Background to the Invention Many classes of antibacterial agents are known, including the penicillins and cephalosporins, tetracyclines, sulfonamides, monobactams, fluoroquinolones and quinolones, aminoglycosides, glycopeptides, macrolides, polymyxins, lincosamides, trimethoprim and chloramphenicol. The fundamental mechanisms of action of these antibacterial classes vary.

Bacterial resistance to many known antibacterials is a growing problem.

Accordingly there is a continuing need in the art for alternative antibacterial agents, especially those that have mechanisms of action fundamentally different from the known classes.

Amongst the Gram-positive pathogens, such as Staphylococci, Streptococci, Mycobacteria and Enterococci, resistant strains have evolved/arisen which makes them particularly difficult to eradicate. Examples of such strains are methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant coagulase negative Staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium.

Recently there has been an emergence of vancomycin-resistant strains of enterococci (Woodford N. , 1998. Glycopeptide-resistant enterococci: a decade of experience. Journal of Medical Microbiology. 47: 849-62). Vancomycin-resistant enterococci are particularly hazardous in that they are frequent causes of hospital based infections and are inherently resistant to most antibiotics. Vancomycin

works by binding to the terminal D-Ala-D-Ala residues of the cell wall peptidoglycan precursor. The high-level resistance to vancomycin is known as VanA and is conferred by a genes located on a transposable element which alter the terminal residues to D-Ala-D-lac thus reducing the affinity for vancomycin.

In view of the rapid emergence of multidrug-resistant bacteria, the development of antibacterial agents with novel modes of action that are effective against the growing number of resistant bacteria, particularly the vancomycin resistant enterococci and beta-lactam antibiotic-resistant bacteria, such as methicillin- resistant Staphylococcus aureus, is of utmost importance.

Many classes of antifungal agents are known, including amphotericin B, azoles and triazoles. The fundamental mechanisms of action of these antifungal classes may vary but fungal resistance to these compounds is a growing problem.

There is an increased awareness of the morbidity and mortality associated with infections by resistant fungal pathogens such as Candida e. g. C. albicans, C. parapsilosis, C. krusei, C. glabrata and C. tropicalis ; and Aspergillus e. g. A. fumigatus, A. terreus and A. niger, Cryptococcus e. g. C. neoformans ; Scedosporium e. g. S. prolificans, and Fusarium species (Canuto et. al. 2002.

Antifungal drug resistance to azoles and polyenes. Lancet Infection and Disease 2; 550-563). Accordingly, there is a continuing need in the art for alternative antifungal agents, especially those that have mechanisms of action fundamentally different from the known classes.

Brief Description of the Invention This invention is based on the finding that certain tertiary amines have antimicrobial activity and makes available a new group of antimicrobial agents. It has been found that the compounds with which this invention is concerned are antibacterial with respect to a range of bacteria, of both the Gram-positive and Gram-negative types. Many of the compounds of the invention show activity against bacteria responsible for infections of the gastro-intestinal tract, such as

Enterococci, and/or against those responsible for respiratory infections, such as Streptococcus pneumoniae and/or Haemophilus influenzae, and/or those usually described as hospital acquired infections, such as Staphylococcus aureus and/or against yeasts responsible for fungal infections.

While the mechanism of action of the compounds with which the invention is concerned may be of some interest, it is their overall antimicrobial effect which makes them useful, and the invention is therefore not limited by any theory of their action.

Detailed Description of the Invention In a broad aspect, the present invention provides the use of a compound of formula (I) or a salt, hydrate or solvate thereof in the preparation of a composition for inhibiting microbial or plant growth: wherein B represents R2R3N-, R2NH-C (=NR3)-, or R2NH-C (=NR3)-NR4- wherein each of R2, R3 and R4 represents hydrogen or a C1-C6 alkyl, phenyl, phenyl (Ci-C6 alkyl)-, monocyclic heteroaryl, monocyclic heteroaryl (C1-C6 alkyl)-, or cyano group, or R2 and R3 form a ring together with the nitrogen atoms to which they are attached, L represents a divalent radical of formula (II) -(Alk1)m-(Cyc1)p-(Alk2)n-[(Alk3)r-(Cyc2)s-(Alk4)t]w- (II) wherein Alk1, Alk2, Alk3 and Alk4 each independently represent (i) an optionally substituted divalent C1-C3 alkylen radical which may

optionally contain an ether (-O-), thioether (-S-) or amino (-NRA-) link wherein RA is hydrogen or C1-C3 alkyl, (ii) an optionally substituted-CH=CH-radical, or (iii) a -C#C- radical, Cyc1 and Cyc2 each independently represent an optionally substituted divalent monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms, m, n, p, r, s, t and w each independently represent 0 or 1, provided that at least one of m, n and p is 1, R represents an optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Cyc-, (Cyc)-(C1-C6 alkyl)-, (Cyc)-(C2-C6 alkenyl)-, or (Cyc)-(C2- C6 alkynyl)-radical wherein Cyc represents a monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms, and R1 represents an optionally substituted (aryl)- (Ci-C6 alkyl)-, (aryl)- (C2-C6 alkenyl)-(aryl)-(C2-C6 alkynyl)-, (heteroaryl)-(C1-C6 alkyl)-, (heteroaryl)-(C2- C6 alkenyl)-or (heteroaryl)-(C2-C6 alkynyl)- radical, In a narrower aspect of the invention, in the compounds (I) : B represents NH2-, CH3NH-, NH2-C (=NH) -, NH2-C (=NH)-NH- N=C-NH2-C (=NH)-NH- or ; L represents a divalent radical of formula (III) -(Alk1)m-(Cyc1)p-(Alk2)n- (III)

wherein Alk1, and Alk2 each independently represent an optionally substituted divalent C1-C3 alkylen radical, Cyc'represents an optionally substituted divalent monocyclic carbocyclic radical having from 5 to 8 ring atoms, m, n and p each independently represent 0 or 1, provided that at least one of m, n and p is 1, R represents an optionally substituted C1-C6 alkyl, cycloalkyl (C1-C6 alkyl)- or phenyl (C1-C6 alkyl)-group and R1 represents an optionally substituted phenyl (Ci-C6 alkyl)-group.

The invention also includes compounds of formula (I) defined above wherein B is R2NH-C (=NR3) -, or R2NH-C (=NR3) -NR4-, and of course the salts, hydrates and solvates thereof. In particular, the invention includes compounds of formula (I) defined above in relation to the broad, intermediate and narrower aspects of the invention, wherein B represents CH3NH-, NH2-C (=NH) -, NH2-C (=NH)-NH-, N-C-NH2-C (=NH)-NH- or and salts, hydrates and solvates thereof.

In another aspect, the invention provides a method for the treatment of microbial (particularly bacterial or fungal) infections in humans and non-human animals e. g. other mammals, birds and fish, which comprises administering to a subject

suffering such infection an antimicrobially effective dose of a compound of formula (I) as defined above.

In a further aspect of the invention there is provided a method for the treatment of microbial (particularly bacterial or fungal) contamination by applying an antimicrobially effective amount of a compound of formula (I) as defined above to the site of contamination.

In a further aspect of the invention there is provided an antimicrobial pharmaceutical or veterinary composition comprising a compound as defined by reference to formula (I) above particularly one wherein B represents NH2- C (=NH)- or NH2-C (=NH) -NH-, and salts, hydrates and solvates thereof, together with a pharmaceutically or veterinarily acceptable excipient or carrier.

Antimicrobial compositions of the invention may additionally include an antimicrobial agent other than one defined by reference to formula (I) above.

As used herein the term"microbe"is to be understood as referring to bacterial or fungal microorganisms.

As used herein the term"(C1-C6) alkyl"means a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms, including for example, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.

As used herein the term"divalent (C1-C6) alkylen radical"means a saturated hydrocarbon chain having from 1 to 6 carbon atoms and two unsatisfied valences.

As used herein the term" (C2-C6) alkenyl" means a straight or branched chain alkenyl moiety having from 2 to 6 carbon atoms having at least one double bond

of either E or Z stereochemistry where applicable. The term includes, for example, vinyl, allyl, 1-and 2-butenyl and 2-methyl-2-propenyl.

As used herein the term"divalent (C2-C6) alkenylene radical"means a hydrocarbon chain having from 2 to 6 carbon atoms, at least one double bond, and two unsatisfied valences.

As used herein the term"C2-C6 alkynyl"refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1-propynyl, 1-and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl and 5-hexynyl.

As used herein the term"divalent (C2-C6) alkynylene radical"means a hydrocarbon chain having from 2 to 6 carbon atoms, at least one triple bond, and two unsatisfied valences.

As used herein the term"cycloalkyl"refers to a saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein the term"cycloalkenyl"refers to a carbocyclic radical having from 3-8 carbon atoms containing at least one double bond, and includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

As used herein the term"aryl"refers to a mono-, bi-or tri-cyclic carbocyclic aromatic radical. Illustrative of such radicals are phenyl, biphenyl and napthyl.

As used herein the term"carbocyclic"refers to a cyclic radical whose ring atoms are all carbon, and includes aryl, cycloalkyl and cycloalkenyl radicals.

As used herein the term"heteroaryl"refers to an aromatic radical containing one or more heteroatoms selected from S, N and O. Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl.

As used herein the unqualified term"heterocyclyl"or"heterocyclic"includes "heteroaryl"as defined above, and in particular means a non-aromatic radical containing one or more heteroatoms selected from S, N and O. Illustrative of such radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups.

The term"lipophilic"as used herein in relation to a substituent means that it has a positive substituent hydrophobicity constant (c). (A positive value for n indicates that the substituent is more lipophilic than hydrogen, whereas a negative value indicates it is less lipophilic, i. e. more hydrophilic, than hydrogen).

Unless otherwise specified in the context in which it occurs, the term"substituted" as applied to any moiety herein means substituted with at least one substituent, for example selected from (C1-C6) alkyl, (C1-C6) alkoxy, hydroxy, hydroxy (C1- C6) alkyl, mercapto, mercapto (C1-C6) alkyl, (C1-C6) alkylthio, halo (including fluoro and chloro), trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, nitro, nitrile (-CN), oxo, phenyl,-COOH,-COORA,-CORA,-S02RA,-CONH2,-S02NH2, - CONHRA,-S02NHRA,-CONRARB,-SO2NRARB,-NH2,-NHRA,-NRARB, - OCONH2,-OCONHRA,-OCONRARB,-NHCORA,-NHCOORA,-NRBCOORA, - NHS020RA,-NRBS020RA,-NHCONH2,-NRACONH2,-NHCONHRB,

-NRACONHRB,-NHCONRARB, or-NRACONRARB wherein RA and RB are independently a (C1-C6) alkyl group. Of the above substituents, (C1-C6) alkyl, halo, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, and phenyl and those most commonly regarded as lipophilic. Other substituents listed which contain alkyl groups may be lipophilic depending on the particular alkyl groups present.

As used herein the term"salt"includes base addition, acid addition and quaternary salts. Compounds of the invention which are acidic can form salts, including pharmaceutically or veterinarily acceptable salts, with bases such as alkali metal hydroxides, e. g. sodium and potassium hydroxides; alkaline earth metal hydroxides e. g. calcium, barium and magnesium hydroxides; with organic bases e. g. N-ethyl piperidine, dibenzylamine and the like. Those compounds (I) which are basic can form salts, including pharmaceutically or veterinarily acceptable salts with inorganic acids, e. g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e. g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic and p-toluene sulphonic acids and the like.

