Abstract:
The present invention, in one aspect, provides a method of inhibiting bacterial growth by contacting bacteria with an effective amount of at least one monosaccharide compound of formula (1) as described herein:

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a National Phase application under 35 U.S.C. §371 of International Application No. PCT/AU2006/001939 filed Dec. 20, 2006 and claims the benefit of Australian Application No. 2005907230, filed Dec. 22, 2005, the disclosures of which are incorporated herein by reference in their entirety. 
     FIELD OF INVENTION 
     The present invention relates to novel carbohydrate compounds and method of inhibiting bacterial growth. 
     BACKGROUND 
     Since the introduction of penicillin over fifty years ago, there has been continuous growth in the number of antibiotics commercially available for treatment of bacterial infections. As a result, today there are about 350 drugs on the market used for the treatment of a wide range of bacterial infections. One of the problems of continued use of existing drugs is the ever increasing acquisition of resistance through mutation and exchange of genes (Ritter et al  Carbohydrate - Based Drug Discovery  (2003), 899-932). Often patients with bacterial infections cannot be treated adequately with the existing drugs, as many bacteria have developed multi-drug resistance. There is a great medical need for new antibacterials that are effective against the various multi-drug resistant bacteria. The Applicant has identified a number of new classes of compounds (PCT AU03/00384; PCT/AU2003/001008)). Several compounds described in these applications have now been shown to possess promising antimicrobial activity, including activity against MRSA (Methicillin-resistant  Staphylococcus aureus ) and VRE (vancomycin-resistant enterococci). In addition, several new chemotypes have been identified with potent antimicrobial activity. The applicant has also discovered disaccharides that have antibacterial properties (PCT/AU2003/01377). None of the new drugs in the art contain small molecules based on monosaccharide scaffolds as disclosed in these patents applications. WO 03/070715 discloses antimicrobial agents comprising glycofuranose compounds derived from hexose sugars which are different from the compounds of the present invention because the compounds of the present invention are either glycopyranose compounds of hexose sugars or glycofuranose compounds of pentose sugars. 
     SUMMARY OF THE INVENTION 
     It is an object of the present invention to provide novel compounds and new uses of various related compounds. 
     The present invention, in one aspect, provides a method of inhibiting bacterial growth by contacting bacteria with an effective amount of at least one monosaccharide compound of formula (1): 
     
       
                 
         
             
             
         
      
     
     Wherein, 
     n is 0 or 1; the ring may be of any configuration and the anomeric center may be of either the α or β configuration; 
     R1 is selected from the group consisting of hydrogen; OZ; SZ; OPO 2 (OZ)Z; SO 2 N(Z)Q; S(═O)N(Z)Q; N-Het wherein N and Het combine to form a heterocycle which may be further substituted with one or more U moieties; and —N(Z)Y wherein: 
     Y is selected from hydrogen, or the following, where G denotes the point of connection to the nitrogen atom in N(Y)Z; 
     
       
                 
         
             
             
         
      
     
