). The latter property suggests greater propensity for accumulation into the central nervous system. This was also the case for WR308427, WR308412 and WR308622 in the present study. Taking all the data into consideration, only WR308396 exhibited efficacy in vivo after oral dosing, lower or equivalent permeability across MDCK cell monolayers relative to mefloquine, and reduced permeability across MDCK cell monolayers relative to lipophilic alkyl compounds such as WRl 77000 lacking the diamine motif. These observations suggest a hypothesis for further investigation. Diamine quinoline methanols will retain the potency of mefloquine but exhibit significantly reduced permeability across the blood:brain barrier.

Conclusion [00195] Structure activity relationships were investigated amongst a library of 200 4- position analogs of mefloquine. The 4-position alcohol and at least one amine met the minimum requirement for equivalent potency to mefloquine. Decreased electron density around the first side chain amine greatly diminished potency. Moderately enhanced potency, increased selectivity and altered cross-susceptibility patterns were achieved with imidazole and benzene containing analogs. Ten- fold greater than potency and selectivity than mefloquine without altered cross-susceptibility patterns were achievable in analogs with alkyl side chains. Introduction of heteroatoms into these latter analogs generally reduced potency, although select analogs exhibited equivalent potency to mefloquine.

EXAMPLE 3: Actual and Calculated Log Ratios of a Drug [00196] A selection of 29 structurally diverse quinoline methanols was synthesized using the methods described. The log of the ratio of brain to blood concentrations was calculated (the cLogBB value) based on the equation cLogBB = (0.205 *LogP) - (0.0094*PSA) - (0.055 *FRBs) + 0.18. These were compared to the actual log of the ratio of brain to blood concentration.

[00197] The actual log of the ratios of brain to blood concentrations was determined in mice as follows. The compounds were administered intravenously to groups of 2-4 FVB mice at a dose of 5 milligrams per kilogram of bodyweight. At 5 minutes, 60 minutes, 4 h and 24 h, brain and plasma concentrations were measured. The maximum brain and plasma concentrations were calculated. The ratio of maximum brain concentration to plasma concentration was determined.

These values were converted to Log units. These values are referred to as the actual LogBB values. They were plotted and are presented in FIG. 24. Linear regression was performed, yielding an r ² value of 0.44 and a significantly non-zero slope of the regression line (P < 0.0001).

This result means that a correlation exists between the calculated and actual values for LogBB, underscoring the utility of the in silico calculation method. EXAMPLE 4: Synthesis and Evaluation of Pentafluorosulfanyl (SF ₅ ) Analogs of Mefloquine [00198] Herein is described an efficient synthesis of 6-SF5 and 7-SF ₅ analogs of mefloquine as well as their biological activities against malaria parasites.

[00199] A straightforward and high yielding synthesis is based on the oxidative decyanation of 2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(pyridin-2-yl)ac etonitrile. This route to access analogs 2 and 3, which were each obtained in 5 steps from the corresponding commercially available amino-(pentafluorosulfanyl)benzenes 4a and 4b (FIG. 28). Condensation of with ethyl 4,4,4-trifluoroacetoacetate in the presence of polyphosphoric acid led to 4-hydroxyquinolines 10 6a and 6b. In the latter reaction, only the desired 4-hydroxy-7-(pentafluorosulfanyl)quinoline 6b was isolated in 75% yield. The absence of the 5-pentafluorosulfanylquinoline isomer is probably due to the large steric demand of the SF5 group and/or electrostatic repulsion of the 4-oxygen substituent. Chlorination with phosphorus oxychloride gave the corresponding 4- chloroquinolines 7a and 7b in good yields. Subsequent nucleophilic aromatic substitution by the 2-pyridylacetonitrile carbanion provided 8a and 8b. Exposure to a mixture of hydrogen peroxide and acetic acid afforded the 4-quinolylketones 9a and 9b in excellent yields.

[00200] Finally, the simultaneous reduction of the carbonyl and pyridyl groups in the presence of quinoline moiety was achieved using catalytic hydrogenation under acidic conditions. This step of the synthesis proved to be problematic. After screening different solvents and acids, and 30 varying hydrogen pressure and catalyst equivalents, optimal conditions for substrate 9a were found to be 0.4 equivalents of platinum oxide in ethanol containing hydrochloric acid, followed by recrystallization of crude 2 in MeOH. In contrast, 9b was best converted to target compound 3 in the presence of milder acetic acid. Gratifyingly, both reactions were highly selective and afforded the desired α«f/-diastereomers. Slow evaporation of a MeOH solution of 3 afforded needle-like crystals suitable for X-ray diffraction analysis. The sulfur atom of the SF ₅ group is situated in an octahedral environment, and the disposition of the two stereocenters is anti as in mefloquine.