Some compounds of the invention contain one or more actual or potential chiral centres because of the presence of asymmetric carbon atoms. The presence of several asymmetric carbon atoms gives rise to a number of diastereoisomers with R or S stereochemistry at each chiral centre. The invention includes all such diastereoisomers and mixtures thereof.

The group B B represents R2R3N-, R2NH-C (=NR3)-, or R2NH-C (=NR3)-NR4- wherein each of R2, R3 and R4 represents hydrogen or a C1-C6 alkyl, phenyl, phenyl (Ci-C6 alkyl)- or cyano group, or R2 and R3 form a ring together with the nitrogen atoms to which they are attached, Examples of R2, R3 and R4 groups other than hydrogen include methyl and benzyl. B may be an amino group NH2-, but is more

preferably an amidino-NH2-C (=NH) -, or guanidino group NH2-C (=NH)-NH-.

When R2 and R3 form a ring together with the nitrogen atoms to which they are attached, that ring may be a monocyclic 5 or 6 membered ring.

The radical L This radical separates a nitrogen atom in B and the nitrogen of the substructure -NRR1. Radicals L have the structure (II) as defined above. In one class of structures (II) p may be 1 while w may be 1 or 0. When present Cyc1 and/or Cyc2 each may be a cycloalkyl ring of from 5 to 7, preferably 6 ring carbons, or a phenyl ring, and Alk1, Alk2, Alk3 and Alk4, when present, may each independently represent-CH2-or-CH2CH2-. For example, w may be 0, m, p and n may be 1, Falkland Alk2 may be-CH2-, and Cyc1 may be 1, 4-phenylene or 1,4- cyclohexylene.

The group R, R1 represents an optionally substituted (aryl)-(C1-C6 alkyl)-, (aryl)-(C2-C6 alkenyl)- (aryl)- (C2-C6 alkynyl)-, (heteroaryl)- (Ci-C6 alkyl)-, (heteroaryl)- (C2-C6 alkenyl)-or (heteroaryl)-(C2-C6 alkynyl)-radical. Optionally substituted heteroaryl groups which may be present in R1 include optionally substituted 2-and 3-thienyl, 2-and 3-furanyl, and 2-, 3-and 4-pyridyl. Optionally substituted aryl groups which may be present in R'include optionally substituted phenyl, and naphthyl, the former being preferred. The optionally substituted C1-C6 alkylen, C2-C6 alkenylene and C2-C6 alkynylene radicals part of R1 may be straight or branched chain and include-CH2-,-CH2CH2-,-CH2CH=CH-and-CH2C=CCH2. Optional substituents which may be present in R'include chloro, bromo, iodo, nitro, cyano, trifuoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfonyl, phenylsulfonyl and methylenedioxy. halo such as chloro, bromo and iodo, nitro, cyano, trifuoromethyl, C1-C6 alkyl such as methyl ethyl and t-butyl, and C1-C6 alkoxy such as methoxy and ethoxy. At present it is preferred that substituents present in R'be lipophilic rather than hydrophilic.

At present it is preferred that R'is benzyl, phenylethyl or phenylpropyl, optionally substituted in the phenyl ring by at least one lipophilic substituent as discussed above.

The group R R represents an optionally substituted Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or (Cyc)-(C1-C6 alkyl)-, (Cyc)-(C2-C6 alkenyl)-, or (Cyc)-(C2-C6 alkynyl)-radical wherein Cyc represents a monocyclic carbocyclic or heterocyclic radical having from 5 to 8 ring atoms. Cyc when present may be cycloalkyl, cycloalkenyl, aryl or aromatic or non-aromatic heterocyclic. Examples of Cyc groups include cyclopentyl, cyclohexyl, cyclohexyl, phenyl, 2-, 3-and 4-pyridyl, 2-, 3-and 4- piperidinyl, 2-and 3-thienyl and 2-and 3-furanyl. Examples of Ci-Ce alkyl, C2-C6 alkenyl and C2-C6 alkynyl radicals which may be present in R may be straight or branched chain, and include methyl, ethyl, n-and sec-propyl, n-, sec-and t-butyl, CH3CH=CH-and CH3C=CCH2. Any optionally substituted C1-C6 alkylen, C2-C6 alkenylene and C2-C6 alkynylene radicals part of R may be straight or branched chain and include optionally substituted-CH2-,-CH2CH2-,-CH2CH=CH-and- CH2C-CCH2 Specific examples of R groups include optionally substituted methyl, ethyl, n-and sec-propyl, n-, sec-and t-butyl, straight and branched chain pentyl and hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, cyclohexylmethyl, cyclopentylmethyl, cycloheptylmethyl, 2-, 3-and 4-pyridylmethyl, 2-and 3- furanylmethyl, 2 and 3-thienylmethyl, 2-, 3-and 4-piperidinylmethyl, and 2-and 3- morpholinylmethyl. Currently preferred R groups are is methyl, ethyl, n-or sec- propyl, n-, sec-or t-butyl, or phenyl or benzyl, optionally substituted in the phenyl ring by chloro, bromo or iodo, nitro, cyano, trifuoromethyl, methyl, ethyl, t-butyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl or phenylsulfonyl.

Specific compounds with which the invention is concerned include those of the Examples herein.

Compounds of the invention may be prepared by literature methods, for example methods analogous to those used in the Examples herein. For example compounds (I) wherein B is R2NH-may be prepared by alkylation of the corresponding compound wherein B is-NH2.

Compounds (I) wherein B is amidino (NH2-C (=NH) -) may be prepared from the corresponding compound wherein B is nitrile, by reaction with the reaction product of ammonium chloride and trimethyl aluminium. The resultant amidino compound may then be substituted on the amidino nitrogens as desired to form compounds (I) wherein R2 and/or R3 are other than hydrogen.

Compounds (I) wherein B is guanidino (NH2-C (=NH) -NH-) may be prepared from the corresponding compound wherein B is-NH2, by reaction with diisopropylethylamine and 1-H-pyrazole-1-carboxamidine hydrochloride. The resultant guanidino compound may then be substituted on the guanidino nitrogens as desired to form compounds (I) wherein R2 and/or R3 and/or R4 are other than hydrogen.

In each of the above cases, the starting compound (I) wherein B is-NH2 may be prepared from an N-protected diamino compound Pr-NH-L-NH2 wherein L has the same meaning as in formula (I), and Pr is an N-protecting group, by reductive alkylation of the free amino group, followed by removal of the protecting group. In a special instance of this synthesis, the protecting group Pr may be a support resin such as Wang resin.

As mentioned above, the compounds with which the invention are concerned are antimicrobially active, and may therefore be of use in the treatment of microbial infection in humans and non-human animals e. g. other mammals, birds and fish.

It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. Optimum dose levels and frequency of dosing will be determined by clinical trial.

The compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties. The orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone ; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine ; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica ; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol ; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

For topical application to the skin, the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.

For topical application to the eye, the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle. Additives, for instance buffers such as sodium metabisulphite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.

The active ingredient may also be administered parenterally in a sterile medium.

Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.

Also as mentioned above, the compounds with which the invention are concerned inhibit plant growth, and may therefore be of use as herbicides. For such uses the compounds may be formulated for spraying as a solution or suspension, as a powder for dusting, or as a thickened solution or suspension for painting onto the plant. It will be understood that the specific dose level for inhibition of plant growth may depend on plant species and/or the stage of the plant's growth cycle. Optimum dose levels and frequency of dosing will be determined by laboratory and/or field trial.

The following Examples describe the preparation of illustrative compounds (I) for use according to the present invention, and the antibacterial and antifungal properties thereof:

A. Typical Primary Amine Synthesis Step 1 Loading of diamine onto PNP-Wang resin

To a round bottomed flask containing 4-nitrophenoxy carbonyl Wang resin (3g, 3. 9mmol) and DMF (30ml) was added 1, 4-cyclohexane bis (methylamine) (5.54g, 39mmol, 1 Oeq). The mixture was agitated for 72 hrs and the resin collected by filtration. The resin was washed with [DMF (3 x 50ml), MeOH (3 x 50ml)] x 3; [DCM (3 x 50ml), MeOH (3 x 50ml)] x 3; 50ml CH2CI2 and TBME (3 x 50ml) and dried in the vacuum oven overnight. To check that the reaction was complete 0.01 g of resin was cleaved (1 ml of 50% TFA/CH2CI2 for 20 mins), filtered and the filtrate concentrated in vacuo to give an oil. HPLC-MS: mlz 143 [M+H]+.

Step 2a Double reductive alkylation to give a symmetric tertiary amine

To a round bottomed flask containing the resin from step 1 (10g, 13mmol) in DMF (100ml) was added 4-t-butyl benzaldehyde (21g, 130mmol, 10eq) and acetic acid (7.8g, 130mmol, 10eq). After shaking for 30 mins sodium triacetoxyborohydride (27.5g, 130mmol, 10eq) was added and the resulting mixture agitated for 20 hrs. The resin was then collected by filtration and washed with [DMF (3 x 100ml), MeOH (3 x 100ml)] x 3; [DCM (3 x 100ml), MeOH (3 x

100ml)] x 3; 100mut CH2CI2 and TBME (3 x 100ml) and dried in the vacuum oven overnight. To check that the reaction was complete 0. 01 g of resin was cleaved (1ml of 50% TFA/CH2CI2 for 20 mins), filtered and the filtrate concentrated in vacuo to give an oil. HPLC-MS: mlz 436 [M+H] +.

Step 2b Reductive alkylation To a round bottomed flask containing the resin from step 1 (13g, 13mmol) was added a solution of acetic acid/DMF (1: 100, 100ml) and the resultant suspension agitated for 10 mins. Cyclohexanecarboxaldehyde (7.28g, 65mmol, 5eq) was added and the mixture agitated for 20 hrs. The resin was washed with DMF (5 x 100ml) and CH2CI2 (5 x 100mol) (care was taken to keep the resin moist during the wash cycles), re-swollen in DMF (100ml) and sodium triacetoxyborohydride (13. 78g, 65mmol, 5eq) added. The mixture was agitated for a further 20 hrs and the resin then collected by filtration and washed with [DMF (3 x 100ml), MeOH (3 x 100mi)] x 3; [DCM (3 x 100mi), MeOH (3 x 100mi)] x 3; 100ml CH2Cl and TBME (3 x 100mol) and dried in the vacuum oven overnight. To check that the reaction was complete 0.01 g of resin was treated with excess benzoyl chloride in CH2CI2 for 1 hour and then cleaved (1 ml of 50% TFA/CH2CI2 for 20 mins), filtered and the filtrate concentrated in vacuo to give an oil. HPLC-MS : m/z 343 [M+H]+ for the amide adduct.

Step 2c Second reductive alkylation

To a round bottomed flask containing the resin from step 2b (14.5g, 13mmol) was added DMF (100ml) and 3, 4-dichlorobenzaldehyde (22.75g, 130mol, 10eq).