     Q is selected from hydrogen or W; 
     the groups W are independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 carbon atoms which is optionally substituted, branched and/or linear. Typical substituents include but are not limited to OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid; the term heteroalkyl includes alkyl groups which incorporate one or more heteroatoms within the alkyl chain; 
     each occurrence of Z is independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, acyl, arylacyl, heteroarylaryl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 carbon atoms which is optionally substituted, branched and/or linear. Typical substituents include but are not limited to OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid; the term heteroalkyl includes alkyl groups which incorporate one or more heteroatoms within the alkyl chain; or 
     wherein each occurrence of U is independently selected from the group consisting of: OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidinium, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid; heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl, thioheteroaryl, alkyl, alkenyl, alkynyl, acyl, arylacyl, heteroarylaryl; of 1 to 20 carbon atoms which is optionally substituted, branched and/or linear. 
     The groups R2, R3, R4 and R5 are independently selected from OZ or N-Het wherein N and Het combine to form a heterocycle which may be further substituted with U groups; or N(Z)Y or OPO 2 (OZ)Z, wherein the groups Z and Y are as defined above. 
     It is understood that the rules of molecular stoichiometry will be upheld by the default addition of hydrogen atoms as required. 
     In a preferred embodiment, the invention relates the method wherein the compound is selected from the group consisting of the gluco- or galacto- or allo-configuration. 
     In a preferred embodiment the invention relates to said method wherein at least one of R1-R5 is N-Het. 
     In a preferred embodiment the invention relates to a method wherein the heterocycle is a monocyclic or bicyclic ring of 4 to 10 membered ring structure. 
     In a preferred embodiment the invention relates to a method wherein the heterocyclic ring is selected from the group consisting of triazoles, benzimidazoles, benzimidazolothione, benzimidazolone, imidazole, hydanthione, thiohydanthione and purine. 
     In a preferred embodiment the invention relates to a method wherein any one of R2 and R4 is N-Het, wherein the heterocycle is a monocyclic or bicyclic ring of 4 to 10 membered ring structure. 
     In another aspect, the invention provides a compound of formula (1) wherein any one of R1-R5 is N-Het. 
     In a preferred embodiment, the invention relates to a compound of formula (1) wherein the heterocycle is a monocyclic or bicyclic ring of 4 to 10 membered ring structure. 
     In a preferred embodiment the invention relates to the compound of formula (1) wherein any one of R2 and R4 is N-Het, wherein the heterocycle is a monocyclic or bicyclic ring of 4 to 10 membered ring structure. 
     In a preferred embodiment, the invention relates the compound of formula (1) wherein the compound is selected from the group consisting of the gluco- or galacto- or allo-configuration. 
     In a preferred embodiment the invention relates to the compound of formula (1) wherein the heterocyclic ring is selected from the group consisting of triazoles, benzimidazoles, benzimidazolothione, benzimidazolone, imidazole, hydanthione, thiohydanthione and purine. 
     In a preferred embodiment, the heterocyclic ring may be further substituted with U groups; wherein each occurrence of U is independently selected from the group consisting of: OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidinium, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid; heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl, thioheteroaryl, alkyl, alkenyl, alkynyl, acyl, arylacyl, heteroarylaryl; of 1 to 20 carbon atoms which is optionally substituted, branched and/or linear. 
     In a preferred embodiment, the heterocyclic ring may be further substituted with U groups selected from the group consisting of substituted alkyl, aryl, carboxyl and amino. 
     In a preferred embodiment, the U group is selected from the group consisting of OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidinium, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, primary or secondary or tertiary amines, aminoacyl, carbonyl and substituted or unsubstituted imine. The term primary, secondary and tertiary amines includes alkyl and aryl amines. 
     In a preferred embodiment, each occurrence of Z is independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, acyl, arylacyl, heteroarylaryl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 carbon atoms which is optionally substituted, branched and/or linear. 
     In a preferred embodiment, the term “optionally substituted” or “optional substituents” include OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid; the term heteroalkyl includes alkyl groups which incorporate one or more heteroatoms within the alkyl chain. 
     In a preferred embodiment, the compound is selected from the group consisting of: 
     
       
                 
         
             
             
         
      
     