[00201] The antimalarial activities and selectivities of 2 and 3 were compared to 1 and mefloquine analogs in which the quinoline ring was substituted at the 6- and 7-positions with a trifluoromethyl group (10 and 11, FIG. 29). The 50 and 90% inhibitory concentrations (IC ₅₀ S and IC90S) against four drug resistant strains of Plasmodium falciparum, and the LC ₅₀ S against a mammalian cell line were determined as previously described (Dow, et al., 2008a). Compound 2 exhibited generally equivalent or lower IC ₅₀ and IC ₉₀ , and greater selectivity than mefloquine and its CF ₃ -congener. The IC ₅₀ and IC90 of 3 were generally equivalent to those of mefloquine and CF ₃ -analog. These data demonstrate the biological mimicry as well as the pharmaceutical potential of the CF ₃ -SF ₅ switch in quinoline containing antimalarials.

EXAMPLE 5: Permeability of a Pentafluorosulfanyl Analog Compared to Mefloquine [00202] A mefloquine derivative was synthesized, wherein the 8-position trifluoromethyl (CF ₃ ) group was replaced by a pentafluorosulfanyl (SF ₅ ) group, and all other substitutions on the mefloquine scaffold were unchanged. The permeability of this compound compared to mefloquine was determined as described herein. The permeability of the 8-position pentafluorosulfanyl mefloquine analog was 4.98 x 10 ^"6 cm/s compared to 9.4 x 10 ^"6 cm/s for mefloquine. These data demonstrate that in addition to the potential improvement in potency imparted by switching of a trifluoromethyl group to a pentafluorosulfanyl group (Example 4), the switch may also allow the permeability of the scaffold to be reduced. This means that SF5- substituted quinoline methanols are potentially more potent, efficacious and less brain penetrant than their correspondingly trifluoromethyl substituted counterparts.

EXAMPLE 6: Synthesis and Evaluation of 8-Pentafluorosulfanyl Analog of Mefloquine and Formation of Novel Intermediates

[00203] As depicted in FIG. 31, the 8-SF ₅ analog 6 of mefloquine was synthesized in nine steps through a novel ørr&o-SFs-substituted aniline intermediate 7. Preclinical assays have determined that this analog of the malaria-prophylactic agent has improved activity against P. falciparum parasites and exhibits lower membrane permeability in an MDCK cell line screen, thus potentially reducing the adverse CNS effects of the parent compound, mefloquine.

[00204] FIG. 31 illustrates that the novel σrt/ιø-SF ₅ -aniline 7 was prepared from commercially available 3-SFs-phenol 8 en route to the 8-SF ₅ mefloquine analog 6a-b. The ortho-aπύno group was installed by regioselective nitration of a suitable pentafluorosulfanyl arene followed by reduction, using 3-SFs-phenol 8 as the nitration substrate. However, the regioselectivity of nitration of the phenol 8 was poor, since the hydroxyl group is a strong ortho/para-dktcύng substituent. To diminish the ortho-άiiecύng effect, the phenol 8 was converted to trifluoromethanesulfonate in 90% yield, and nitration proceeded in 75% yield to give exclusively the desired product 9 with the nitro group in the ortΛo-position to the SF5- moiety. Subsequent Pd-catalyzed reduction of the nitro group furnished the ortho-SFs aniline 10 in good yield (80%). Removal of the triflate was not trivial. Initial attempts using Pd(II) and hydrogen transfer conditions led to the reductive cleavage of the SF5 group or decomposition. However, when Pd(O) catalyst was employed in the presence of formic acid and triethylamine, the desired compound 7 was formed. The subsequent Conrad-Limpach reaction with 4,4,4- trifluoroacetoacetate 11 in polyphosphoric acid led to the 8-pentafluorosulfanylquinolyl intermediate 12 in 46% yield over two steps. The previously used chlorination conditions with phosphorous oxychloride in 110 ⁰ C proved to be too harsh for quinoline 12, but the milder thionyl chloride afforded the product in good yield (80%). After nucleophilic aromatic substitution with 2-pyridylacetonitrile, oxidation of the carbon-nitrile bond and Pt-catalyzed reduction of ketone and pyridine moieties in 13 proceeded in moderate yield to afford the target 8-SF ₅ molecule 6a-b. This synthesis could be used to prepare the 8-SF ₅ molecule 6a-b on 200 mg scale.

[00205] All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the following claims. REFERENCES

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