After shaking for 10 mins acetic acid (7.8g, 130mol) was added and the flask agitated for a further 20 mins. Sodium triacetoxyborohydride (27.5g, 130mmol, 10eq) was then added and the reaction mixture agitated for 20 hrs. The resin was collected by filtration and washed with [DMF (3 x 100ml), MeOH (3 x 100ml)] x 3; [DCM (3 x 100ml), MeOH (3 x 100mi)] x 3; 100ml CH2CI2 and TBME (3 x 100ml) and dried in the vacuum oven overnight. To check that the reaction was complete 0.01 g of resin was cleaved (1 ml of 50% TFA/CH2CI2 for 20 mins), filtered and the filtrate concentrated in vacuo to give an oil. HPLC-MS: m/z 397 [M+H] +.

Step 3 Cleavage of primary amine from resin To a round bottomed flask containing the resin from step 2c in CH2Cl2 (100ml) was added a solution of 1: 1 TFA/CH2CI2 (100ml). After shaking for 1 hr the resin (that was now purple in colour) was collected by filtration and washed with CH2CI2 (100ml). The filtrate was concentrated in vacuo to give the crude product as a yellow oil. The crude oil was re-solvated in EtOAc (100mi) and washed with

sat aq NaHCO3 (100ml) and the aqueous phase was re-extracted with EtOAc (2 x 50mi). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give the desired mixture of diastereomeric products as a yellow oil (6. 09g) which was pure enough to use in the next step without further purification. HPLC-MS: m/z 397 [M+H] +.' H NMR (MeOD): 7.39 (s, 0.5H, diastereomer A), 7.38 (s, 0.5H, diastereomer B), 7.33 (d, J= 8 Hz, 0.5H, diastereomer A), 7.32 (d, J = 8 Hz, 0.5H, diastereomer B), 7.11-7. 15 (m, 1 H), 4.47-4. 78 (br s, 2H), 3.35 (s, 1 H), 3.34 (s, 1 H), 2.67 (d, J = 7 Hz, 1 H), 2.64 (d, J = 7 Hz, 1H), 2.14 (d, J= 7 Hz, 1H), 2.02-2. 07 (m, 3H), 0.65-1. 86 (m, 22H).

B. Typical Guanidine Synthesis To a solution of the primary amine (1.5g, 3. 54mmol) (obtained from step 3 of the primary amine synthesis above) in DMF (1. 77mi) was added diisopropylethylamine (548mg, 4. 23mmol, 1.2eq) and 1-H-pyrazole-1- carboxamidine hydrochloride (570mg, 3.89 mmol, 1.1 eq). The resulting solution was stirred for 20 hrs by which time HPLC-MS showed the reaction to be complete. The solvent was removed in vacuo and the residue purified by column chromatography on Si02 using 10% MeOH/CH2CI2 as eluent to give the desired mixture of diastereomeric products (Compound 6) as a white powder (450mg, 28% yield). 1H NMR (MeOD): 7.52 (s, 1 H), 7.45 (d, J = 8 Hz, 1 H), 7.25 (d, J = 8 Hz, 1 H), 3.45-3. 54 (m, 2H), 3.30-3. 34 (m, 1 H), 3.00-3. 06 (m, 2H), 2.14-2. 31 (m, 4H), 0.76-1. 97 (m, 23H).

C. Typical Amidine synthesis Step 1 Preparation of tranexamic acid methyl ester To a solution of tranexamic acid (10g, 63. 7mmol) in MeOH (100ml) under an inert atmosphere at 0°C was added thionyl chloride (11. 4g, 95. 5mmol, 1.5eq) dropwise. After stirring the reaction at room temperature for 4 hrs HPLC-MS showed the reaction was complete. The solvent was removed in vacuo to leave the desired product as a white crystalline solid (13. 25g, 100% yield). HPLC-MS: m/z 172 [M+H] +. 1H NMR (MeOD): 3.67 (s, 3H), 2.82 (d, J = 7Hz, 2H), 2.34 (tt, J = 13,4 Hz, 1 H), 2.02-2. 08 (m, 2H), 1.88-1. 95 (m, 2H), 1.61-1. 72 (m, 1 H), 1.47 (dq, J= 14,4 Hz, 2H), 1.11 (dq, J= 13,3 Hz, 2H). 13C NMR (MeOD): 177.7, 52.2, 46.2, 43.9, 36.7, 30.2, 29.3.

Step 2 Double N-alkylation

To a solution of tranexamic acid methyl ester hydrochloride (5g, 24mol), sodium iodide (360mg, 2. 4mmol, 0. 1 eq) and cesium carbonate (27. 4g, 84mmol, 3.5eq) in DMF (100ml) at 0°C was added 4-chlorobenzyl bromide (10. 36g, 50. 4mmol, 2. 1eq). The reaction mixture was stirred at room temperature for 72 hrs after which time HPLC-MS indicated that the reaction was complete. The reaction was quenched by the addition of H20 (20mi) and diluted with EtOAc (200ml). The phases were separated and the organic layer washed with H20 (6 x 20ml). The combined aqueous phase was extracted with EtOAc (2 x 100ml).

The organic extracts were then combined, washed with H20 (6 x 20ml), dried over MgS04, filtered and the solvent removed in vacuo. The crude material was purified by column chromatography on Si02 using 10% EtOAc/hexane as eluent to give the desired product as a white waxy solid (8.2g, 82% yield). HPLC-MS: mlz 420 [M+H] +. 1H NMR (CDCI3) : 7.23-7. 29 (m, 8H), 3.65 (s, 3H), 3.44 (s, 4H), 2.13-2. 22 (m, 3H), 1.94 (dt, J= 17,3 Hz, 4H), 1.48-1. 60 (m, 1H), 1.39 (dq, J= 13,4 Hz, 2H), 0.73 (dq, J= 12,3 Hz, 2H). 13C NMR (CDCI3) : 176.5, 138.2, 132.5, 130.0, 128.4, 60.4, 58.1, 51.5, 43.4, 35.0, 30.5, 28.7.

Step 3 Nitrile formation ci ci I I i) Me3Al, NH4CI, toluene, 85°C N ii) SOCh, reflux N ,- ( : : ci laci Cl Cl

To a suspension of anhydrous ammonium chloride (766mg, 14. 32mmol, 1.5eq) in dry toluene (50mi), under nitrogen at 0°C, was added trimethyl aluminium (7. 2moi, 14. 32mmol, 1.5eq, 2M solution in toluene), followed by a solution of the ester from step 2 (4g, 9. 55mmol) in toluene (10ml). The resulting mixture was heated at 85°C for 20 hrs. After cooling to room temperature dry MeOH (20ml) was added and stirring continued for 1 hr. The solids were removed by filtration and the filtrate concentrated in vacuo. To the residue was then added thionyl chloride (5ml) and the mixture heated at reflux for 1 hr. The mixture was concentrated in vacuo, re-dissolved in EtOAc (50mi) and washed with sat aq NaHCO3 (2 x 50ml).

The organic phase was dried over MgS04, filtered and the solvent removed in vacuo to give the crude product as a yellow oil (2.31 g, 63% yield) that was used in the next step without further purification. HPLC-MS: m/z 387 [M+H] +.

Step 4 Amidine formation ci cl C ! C ! Y-N"Me, A !, NH, C ! toluene, 850C HN, NC I \ NC NH2 I CI To a suspension of anhydrous ammonium chloride (956mg, 17. 9mmol, 3eq) in dry toluene (30ml) under nitrogen at 0°C was added trimethyl aluminium (8. 94ml, 17. 9mmol, 3eq, 2M solution in toluene). The mixture was stirred at 0°C for 30

mins by which time efforvescence had ceased. The nitrile (2.3g, 5. 96mmol) from step 3 was added as a solution in toluene (1 Omi) and the reaction heated at 85°C for 36 hrs. The reaction mixture was cooled to room temperature, whereupon MeOH (50moi) was added and the mixture stirred for 1 hr. The precipitated solids were removed by filtration and the solid washed with MeOH (20ml). The filtrate was concentrated in vacuo and the residue purified by column chromatography on Si02 using 10% MeOH/CH2CI2 to yield the desired amidine (Compound 4) as a white crystalline solid (1.6g, 67% yield). HPLC-MS: m/z404 [M+H] +. 1H NMR (MeOD): 7.29-7. 37 (m, 8H), 3.49 (s, 4H), 2.36 (tt, J = 13,4 Hz, 1 H), 2.22 (d, J = 7 Hz, 2H), 2.04 (dd, J= 14, 3 Hz, 2H), 1.93 (d, J= 12 Hz, 2H), 1.61-1. 72 (m, 1H), 1.55 (dq, J= 13,3 Hz, 2H), 0.81 (dq, J= 13,3 Hz, 2H). 13C NMR (MeOD): 176.5, 139.9, 133.7, 131.5, 129.3, 61.4, 59.3, 43.8, 36.0, 31.7, 30.5.

Preparation of N-[(4-{[di (4-chlorobenzyl) amino] methyl}-cycloheXyl)-methyl]- N'-methyl-N'0cyanoguanidine (Compound 12) Step 1 N-[(4-{[di(4-chlorobenzyl)amino]methyl}-cyclohexyl)-methyl]- amino cyanoiminophenoxide To a solution of N-{[4-(aminomethyl)cyclohexyl]methyl}-N-(4-chlorobenzyl)-(4- chlorophenyl) methanamine (100mg, 0.256 mmol, 1 eq) in i-propanol (1 ml) was added diphenyl cyanocarbonimidate (64mg, 0. 269mol, 1.05eq). The mixture was stirred at room temperature for 18hrs, the solvent removed in vacuo and the residue purified by column chromatography on Si02 using 10-25% EtOAc/hexane as eluent to give the desired product as a colourless oil (1 02mg, 75% yield).

HPLC-MS: m/z 535 [M+H] +.'H NMR (CDCI3) : 6.97-7. 40 (m, 13H), 6.38-6. 50 (m, 1H), 3.39 (s, 4H), 3.13-3. 22 (m, 2H), 2.09-2. 19 (m, 2H), 0.61-1. 88 (m, 10H).

Step 2

To a solution of N-[(4-{[di (4chlorobenzyl) amino] methyl}-cycloheXyl)-methyl]- amino cyanoiminophenoxide (90mg, 0. 168mmol, 1eq) in 1: 1 THF/i-propanol (1 ml) was added triethylamine (0. 35ml, 2. 52mmol) and methylamine hydrochloride (113mg, 1. 68mmol, 10eq). After stirring for 16hrs the reaction was quenched by the addition of brine (1 Oml) and extracted with CH2CI2 (2 x 10ml).

The combined organic extracts were dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on Si02 using 20-50% EtOAc/hexane as eluent to give the desired N- [ (4- { [dj (4- chlorobenzyl) amino] methyl}-cyclohexyl)-methyl]-N'methyl-N"cyanoguanidine as a mixture of diastereomeric products, as a colourless oil (11 mg, 14% yield).

HPLC-MS: m/z475 [M+H] +. 1H NMR (MeOD): 7.18-7. 22 (m, 8H), 3.36 (s, 4H), 2.90 (d, J = 7 Hz, 1 H, diastereomer A), 2.86 (d, J = 7 Hz, 1 H, diastereomer B), 2.67 (s, 3H), 2.20 (d, J = 7 Hz, 1 H, diastereomer B), 2.08 (d, J = 7 Hz, 1 H, diastereomer A), 0.55-1. 84 (m, 1 OH).

The following compounds were prepared by methods analogus to those described above: N-{[4-(aminomethyl) cyclohexyl] methyl}-N-(4-chlorobenzyl)-(4- chlorophenyl)-methanamine (compound 1) Mixture of diastereomers (1: 1). Mono TFA salt. HPLC-MS: m/z391 [M+H] +.' H NMR (MeOD): 7.25-7. 35 (m, 8H), 3.44 (s, 4H), 2.73 (d, J = 7Hz, 1 H, diastereomer A), 2.66 (d, J = 7 Hz, 1 H, diastereomer B), 2.30 (d, J = 7 Hz, 1 H, diastereomer B), 2.20 (d, J = 7 Hz, 1 H, diastereomer A), 1.32-1. 99 (m, 7H), 0.92- 1.12 (m, 2H), 0.68-0. 79 (m, 1 H, diastereomer A).

N-{[4-(aminomethyl)cyclohexyl]methyl}-N-mesitylmethyl-(3, 4- dibromophenyl)-methanamine (Compound 2) Mixture of diastereomers (1: 1). Mono TFA salt. HPLC-MS: m/z523 [M+H] +.' H NMR (MeOD): 7.44-7. 52 (m, 2H), 7.04-7. 10 (m, 1H), 6.77 (s, 2H), 4.98 (brs, 3H), 3.43 (d, J = 11 Hz, 2H), 3.29-3. 34 (m, 2H), 2.74 (d, J = 7 Hz, 1 H, diastereomer A), 2.58 (d, J = 7 Hz, 1 H, diastereomer B), 2.27-2. 30 (m, 4H), 2.25 (s, 3H), 2.20 (s, 3H), 2.12 (d, J= 7 Hz, 1H, diastereomer A), 1.30-1. 90 (m, 7H), 0.82-1. 02 (m, 2H), 0.63 (q, J = 13 Hz, 1 H, diastereomer A). N-[(4-{[di (4-chlorobenzyl) amino] methyl} cycloheXyl) methyl] guanidine (Compound 3)

DiastereomerA: HPLC-MS: m/z433 [M+H] +.'HNMR (MeOD): 7.19-7. 23 (m, 8H), 3.38 (s, 4H), 2.82 (d, J= 7 Hz, 2H), 2.20 (d, J= 7 Hz, 2H), 1.70-1. 80 (m, 1 H), 1.20-1. 60 (m, 7H), 0.90-1. 00 (m, 2H).

Diastereomer B: HPLC-MS: m/z433 [M+H] +.'H NMR (MeOD): 7.18-7. 24 (m, 8H), 3.38 (s, 4H), 2.89 (d, J= 7 Hz, 2H), 2.10 (d, J= 7 Hz, 2H), 1.83 (brd, J= 13 Hz, 2H), 1.67 (brd, J= 13 Hz, 2H), 1.18-1. 48 (m, 2H), 0.86 (q, J= 12 Hz, 2H), 0.61 (q, J= 12 Hz, 2H).

N-[(4-{[(3,4-dibromobenzyl)(mesitylmethyl)amino]methyl}cy clohexyl)- methyl] guanidine (Compound 5) Mixture of diastereomers (2: 1). HPLC-MS: m/z565 [M+H] +. 1H NMR (MeOD): 7.52-7. 58 (m, 2H), 7.09-7. 15 (m, 1H), 6.80 (s, 2H), 3.50-3. 52 (m, 2H), 3.38-3. 41 (m, 2H), 3.00 (d, J = 7 Hz, 0.66H, diastereomer A), 2.88 (d, J = 7 Hz, 1.34H, diastereomer B), 2.19-2. 30 (m, 11H), 1.30-1. 90 (m, 7H), 0.60-1. 00 (m, 3H). N-{[4-({di [4-(tert-butyl) benzyl] amino} methyl) cycloheXyl] methyl} guanidine (Compound 7)

Mixture of diastereomers (3: 1). HPLC-MS: mlz477 [M+H] +. 1H NMR (CDCl3) : 7.68 (t, J = 5 Hz, 0.25H, diastereomer A), 7.60 (t, J = 5 Hz, 0.75H, diastereomer B), 7.33 (d, J = 8 Hz, 4H), 7.27 (d, J = 8 Hz, 4H), 3.50 (brs, 4H), 2.89 (t, J = 6 Hz, 0.5H, diastereomer A), 2.77 (t, J = 6 Hz, 1. 5H, diasteromer B), 2.28 (d, J = 6 Hz, 1.5 H, diastereomer B), 2.21 (d, J = 6 Hz, 0.5H, diastereomer A), 1.32-1. 98 (m, 7H), 1.31 (s, 18H), 0.75-1. 02 (m, 3H).

N-[(4-{[(4-chlorobenzyl) (3, 4-dichlorobenzyl) amino] methyl} cyclohexyl) methyl]-guanidine (Compound 8) Mixture of diastereomers (1: 1). HPLC-MS: m/z469 [M+H] +. 1H NMR (MeOD): 7.42-7. 50 (m, 2H), 7.23-7. 33 (m, 5H), 3.45-3. 49 (m, 4H), 3.00 (d, J = 7 Hz, 1 H, diastereomer A), 2.98 (d, J = 7 Hz, 1 H, diastereomer B), 2.32 (d, J = 7 Hz, 1 H, diastereomer B), 2.23 (d, J = 7 Hz, 1 H, diastereomer A), 1.36-2. 00 (m, 7H), 0.70- 1.13 (m, 3H). N-[(4-{[(4-bromobenzyl)(2-methylbutyl)amino]methyl}cycloheee xyl)methyl]- guanidine (Compound 9)

Mixture of 4 diastereomers. HPLC-MS: m/z423 [M+H] +. 1H NMR (MeOD): 7.20- 7.46 (m, 4H), 3.30-3. 50 (m, 2H), 2.99-3. 04 (m, 2H), 0.70-2. 30 (m, 23H).

N-(3-{[di(4-chlorobenzyl)amino]methyl}benzyl)guanidine (Compound 10) HPLC-MS: m/z427 [M+H] +. 1H NMR (MeOD): 7.29-7. 40 (m, 11H), 7.18-7. 22 (m, 1 H), 4.44 (s, 2H), 3.52 (s, 2H), 3.50 (s, 4H).

N-2- [ (4- {[di (4-chlorobenzyl) amino] methyl} cyclohexyl) methyl]-4, 5-dihydro- 1H-2-imidazolamine (Compound 11) Mixture of diastereomers (1: 1). HPLC-MS: m/z459 [M+H] +. 1H NMR (MeOD): 7.19-7. 23 (m, 8H), 3.62 (s, 4H), 3.42 (s, 4H), 2.95 (d, J = 7 Hz, 1 H, diastereomer

A), 2.89 (d, J = 7 Hz, 1 H, diastereomer B), 2.36 (d, J = 7 Hz, 1 H, diastereomer B), 2.14 (d, J= 7 Hz, 1H, diastereomer A), 1.27-1. 90 (m, 7H), 0.60-1. 05 (m, 3H).

4- { [di (4-chlorobenzyl) amino] methyl}-1-benzenecarboximidamide (Compound 13) HPLC-MS: m/z 398 [M+H] +. 1H NMR (MeOD): 7.42-7. 99 (m, 12H), 4.32-4. 55 (m, 6H). <BR> <BR> <P>N-[(4-{[(4-chlorobenzyl) (2-thienyl methyl) amino] methyl} cyclohexyl) methyl]- guanidine (Compound 14) Mixture of diastereomers (1: 1). HPLC-MS: m/z 371 [M+H]+. 1H NMR (CDC13) : 7.10-7. 40 (m, 8H), 6.84-6. 93 (m, 2H), 3.70 (s, 2H), 3.52 (s, 2H), 2.80-2. 96 (m, 2H), 2.30 (d, J = 7 Hz, 1 H, diastereomer A), 2.22 (d, J = 7 Hz, 1 H, diastereomer B), 0.70-1. 92 (m, 10H). N-(4-chlorobenzyl)-N-({4-[(methylamino) methyl] cycloheXyl} methyl)-(4- chlorophenyl) methanamine (Compound 16)

Mixture of diastereomers (1: 1). HPLC-MS: m/z 405 [M+H] +. 1H NMR (CDCl3) : 8.40 (brs, 1 H), 7.27-7. 40 (m, 8H), 4.20 (brs, 4H), 2.62-2. 80 (m, 4H), 2.56 (s, 3H), 0.63-1. 90 (m, 10H).

Analytical Method The analytical methods used to characterise compounds comprised HPLC-MS and 1H and 13C NMR.

HPLC-MS instrument comprises: Hewlett Packard 1312A binary pump Hewlett Packard 1314A variable wavelength detector (set at 215nm) Gilson 215 autosampler fitted with a 1ml syringe Polymer Labs PL1000 Evaporative Light Scattering Detector (where fitted) Micromass ZMD mass spectrometer operating in Electrospray positive ionisation mode.

The LC eluent is split, after flowing through the VWD uv detector, and approximately 300µl/min enters the mass spectrometer, 800, u1/min to the ELS (where fitted). The instruments were controlled using Micromass MassLynx 3.5 software under Windows NT4.0 HPLC Conditions Mobile Phase: Aqueous-Water + 0. 1% Trifluoroacetic acid Organic-Acetonitrile + 0. 1% Trifluoroacetic acid Gradient: Time (mins) % Aqueous % Organic 0.0 100 0 1. 8 5 95 2.1 5 95 2. 3 100 0 2.4 100 0

Run time: 2.4 mins Flow rate: 1 ml/min Injection vol : 3 gel Column temperature: ambient (20°C) Column : 50 x 2. 0mm Hypersil C18 BDS; 5, um UV Detector Variable wavelength detector set at 215nm ELS Detector Nebuliser Temperature 80°C Evaporation temperature 90°C Gas Flow 1. 5 I/hr MS Detector m/z 150-800 @ 0.5secs/scan, 0. 1 second interscan delay Cone voltage 25V, Source Temp. 140°C Drying Gas 350 I/hr NMR 1 H NMR spectra were recorded on a 400MHz Bruker NMR machine.

The above compounds, and others prepared by the above described methods, were tested for antibacterial and antifungal activity according to the protocols described in the Assay Methods section below. The compounds and results are shown in the following Table. LC Retent- ound Structure ion pu ty [MtH] G-ve G+ve yeast time (Mins) ci i N 1 H, 1. 15 100 391 A A B cl Cri H-cul BER N Br Bu N I Br H3C, CH3 2 WCßCHa 1. 29 100 523 C A A CH3 H-cul H-C Cl HCI HCI 3 1. 18 100 433 A A B H N H, Ny N NU cri ce 4 N N) G 1. 14 100 404 A A B NH Cl-H W Br Br HZNNH N CH3 5 A, 1. 34 98 565 C A A zu H3C CH3 H-CI H-CI H2NorNHeruN 6 HNJxp >rCI 1. 26 100 439 A A B zut H-CI H-CI CL i 7 H XNJ 1. 42 100 477 B A A H2N yNfy CH3 NH H3 H3 H-CI H-CI ci Cl H N 8 Nu tri 1. 24 98 469 B A A INCH Cl Ber Br H N N 9 H2NYNv tCH 1. 16 100 423 A A B If 3 NU Cul Ci Nigh HN 10 k, 1. 19 100 427 A A A cl Cl H-ci cri ZIZI H 1. 12 98 459 A A B H-cl H-cl ce 12 v 1. 18 93 475 C A B N N -CH. a HN. CH v'Ct 3 Cl M « 1. 16 80 398 B A B /CL H2N I/ NH H-CI H-Cf NH 14 H2N'U, N 1. 54 100 371 B B C H r-o VS N N Su 15 0 1. 56 95 385 B A B FXF'OH a. H3 N I W , cl3 16 cl I-.'c 1. 19 91 405 B A B 0 FXF'OH -OH 17 X 1. 71 100 501 C A A N, e F I IF F F CI OH F F F Cl I 18 H 0CHs I \3 H3C'%'CH3 18''1. 09 70 405 B A C 0 FF OH Table (Continued) LC Reten COMP Structure Reten LC Gram Gram ound Time Purity-ve tve Mins zon cl. N 19 HzN I 0. 98 89 336 A A B zon N H3Cs1zCH3 O. OH3 Han 20 H-c 1. 02 95 361 B B C X CH3 CH, N NH, /I NNHZ 21 Hs0 CH3 I \ 1. 07 54 283 C B C fez OH FEZ F FXF OH r NHz N NH, "°" 0 22 H3C CH3 0. 94 94 283 C B C / ci 0 Fuzz Holz CI O HO W F F 23 NHz 1. 07 88 317 B B B 0 F HO F /F F Ho - 24 N ~ ~ O ~ NH 0. 89 83 329 C B C NHZ N 25 1 93 275 C B C jazz COOH . __ F JG F OH CH, H3C \ CH3 N. NH, X ß 1. 47 78 359 B A A /I 3 0 CRI Cl cri FXF or CI NHZ N 27 H3 1. 24 94 351 B A B /3 0 COOH Fuzz FXF or zu 0 28 \ (0. 97 94 363 B B C oh cri jazz Cl r-F /F HO \ I F F ci ci u NH, N c3 30 CH. 1. 14 89 305 B B C CHz, 0 O H3C OH F cl NHz 31 N NH, 1. 02 100 297 C B C H3C H3C CH3 H3C 0 O NH Nu, NHZ cul fizz cl o Fuzz F G F OH N 33 nu 0. 94 100 323 B B C 0 zozo F F NHZ 34 N 1 100 357 B A c ci 0 F Fuzz FXF OH CH3 I N N NH, 35 I 0. 91 93 298 B B C 0 F OU FXF or 0 CH HO F F F CH3 CH3 N N NH 0. 88 81 278 B B C NH nu, 0 NHz _ _ HA 37 Fy- HO 37 F F 1. 08 71 359 A A B N ho /N hic CH3 HsC CHEZ , \ H30 CH3 38 CH N 1. 25 84 401 C B B nu2 H3C OH O F COOH NH NHZ 39 4f N 1. 15 100 393 C B B k H c C hic a OH F F ce 40 CH, N 1. 14 100 399 B A B nu, HC CH, 0 OH F F OH F F - I CHUS I N CHs N NHZ 41 1. 06 81 340 C B C r H9° CHs O COOH CH, CHs HC CH CH I N 42 SN N NH 1. 16 98 382 B B C I Zu F COOH ci CI O F F HO I F F CH3 43 N 1. 16 98 374 B B B CHs N NH, HC CH CHUS CHU CHUS N N N 44 N ~-NH2 1. 02 83 320 B B C I H9C/CHs F HO F F Ci CHEZ T CH I 45 NNNH2 1. 12 88 366 B B B ci cl X-k OH F COOH F F CI 46 N'\ 1 92 330 B A C HIC / NHz H3C O F t ; oH F F N N 47 H, C 0. 94 100 303 C B C P HAN OU CHEZ CL, C3 O HO H3C \ I F F c3 48 1. 08 73 345 B A C N HzN NHZ H3C N NHz 0. 92 100 317 B A B \ o F F F 50 HC 0. 92 100 297 B B C HsC O han ZU CH F F CH3 CH3 51 H, c N \ 0. 93 100 277 C B C zozo NOz H3C 0 F OH F F NH CHEZ fYN'CH, 52 1. 1 80 365 A A B i F Xt OH ZU 0 COOH F F NH 53 \ 53 Cl N CH, 1. 18 100 399 A A B ci/ CH OH3c/cH3 OH ? NU, NHZ /I \ 1. 18 82 385 B A B 0 Cl °/a F 6 F NU2 OU F NHZ COOH NH, 55 1. 12 100 351 B B C F \/ NHZ O F OH F F 56 0. 91 100 366 B B Salz chez CL, c9 NHz F F F OH F F 57 ou100329 c B C N - NHz F 'k OH F F 58 0. 97 100 328 B B C N 0 NU, O NHz F COOH F F 59 1. 18 100 385 B B C I\ N CI / NHz cri 0 nu, FLA COOH up" N /S cl 0 NHZ F F COOH F F 61 1. 01 100 353 C B C N HsC. \ b 0 NHz OU OH F F 62 1. 11 100 387 B A C N Hz O I /CI 0 "°" NH2 OH F F 63 1. 14 100 381 B B C N H, c. I zu" NHZ 64 HåC s 1 100 359 v C B C hic ZU OU 0 COOH F F O NHZ OH F F 65 1 100 359 B A N H. C, 0 Six 0 F NHZ OH F F 66 1. 09 100 367 B A C Fuzz H'C, O \ \ c CH3 0 F NH , A OH F F 67 1. 13 100 391 A A C I \ N cri cul Gui b NHZ fi F OH F F 68 1. 21 100 425 A A B ci cl 0 NH, zu O NH2 FI OH F F 69 Cl" (, N 1. 16 93 421 A A c cri Cl \ OH, CH3 F0 NH, F OH F F 70 1. 26 93 461 C A B /\ cul ou ci ou CH2 N 1. 24 100 419 B A C ci cul F F OH F F NH, 0 F OH F F 72 1. 22 100 397 A A C Zu ci k Cl/ 0 F t C F F 73 1. 12 100 397 B A C CN ci CI CI 0 NHZ F oH F F 74 N 1. 22 85 415 A o nu, \i COOH O F OH F F 75 N 1. 27 85 449 B ci HCI 0 nu, nu _ F F oH F F 76 I \ N 1. 23 100 445 B A C b chu i \ o \ CH3 NHZ 0 F OH F F 77 I N 1. 3 91 483 C A B ci b cri CH2 0 zazou OH F F 78 N 1. 37 94 507 C A B nez N NH2 N 1. 3 89 443 B A C if 0 FUZZ OH NH, NHZ N k oH, i 1. 19 100 381 B B C 0 lu chez 0 F OH F F 0 F NHZ COOH F F 81 N 1. 14 100 458 B A C 43 t N N Oz f nu, NHz O F F OH F F 82 N 1. 2 100 421 A A C ors nez NHZ F F , k OH F F 83 N 1. 26 90 429 A A ou /I/CH3 0 F NHZ F NOz ZION F F 84 ! 1. 04 95 323 B B C Y 1'N q CI NH zu F OH F F 85. J 1. 1 100 357 B A C zon Y _N Ci CL HIC H9C 86 N 0. 81 100 332 C B C CH Chez zon 0 1 CHU Fez -6 COOH F NU, OU F NH2 OH F F 87 1. 06 94 357 B A C T O f NNz cul 0 nu, O NHZ OU COOH F F cl cri 0 NHz OU CI O NHz F OH F F 89 N 1. 11 100 387 B B i i c. 0 CH3 O NHZ F COOH F F 90 1. 21 100 425 B A B N / CI cl/ CI nu2 O F F OH F F 91 1. 26 85 449 B A B ZON / / ci NHZ 0 F OH a 92 1. 16 81 385 B B C w _N // cl CH2 0 F OH FF 93 1. 02 100 323 B B C N --r CH, a cH, 0 NH, F IN OH F F 94 1. 14 99 391 A A C N cri Cl/ NHZ 0 CL F F F F 95 1. 06 100 363 A A C Cl X /S ce NH, 0 OU F 1= F F 96 1. 17 100 363 B B C N ol NH, NHZ O F F OH F F 97 1. 27 86 421 A A C N 0 NH, 0 NHZ , k OH F F COOH F F 98 N 1 93 372 B B C \. Hs CL, L ; N3 NHZ 0 FIV OU F F 99 1. 15 100 363 B A C N cl NHZ NHZ OU F OH F F 100 1. 16 100 335 C B C NHZ NHZ... NH, F OH F F 101 J 1. 05 89 337 B B C I\ N HsC// nu, 0 F F COOH H, C cl I \ N HsC \ OH CI O F NHZ OH F F 103 1. 18 94 405 A A C cul /\ cul s cl CH2 0 F zu OH F F 104 N 0. 96 94 380 B B C Hic N'chez CHEZ 0 NH, OU3 OH F OH F F 105 1. 14 100 371 A A N cri HIC nez NHz F F L NU, 106 1. 16 100 343 C B C Zu / hic NHZ O F F OH F F 107 1. 05 100 343 B B C I\ N Nu, NHZ ZU OU OH F F 108 1. 14 100 351 B B N H30/\ CH CH3 0 F \ NHa P OH 9~ 109/I N 1. 09 92 345 B B C \ F nez , k OH F F FOH I 1 10 W N 0. 98 100 323 B B C N 0 F \ NHa OH I/ F F 111 cl « 1. 09 87 381 B A C ci 0 CH2 X OU, Xt OH NH F F OH F F 112 1. 23 90 419 B A B cl ci ci 0 Cl t OH/ F F Cl nez Zizi 0 F \ NHz OH I/ 4 OH 114 « 1. 17 91 379 B B C ci//I 0 NHZ FOH I \ / Cl N 1. 06 92 357 B B C 1-1 cul 0 P OH 19 OU F F 116/I N 1. 02 93 347 B g C H \ \I O- \ NHz OH F F/ 117/I N 1. 02 100 377 B B C H'O, O \/ zozo 0 chez c3 O \ NHz oH F F/ H, C. N 1. 12 89 375 B B C H3c. o W i 0 F OH NH, OH 119 1. 07 97 353 B B C N HC 0 O II NHz F OH/ F F 120 N3 1 | 04 98 317 B B C N cl chez - _ \ NHZ COOH F F/ 121 1 86 388 B B C H, c. N CHEZ 0 NHz FOH I, 122 CH XNa 0. 66 92 326 B B C N I y CH CH F O I \ NHz ill OH F F 123 0. 95 85 366 B B C N N N CL, I I I \ NHz OH F F/ 124 I \ N 1. 08 89 351 B A C g OH 9~ ci 0 F \ NHz OH F F 125 ! \ N 1. 16 100 385 B A B cri ci cl 0 fi F OH I/NHz 126 W N 1. 07 98 381 B A C ci ce cl, CH3 0 FOH NH, F OH/ F F 127 1. 26 100 419 B A B cl ou ci F \ w NHz F nez F F 128 1. 27 86 443 B A B cl 0 F F F/ 129 43 1 16 83 379 B A C // cl F O I NH2 OH/ F F 130 mN) 1. 02 90 317 B B C chez CI CH 0 CH J F [OH I/ 131 I N 1. 16 99 385 B A B /\ cl cl 0 OH NH ou F F 132 N 1. 06 90 357 B A C /s cl 0 NHz OH OH/ F F 133 N 1. 13 91 357 B A C ci Nu, NHz OIT F_ OH F F 134 N 1. 04 95 329 B B C s zu OH OH NH, F OH/ F F 135 WH3 0 96 80 283 C B C CH CH, O I \ NHZ ZU 13O./ F F 1 tfY" \ sH\ CH3 F F F I \ NH2 OH/ F F 137 I \ N 1. 13 83 365 B A C ci /cl 0 I \ NHz F F OH/ N 1. 2 85 399 A A B ce Han/\ /cri O F \ w NHz e OH 9~ F F 139 1. 27 98 423 B A c Hic /O'/ F C \ NHz OH F F jazz HCI \ F O I \ \ NHz OH/ F F 141 N 1 87 297 C B C CHEZ HIC CHUS 0 OH NHz OH 142 1. 12 100 365 A A C cri 0 F C \ NHz OH F F t vN 1. 13 98 337 B B C HIC 0 NU, OH/ F F CH. F F ! 144 I \ N 1. 1 94 345 B A C N HC CH I W NHZ 0 NHz Oh OU F F 145 < N 1. 12 84 329 B B C HC OH, Zu 146 v \/1. 16 98 375 B A 0 o I/o \ I F OH 0 NHz O I NHz F F COOH F F 147 N 0. 88 94 289 C B C CHU CHEZ chus OH F OH F F 148 N 1. 2 96 391 B A B ci ci ci 0 ci "A OH FOH / 149 1. 48 87 515 B B ci CRI 0 cri X OH COOH F F'/ 150 OH3\ N N 1. 28 92 511 C B B ci CI 0 ci F OH F F 151 1. 28 96 481 C A B ci 0 ci ° cul F OH I/ 152 ^ F N 1. 31 100 487 C A B ci zon /CI O w NHz F I OH F F 153 1. 27 92 415 A A B N 0 NHz zu OH COOH F F 154 1. 04 95 335 B B C S N NH, 0 OU OH F F 155 0. 9 100 335 B B C , N \\..--s S NHZ F F OH F F 156 N 0. 91 97 329 B B C \ s s o \ NHZ F 0 1 CHEZ 0 nu, oh 0 i CH3 O I \ NH2 F OH F F 158 N ci 1. 14 86 391 B A B ci ce 0 F I \ NHz OH/ F F 159, N 1. 05 83 351 B B B cl F OH F' F N N, N ci 0 ci ° cul F \ OH/ F, F _ N 161 y 1. 25 100 346 C A B N H Ci ci 162 N \ cl 1. 44 97 395 C A B N H NH I\ 0' 163 FX b 1. 6 87 399 B A B OH F F y NHZ I\ N NHz CI N 164 0 OH 1. 64 90 433 A A B OH F/ \ F' Han 1- N 165 1. 76 98 455 B A A 0 9 ou F L-CH, F' HIC CHEZ CH2 CH, H3C 'N X W t 1. 55 92 365 B B C COOH F F F N NHZ N 167 1. 67 97 405 A A B o \ oH F F H, N 1-- han 168 N 1. 71 100 441 C A A CH3 0 HIC OH /'-F F F CH NHZ Bu /N 169/I 1. 65 94 477 B A A OH \ F F Nez NHZ N HsC : X CHz 393 B B B H3C CH, OH A,'' F F NU, N nu2 '' /N /CHEZ Hic Nez /F F HIC c3 HIC NHZ HIC H. O N 172 1. 69 85 413 A A B o I \ OH/ F F HsC CH3 H3C HAN CL, N 173 X 1. 8 97 435 A A B - OH , F CH F Chu HIC NH, CHEZ C3 c. 174 v 0 1. 6 91 345 B B C 174 . o 1. 6 91 345 B B C OH ich F F HIC CH, HIC NHZ N k 175 g w) 1. 72 96 385 B A B OH F F F F H3c _ H3C ( NHZ H, C FUZZ 176 ß F ß 1. 76 98 421 B A A Oh F F T-CH HIC H, C CH2 bu /N O 177 H 1. 69 95 457 A A B I \ F F F t ACX HsC NHZ ZON O 178 Hso oH 1. 7 91 373 B B B HsC I F HIC H. C'-L HIC CHUS HsC han OH C3 179 1. 77 96 481 B A A F F ci Oh Cri ci HZN CI CI N 180 1. 54 89 391 A A B 0 COOH \,-F F F Han ci ci N 181 1. 61 88 427 B A A 0 K, N oh ci H, N ce ci CRI CI N 182 0 1. 73 89 447 B A A OH t F g F F 182 | X o | 1-73 | 89 | 447 | B | A | A CH3 HIC CHEZ NH NHZ HzN 183 1. 47 87 357 B A C fY" ci 0 OH /F F F CL Han ci ce 184 N 1. 6 96 397 A A B 0 COOH /F F F NHZ Chez 185 <) 1. 68 97 433 C A A CH3 \ CI O I _/\F HAN CL han CRI CI N 186 1. 63 91 471 B A A 0 OH F F F ber NH r 187 N $ o 1. 58 88 385 B A B H CI OH HsC I F/ Chez F F OU HAN ci CI N 188 oH 1. 78 98 493 C A A 0 OH F fez x F F F F ci NH N 0 N O 189 i CH 1 63 87 411 A A B /% %"F H, N han 190 N 1. 67 90 445 B A A o OH /F ci CL han N \ 191 1. 79 100 467 B A A 0 OH /F F F CHEZ HsC CH, NU ; _ CH3 H3C ~t N 0 192 1. 59 97 377 B B B OH F F F F NU, N 193 1. 7 97 417 A A B °'\ oh ) H, N han 194 N 1. 74 100 453 C A A chus o HC H3C \ OU HO HAN c9 han 195 N 1. 69 93 489 B A A 0 OH Br NH r NU, N X $ 1. 69 93 489 B B B X OH CH F F F HAN 0 197 N 1. 76 92 513 C A A (- ° F /'OH X OH F F ci F CH2 /N O 198 °H 1. 43 84 368 B B C F F 0 o- HzN \1 HzN O - 0 NO- N 199 1. 51 86 402 A A B 0 ou F'F cl CI NHZ °H3 0 200 1. 37 91 334 C B C COOH F F o- po NHZ N O 201)/-OH 1. 51 95 374 B B C F F 0 o- " N+ O'O NHZ H9C/CH N O 202 OH 1. 59 95 410 B A A '/"OH I \ F F 0 N, o- nez Ber N NHz Br N O 203" (°H 1. 52 89 446 A A B F F X. NHz N O r L OH 1 49 93 362 C B C OFF F HIC Chu/ O O HZN 0 o- " C N L X ò 1. 65 86 470 B A B f J" OH F \ F F F F F CRI HN . 0 206 t N 1. 46 89 401 A A B OH Br '"0 HAN N han W F F Han HN ,-F zu OU Han N Jr o \ OH CH9 F F''F OH, CHEZ nu2 CHUS Chu X W t OH 1. 38 82 367 B B C zu F F Han C 210 OH N 1. 52 100 407 A A c F Br F F HAN zu Han 211 OH CH3 Br 1. 57 96 443 A A A / OH CHs F H3C \ F F CHUS HAN 1- N X C R » W e A A B OH F F Ber nu, bu NH2 O 213 N 21oH 1. 51 96 395 B B C H'C/Br F F F CL, Chus Han OU N CH N CH J E X 8, 1. 67 82 503 B A A F bu F F Fx NHZ ß NH N O 215 21oH 1. 69 97 433 B A A Roi'' F F Ci ci H, N zu N /CI 216 1. 6 93 470 B A A o OH ./, CF BrF bu NHZ N O OH 1. 62 83 385 ; B B ; B ; F Chai Cl CL NHZ r" \ I N O 218 OH 1. 57 86 373BAB F F F | 19 | > | 1. 62 | 66 | 407 | A | A | B | 2~ OH [jß NH, ci N zon 219 1. 62 88 407 A A B COOH oH HAN 1- H2N 220 1. 75 85 429 B A B F / oh F F \ °H3 HIC NH NHZ Chu Hic N 0 221 OH 1. 52 93 339 B B B FEZ NH N 0 nu2 N o 222 1. 65 100 379 B A B OH \ F F F HAN 1-- "'je3 223 1. 68 100 415 B A A Chez NaC \ OH OH, NHZ Br NHz Et O N 224 ß ß OH 1. 63 100 451 B A B ! F NHZ 0 ni F fez r oh F F N 225 1. 63 96 367 B B B H3 H30 H3 \ H2 X N N 226 1. 72 82 475 B A A o F \/ oN XI p F F CI F F HAN 0 zu L r o 1 77 88 471 B A B FF I F F \ CH3 HIC HzN Cl3 0 H, o F fi CH, Cl, Q Chu HzN O 229 1. 67 81 493 B A B 0 Q FF Br Han 0 230 N X 1. 74 94 517 C A A 0 F I FoH F \ p F F FI nu2 N O FOH 1 -7<"OH 231 F F 1. 75 90 446 B B B N OU, Zu N N 232 N 1. 8 90 482 C A B CH, H30 0 OH CH3 F F HzN'CH3 N 233 N 1. 75 86 518 B A B fuzz \ oH F F Br NH N r 234"s°, 1. 76 80 434 C B B H, Ci, 0 NHZ OH N FF N Hic N N 235 1. 81 80 542 C A A 0 F FACH F fi F F Cri HAN Br c 236 Cl 1. 49 86 401 A A B 0 OU F F HAN Br N 237 1. 57 97 435 A A B 0 COOH a ci NHz CH. V 238 H'c F JL 1. 47 91 367 B B C Ber HAN Br HzN 0 F IIH 239 N 1. 58 100 407 B A B 0 FoH F F HzN Or " zu 240 1. 63 100 443 B A A CH, COOH F F cl, CH3 HAN bu N 241 1. 58 98 481 A A B FOR F F Br NH r 242 N 1. 58 97 395 B B C H, CAS CHEZ Cl, Br HAN Bu N 243 1. 68 87 503 A A A CF CUL Cl //NOz Cl, ruz H3C N 244 1. 5 85 357 B B C cl, CES NHz N 245 1. 61 95 397 B A C OF3 CFa NHz H, C/CH, \ I N 246 1. 66 91 433 B A A CL, CFy NA er I \ N 247 1. 62 87 469 A A B CF, CH2 N 248 no)) 1. 61 87 385 B B B v NH3 OF3 NU, jr" CI \ C'v 249 1. 72 83 493 B A A OF, ces N CL' N 250 1. 56 87 407 A A B CF 0 CFy HN I Fs I 0 N 251 1. 74 85 463 A A B CHEZ Chu CHU CHIA N zon 252 1. 64 93 413 A A B rID" NH2 0 CF NHi H, c/CHa \ I N 253 osa 1. 69 100 449 B A A zu 0 CFa NA Hic \ I N 254 CH3 1. 64 88 485 A A B 0 CF NH NHZ a. CF3 255 S N D 1 65 85 401 C B C H. cr OH, HAN Br bu o 256 1. 64 84 515 B A A ci cul NHz I 257/N 1. 67 90 459 B A B F | NN, NHZ Cl I\ /N CF3 258 1. 74 96 509 B A A cl3 Han Ber Ber Bu Br N 259 1. 75 98 537 B A A I C§ CHEZ HIC CH3 NH2 HC/CH9 260 \ I N 1. 89 96 501 C A A X Cs CF3 CF3 NHz N N 261 1. 58 87 425 A B , ; F3 ci CL NHz CH, 262 H'c 1. 53 88 447 B A C Br Br Bu Nu, er X $ 1. 78 94 537 B A A CF3 CF3 //NHz CI CH HcN 264 1. 55 85 391 B A C /CFy OF HAN CL Ber er Br 265 N 1. 64 100 487 A A B Han CFy 1 CFy N 266 CF, 1. 97 93 661 C A A ci, ci NHz n r 267 1. 65 96 431 A A B CF, ci CL NHz HsC/CH3 \ I N 268 1. 72 98 467 C A A zu ci H, N Cl HzN bu N/- N 269 1. 63 92 560 B A A ber NH2 NHz CI \ CF3 270 1. 79 80 527 C A A Cl, ci CL NHs 271 N 1. 65 89 475 B B B .,. V I Cl, Dur Br Br HAN Br bu 272 « 1. 53 90 481 A A A HN H2N Br ber N 273 1. 76 97 583 C A A CF3 cl cri CI 274 H, N N 1 86 357 B B C 2 w//I w OH F F F OH F F F 275 N 1 95 359 B B c H2N"r zu ZU ZU COOH F F CI N 276 H2N 1. 08 89 363 B A C 0 ZU F F F F F- 277 N 0. 96 95 341c B F Xt OH o J F OH F F 1 278 N 1. 17 95 575 B A B 0 lai O I/ ZU F OH F F F 279 H2N 1. 08 94 347 C B C HZN F ZU OH F F I 280 HN N 1. 07 95 449 B A B FF PF OH O ZU 6 F F I 281 N 1. 18 92 455 B A B HxN F OH F F ci 282 C, HS t 1. 11 91 419 A A B HC a ci HCI F OH ci CI N 283 H, v X 1. 03 100 391 B A B 0 cil COOH F F 284 H2N NJ k 1. 28 87 330 C B C 0"ON F ?. F F N 285 HAN v OH 1. 44 94 380 B B C N O. N ZU COOH F F O F FOH 286 v N 9 1. 66 100 369 B B C Han ouzo 0 O F F 9 FXF-OH 287 Cl 1. 4 100 364B B c HzN 0 f sF OH X FF _OH So 0 S O FF OH N 289 uN 1. 58 95 407 B A C ION i " 9--- O FXF _OH 290 F F N9 1. 36 94 358 B B B H2N ci / Cl OI F [F'OH I/ 291 F F 1. 39 93 364 B B C N Cri S Cl O \ FF. OH I/ 292 1. 52 95 408 A A A NHz HZN v v N cl O \ OH I/ 293 F F 1. 45 93 358 B B C HZN HzN N Ci Zu °"Y F F OH 294 N 1. 47 91 361 C B C H2N"-I f H, C'N Ci 0 Q F F 295 N 1. 57 100 397 A A B If ouzo 0 ci O cl Fi 0- 296 1. 46 82 395 B B C N HZN v v . CH3 0 cl Cl FI FOH I \ 297 N 1. 59 94 413 B A A HZ V1VJN zu 0 cl 6 / 298 1. 37 94 347 C B C N Nu NH O ci °"0 fi 299 N Cl 1. 45 91 392 B B B f1 ? 0 cul O ci F' [F _OH I \ 300 N 1. 41 94 424 B B C lo, N, N N zon O cl FOH I \ 301 H2N 1. 32 96 455 B A B HzN \ ZU 0 cri O ci FI 302 1. 35 80 351 C B C FRY 'CL 0 ci O C /I FOH I \ 303 1. 62 97 414 A A A HZN zu ci Xi fuzz FF OH 304 1. 43 92 425 B B C N zozo Zozo zu p I \ FF OH 305 N 1. 51 92 442 C B C Ru ou-) cl Cl p I \ F F FOH 306 H2N N N 1. 58 95 435 B A B HAN CRI o fi / CI p I \ 307 F J o. 82 100 347 B B C N H2N _ Ci N CI HCI 308 1. 25 92 405 C A B 'N Han \ p CI 309 NO COMPOUND 309 0 F 310 S 1 52 63 366 C B B H2N X H zu . 9 F F] F _OH 311 t N, Nt 1. 43 100 396 C B C Z wiz N 0 0 ruz Ffil 312 N 1. 46 100 367 C B C Han ci Cl zu Fi FxF'OH 313 H2N 1. 04 84 396 B B B Cri HzN H zu O H rrf N 0 315 NO COMPOUND 315 HIC H3p iH3 CL, COOL CF3COOH 316 CF3COOH 1. 28 90 451 B A B H, N N /\ /Br CF3COOH CF3COOH 317 N 0. 92 100 336 B B C HAN Spi) 0 CH3 _ HCI HCI 318 1. 03 100 425 C B C H N H, N y N /ha O 319 NO COMPOUND 319 320 NO COMPOUND 320 321 NO COMPOUND 321 Cl CF3COOH CL, COOL zu HA 322 N 1. 42 97 360 C A B Lc, CL Hucha. HCI HCI \ 323 0. 99 94 390 B B C zon HzN I/\ NH I/O. CHa HCI HCI 324 \ N 1. 19 98 404 B A B HzN I/\ CI NH ce Ci HCI HUI 325 C N 1. 54 98 447 B A C H2N N NU q CI 326 NO COMPOUND 326 Ci HCI HUI 327 N 1. 6 97 433 A A B H2N II N\ \ NH I/ ci CRI HCI HCI I \ 328 N 1. 54 100 433 A A A H r T HZN N \ NH I-aci Cl Bu HCI HCI 329 N 1. 52 92 395 A A B Ber hui Bu HCI HCI 330 N 1. 58 100 437 A A B HzN N ^ NH'CCH3 HUI HO HCI \ HCI 331 H, N 1. 18 97 371 C B B FIZZ /CI 332 NO COMPOUND 332 Br HUI HCI 333 1. 45 100 409 A A B H N H rr ? NH CH, NH CHg 334 NO COMPOUND 334 cl HCL \ HCI A Ha [ ! j 335 1. 57 99 447 A A B H H N I/ CL Ci HCI \ HCI HCI 1 336 1. 23 100 371 C A A HzN/I \ cri CI HCI HCI Ha [ ! j 337 HCI ¢ 1. 54 98 405 A A B N Han Cl ci HCI HCI 338 H2N N 1. 14 100 365 B A B M /CI Cl HCI HCL / 339 Hay N 1. 28 93 407 A A B [f',' NU Cil CRI CI HCI HCI / 340 H2Ns"s 1. 12 100 351 B A B N cl Table (Continued) LC structure Mms) Time surit Mine cl HCL HUI / 341 X HCL f 100 393 A A B NU cl HCI HCL ! CI HCL HCI / 342 NH 1. 21 94 413 A A B I \ N Cl C cl CL Cj HCL HCI / 343 H2NYNX \ 1. 18 94 413 A A A HzN zu CI HCL HCI HzN N H, NN\ 344 N 1. 58 100 428 B A A ZON su ce HCI HCI H 345 HN IN N 1. 25 87 456 A A A N IvJH su 346 NO COMPOUND 346 ci HCL HCI 347 1. 18 100 427 C A A NH Cl NU cl HUI CI CI HCI HCI 348 N 1. 6 94. 94 427 A A ND H \ N NU NH / CF3COOH Cl CL, COOL 349 HO \ N 1. 18 98 443 A A A 349 HO) ( H N NHZ CL CL CF3COOH CL, COOL CF3COOH COOH 350 NH N 1. 19 90 414 C A B N ci / cl Cl CL, COOL CL, COOL OH OH 351 1. 14 89 443 B A A H "c. NH laci CI CF3COOH CL, COOL 352 \ N 1. 55 84 329 B ND B Cl, cool CF3COOH CF, COOH 0 353 H, N N ? 1. 41 80 313 B ND C HZN/ CF3COOH CF, COOH 354 I \ N 1. 15 91 351 A ND B ci zu C ! CL, COOL CF, COOH 355 XNJ 1. 16 91 395 B ND A H2NX t0 _ -0 pu 0 CL, COOL CL, COOL 356 1. 11 100 405 B ND B H2N X tCo o CF3COOH \ CF3COOH COOH 357 MNJ 1. 15 100 323 B ND C cl cri CL COOL CF, COOH3 358 1. 21 100 357 A ND A H nui HzN b on 0 CF3COOH Fuzz CF, COOHS 359 1. 15 100 367 B ND C f ! T HzN rl\ _/ CF, COOH CF3COOH r 360 mon 1. 05 95 323 B ND B H2N JS % ci CF3COOH COOH CF3COOH w 361 SNJ 1. 13 96 357 B ND B N HZN /S 0-\ 0 CF, cooH CF, COOH 362 1. 08 98 367 B ND C IDES CON ILS CFCOOH CF, COOH CF, COOH 363 H, N NY 1. 12 83 329 B ND C NO, NOS CF, COOH CF, COOH 364 1. 12 100 368 B ND N HAN ILS C02CH, C02CH3 cF, caoH I/ D 0."U 365 HN N 1. 18 87 381 B ND B HzN I/ CN CF, COOH cF, cooH 366 H2Ns) t 1. 13 92 348 B ND B CF, COOH ß | ___ __ HAN 10- COACH3 CF, COOH CF, COOL 367 1. 09 97 381 B ND C H, N Sil CL, COOL CF3COOH H3C\ S 368 EN 1. 14 95 369 B ND B HzN /S / CF3COOH CL, COOL 369 I \ N 1. 39 94 362 B ND B XNO cl Cl CF3COOH fi) CL, COOL 370 N 1. 51 97 396 B ND A HzN I/\ NO, ou CF, COOH 0 CF3COOH 371 N 1. 41 94 406 B ND B H2N, , loN02 I/NOz CL, COOL CL, COOL 1. 46 95 368 B ND B H2N, + NO, NOz CF3COOH cool CF3COOH COOH 373 1. 55 85 407 B ND B H2Ns9 + NOz Ci CL, COOL CL, COOL 374 mNJ 1. 41 94 352 B ND C N HzN I/\ ion CF3COON I \ CF, COOH 375 \ N 1. 41 96 375 B ND C HaN\JJI/ \ cul cri CL, COOL CF3COOH COOH 376 1. 5 97 409 A ND B H fut 0--\ O-- j ! o CF3COOH \ O CF, COOH 1 377 N 1. 42 100 419 B ND B C02CH, I/CO2CH3 NOz CF, COOH CL, COOL 1" 378 N 1. 51 83 420 B ND HzN I/\ COOH3 CFaCOOH ) CF3COOH COOH 379 1. 5 95 345 B ND B H2N HzN I/\ I ci CF3COOH CI, COOH 380 1. 58 100 379 A ND B H2NN ci CI CF3COOH cool CF, COC, H 381 1. 51 96 389 B ND C N H2N N, Nez NO2 _ CF, COOH 382 1. 53 88 390 B ND B Han HzN I/\ I CF3COOH \ CF3COOH COOH 383 ENJ 1. 37 92 342 B ND C H2N\J + Zon a CI CF3COOH cool CF3COOH 384 1. 48 94 376 B ND B H, N I-ACN HzN I/\ CN O CF, COOH 0 CL, COOL 385 1. 38 94 386 B ND C N HzN I/ 'lez CN ce CL, COOL CL, COOL 386 N 1. 37 95 408 B ND C HZN I/\ O . CF3COOH CL, COOL 387 N 1. 35 88 380 B ND C Han/\ O H OMe CL, COOL CF3COOH COOH 388 mNJ 1. 42 89 392 B ND B < H2NXJ tt _ _ _X 0 OMe N0. NOS O OMe CF3COOH cool CL, COOL 389 N 1. 46 100 433 B ND B HzN I/\ OMe 0 O OMe CF3COOH cool CF3COOH 390 1. 52 96 403 B ND C N Ho \ CN CF3COOH CL, COOL 391 N 1. 5 96 370 B ND C H2N I/\ zu S \ CF3COOH CF3COOH 392 < 1. 5 84 351 B ND B HzN'i/I/ \ CF3COOH cool CF. COOH ! H3C. S I/ 393 \ N 1. 57 93 391 B N D B H2N ow C OMe CF3COOH cool CL, COOL 394 N 1. 53 95 375 B ND B H2N 1 ! 5 : HzN I/\ O OMe CF3COOH cool CL, COOL " 395 J 1. 43 95 400 B ND C fui HzN r SUCH, CF3COOH COOL CF3COOH 396 1. 5 94 408 B ND HzN I/\ Nez SCHIZ ; ; OH ¢ CL, COOL 397 N 1. 51 91 421 A ND B H2N \J/J I/ \ /ORME 0 Me0 \ CL, COOL 19 398 N 1. 53 98 375 B ND B HzN \J/I/ \ SUCH, H2N cool CF3COOH fizz 399 1. 6 100 391 B ND C H2N ow C I/ I HAN CL, COOL 400 < t 1 33 100 323 B ND B S ci CL CF3COOH CF, COOH 401 1. 42 100 357 B ND B ho ri H2N e vs OVVVl-1 O CF3COOH CF, COOH 402 1. 36 90 367 B ND B N H2N N I S CL, COOL CL, COOL 403 H, N N9 1. 41 84 329 B ND B S NO, NOz NO2 cool CF3COOH COOH 404 1. 38 86 368 B ND B HaN COOH I S CF3COOH N 405 \ N sCH3 1. 45 91 363 A ND B H2N,,,,, l cri CL CF3COOH CF, COOH 406 N SCH3 1. 53 96 397 A ND A HAN H'*k, on. CF, COOH 0 CF3COOH 11 407 N SCH3 1. 46 100 407 B ND B N SCH3 H2N,, CF, COOH CF3COOH CL, COOL 408 mN SCH3 1. 51 97 369 B ND B _ H2N sw t _ NOS CL, COOL CF, COOH 409 N SCH, 1. 54 86 408 B ND B N SCH3 H2N N CF, COOH CF3COOH J 410 \ N 1. 43 96 347 B ND C CF3COOH _aoM. ci cul CL, COOL CF3COOH 411 e N 1. 5 97 381 A ND B f ! T H2N JU +} OMe CF3COOH CL, COOL 412 \ N 1. 5 92 353 B N D C "OMe ci CI CF3COOH cool CF3COOH COOH 413 SNJ 1. 37 95 383 B ND C H2N N OH OH O OMe CL, COOL CF, COOH 414 1. 37 97 381 B ND B HN eS vs 0 OMe CF, COOH CF3COOH cool 415 1. 49 100 421 A ND B N SCHQ HzN _| con CN CF3COOH cool CF, CCOH 416 N SCH, 1. 48 95 388 B ND B \ N SCH3 S zon S CF3COOH CL, COOL 417 I \ N scH3 1. 43 90 369 B ND B Han CF3COOH cool CF, COOH SCH3 418 SCH, 1. 48 100 409 B ND C HzN I/\ CF3COOH COOH CF, COOH sCH 3 419 N 1. 49 100 393 B ND B H2N \/9 to A _ _ CF, COOH OMe CF3COOH CF3COOH 420 \ N OMe 1. 11 85 369 B ND B OH _ OH ce CL, COOL CL, COOL 421 1. 38 100 397 B ND C N H2NX WOH I/OMe CL, COOL CFaCOOH J 422 XN) 1. 37 89 369 B ND B H kOH OMe CF3COOH CF3COOH 423 \ N 1. 39 94 347 B ND B H2N N OMe Cri cri CL, COOL CF3COOH 424 N 1. 47 97 381 A ND B N H2N N oye ru zu °Y CL, COOL CF3COOH COOH 425 1. 4 100 391 B ND B H2N OMe CF, COOH I/ CFsCOOH \ CF3COOH 426 \ N 1. 47 94 353 B ND B H, N ome / N0z CF3COOH CI, COOH 427 ~ nu 1. 44 85 392 B ND B N HZN I/\ OMe CL, COOL CF, CCOH 428 N 1. 32 90 333 B ND B H 2N, _ OH ce CF, COOH CF, COOH 429 N 1. 41 96 367 B ND B fiez H2N OH / po CF3COOH CF3COOH CF, COOH 430 HN N 1. 34 91 377 B ND C OH CF, COOH I/ CF3COOH CL, COOL 431 N 1. 39 94 339 B ND B H2N, , OH NO, NOz CF3COOH Ils CF, COOH 432 1. 37 86 378 B ND B \ N HzN I/\ OH CF3COOH of CFgCOOH"Y 433 N ? 1. 27 98 323 B ND C H2N SJ\ <COH ci cl CL, COOL CF, COOH 434 N Ome 1. 43 90 397 B ND C H2N OMe Cri OH CF, COOH CL, COOL 435 mNJ 1. 38 100 352 B ND C H2N » WN W CF, COOH CF3COOH SCH, SCH3 436 N OH 1. 36 96 409 B ND B H r) OME 0OMe CL, COOL CF3COOH Cool 437 1. 42 100 405 B ND B "lu N H2N4 +OMe Cl CON CF3COOH COOH 438 1. 39 100 372 B ND C \ N H, N OMe I/ s-\ CFgCOOH/ CF3COOH 439 < 1. 37 91 353 B ND C HZN/ OMe CL, COOL CF3COOH SCH 3 440 N 1. 45 100 393 B ND B H2N OMe CF, COOH CF3COOH CF3COOH 91 SUCH3 441 1. 38 89 379 B ND c H2NSJ\> N OH Me0 CL, COOL CF3COOH 442 N 1. 41 100 377 B ND B H2N S XOMe Me0 CL, COOL CL, COOL 443 P NJ 1. 36 100 363 B ND C H2NSJ\ XOH SCH3 CF, COOH 11 CL, COOL 444 1. 42 96 379 B ND B N HZN I/ OH MA kOH ci CL, COOL CF3COOH Cool 445 1. 11 100 429 B ND B SO2CH3 I/SOZCH3 CF3COOH CF3COOH 446 f N 1. 18 93 363 A ND B H, N I SCH, cl CL, COOL CF, COOH 447 N 1. 24 100 397 A ND A HZN /\ SCH3 0 O CFgCOOH CF3COOH COOH 448 N 1. 19 94 407 B ND B _ XSCH _ _ HzN I/\ SUCH3 CF3COOH CL, COOL 449 \ N 1. 22 88 369 B ND B SCH3 CON CL CF3COOH \ CF3COOH cool 450 1. 15 100 388 B ND c HzN I/\ SUCH3 O OMe CF3COOH fuzz CL, COOL 451 N 1. 08 96 420 B ND B N HzN I/\ SCHWA CF3COOH S CF3COOH COOH 452 nu 1. 13 100 369 B ND B HaN I/\ I/ SCHa CF, COOH H, C, s CL, COOL 453 N 1. 2 89 409 B ND B HzN\J/JI/ \ OYE SCHWA OMe CF3COOH \ CF3COOH COOH 454 N 1. 18 83 393 B ND B HzN I/\ SCHWA CH30 \ CF3COOH CL, COOL 455 N 1. 48 87 393 B ND B H, nu SCHWA SCH3 _ _ CF3COOH CL, COOL 456 m NJ 1. 53 89 409 B ND B H2N \/9 + WISCH3 J SOTCH3 CF, COOH CF3COOH COOH 457 N 1. 38 97 441 B ND c HzN \ HAN 458 NO COMPOUND 458 459 NO COMPOUND 459 460 NO COMPOUND 460 CFgCOOW !) CL, COOL 461 SNJ 1. 11 87 351 B ND B H2N sJW C i CF, COOH S CL, COOL 462 < 1. 01 89 351 B ND C HO HO CF3COOH CL, COOL 463 N 0. 82 100 339 B ND C HZN \J// S U CL, COOL CF, COOH 464 1 95 369 B ND B \ N SCHIZ CF3COOH cool CL, COOL 465 0. 95 100 353 B ND C N Han iso 466 NO COMPOUND

Assay Methods The following bacterial and yeast strains were used: Bacillus subtilis 168CA, Candida albicans ATCC 90028, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Haemophilus influenzae ATCC 49247, Pseudomonas aeruginosa 101021, Saccharomyces cerevisiae MYA-658, Staphylococcus aureus MS 601055 and Streptococcus pneumoniae ATCC 49619.

M ! Cs were determined by the broth microdilution method (National Committee for Clinical Laboratory Standards. 2000. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically ; approved standard-5th ed. ). Microtitre plates containing the test compounds (standard concentration range : 0. 125-64 tg/mi) were inoculated with a starting inoculum of 5x105 cfu/ml.

Mueller-Hinton broth (Oxoid) was used for all non-fastidious organisms. S. pneumoniae and H. influenzae were grown in brain heart infusion (Sigma) supplemented with 5% horse serum and 2 mg of NAD per litre (H. influenzae).

The MIC was defined as the lowest concentration of compound inhibiting visible growth.

For S. cerevisiae and C. albicans, Sabouraud dextrose broth (Sigma) was used.

Microtitre plates containing the test compounds were inoculated with 1: 100 dilutions of cultures at an absorbance at 600 nm (A600) of 0. 09. S. cerevisiae and C. albicans were incubated at 30°C for 44-48 h and at 37°C for 28 h, respectively. The MIC was defined as the lowest concentration of compound inhibiting visible growth. The IC50 was defined as a reduction in A600 of #50% compared to A600 of a culture grown in the absence of compound.

Activities were scored as'A'if the MIC was single digit eg. <8 microgrammes/ml, 'B'if the MIC was 16 to 64 microgrammes/ml and'C'if the MIC was greater than 64 microgammes/ml. The data set in the above table is data collected from B. subtilis, E. coli and S. cerevisiae tests. IC50 values were used to evaluate effects of compounds on the growth of yeast.