     In another aspect, the invention provides a compound of formula (1) wherein R1 is silyloxy and R2, R3, R4 and R5 are as defined above. Typical silyloxy groups include tertiary-butyldiphenylsilyloxy, tertiary-butyldimethylsilyloxy and other similar alkyl and aryl silyloxy groups. 
     The term “halogen” denotes fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. 
     The term “alkyl” used either alone or in compound words such as “optionally substituted alkyl”, “optionally substituted cycloalkyl”, “arylalkyl” or “heteroarylalkyl”, denotes straight chain, branched or cyclic alkyl, preferably C1-20 alkyl or cycloalkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3 dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-methyloctyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3 or 4-propylheptyl, undecyl 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8 or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2 pentylheptyl and the like. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. 
     The term “alkylene” used either alone or in compound words such as “optionally substituted alkylene” denotes the same groups as “alkyl” defined above except that an additional hydrogen has been removed to form a divalent radical. It will be understood that the optional substituent may be attached to or form part of the alkylene chain. 
     The term “alkenyl” used either alone or in compound words such as “optionally substituted alkenyl” denotes groups formed from straight chain, branched or cyclic alkenes including ethylenically mono-, di- or polyunsaturated alkyl or cycloalkyl groups as defined above, preferably C2-6 alkenyl. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl; 1,4-pentadienyl, 1,3cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl. 
     The term “alkynyl” used either alone or in compound words, such as “optionally substituted alkynyl” denotes groups formed from straight chain, branched, or mono- or poly- or cyclic alkynes, preferably C2-6 alkynyl. 
     Examples of alkynyl include ethynyl, 1-propynyl, 1- and 2butynyl, 2methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 10-undecynyl, 4-ethyl-1-octyne-3-yl, 7-dodecynyl, 9-dodecynyl, 10-dodecynyl, 3-methyl-1-dodecyn-3-yl, 2-tridecenyl, 11tridecenyl, 3-tetradecenyl, 7-hexadecenyl, 3-octadecenyl and the like. 
     The term “alkoxy” used either alone or in compound words such as “optionally substituted alkoxy” denotes straight chain or branched alkoxy, preferably C1-7 alkoxy. Examples of alkoxy include methoxy, ethoxy, propyloxy, isopropyloxy and the different butoxy isomers. 
     The term “aryloxy” used either alone or in compound words such as “optionally substituted aryloxy” denotes aromatic, heteroaromatic, arylalkoxy or heteroaryl alkoxy, preferably C6-13 aryloxy. Examples of aryloxy include phenoxy, benzyloxy, 1-naphthyloxy, and 2-naphthyloxy. 
     The term “acyl” used either alone or in compound words such as “optionally substituted acyl” or “heteroarylacyl” denotes carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl or a heterocyclic ring which is referred to as heterocyclic acyl. Examples of acyl include carbamoyl; straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, and icosanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t butoxycarbonyl, t-pentyloxycarbonyl and heptyloxycarbonyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; alkoxysulfonyl such as methoxysulfonyl and ethoxysulfonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl, phenylpropanol, phenylbutanoyl, phenylisobutyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl, naphthlpropanoyl and naphtliylbutanoyl); aralkenyl such as phenylalkenoyl (e.g. phenylpropenyl, phenylbutenoyl, phenylmethacrylyl, phenylpentanoyl and phenylhexanoyl and naphthylalkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aralkoxycarbonyl such as phenylalkoxycarbonyl (e.g. benzyloxycarbonyl); aryloxycarbonyl such as phenoxycarbonyl and naphthyloxycarbonyl, aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and naphthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolylglyoxyloyl and thienyglyoxyloyl. 
     The term “aryl” used either alone or in compound words such as “optionally substituted aryl”, “arylalkyl” or “heteroaryl” denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbons or aromatic heterocyclic ring systems. Examples of aryl include phenyl, biphenyl, terphenyl, quaterphenyl, phenoxyphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, azulenyl, chrysenyl, pyridyl, 4-phenylpyridyl, 3-phenylpyridyl, thienyl, furyl, pyrryl, pyrrolyl, furanyl, imidazolyl, pyrrolidinyl, pyridinyl, piperidinyl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl and the like. Preferably, the aromatic heterocyclic ring system contains 1 to 4 heteroatoms independently selected from N, O and S and containing up to 9 carbon atoms in the ring. 
     The term “heterocycle” used either alone or in compound words as “optionally substituted heterocycle” denotes monocyclic or polycyclic heterocyclyl groups containing at least one heteroatom atom selected from nitrogen, sulphur and oxygen. Suitable heterocyclyl groups include N-containing heterocyclic groups, such as, unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated to 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidin or piperazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl or tetrazolopyridazinyl; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, such as, pyranyl or furyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms, such as, thienyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, oxazolyl, isoxazolyl or oxadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolyl or thiadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolyl. 
     In another form, the invention comprises a method of inhibiting bacterial growth in an animal or human comprising administering an effective amount of at least one monosaccharide compound of formula (1). 
     In another aspect, the invention provides for a pharmaceutical composition comprising at least one of the compounds described herein, or tautomers, esters, solvates, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. 
     The bacterial may be Gram-positive or Gram-negative bacteria. The bacteria may comprise an  E. coli  bacteria, a Staphylococci Bacteria such as  Staphylococcus aureus , or other bacteria such as  Micrococcus luteus  (ATCC272),  Staphylococcus aureus  (ATCC29213),  Staphylococcus aureus  (ATCC43300) MRSA,  Enterococcus faecalis  (ATCC29212),  Enterococcus faecalis  (ATCC51299) Vancomycin resistant and  Streptococcus pyogenes  (ATCC8668). 
     The method may comprise administering an effective amount of a compound of the first aspect, to a subject in need of such treatment. The subject may be a human, or may be a domestic, companion or zoo animal. 
     In another form, the invention may reside in an antibacterial composition comprising at least one compound as described above. The composition may comprise a pharmaceutical composition. 
     The compounds of the invention may be mixed with a pharmaceutical acceptable carrier, adjuvant, or vehicle, which may comprise a-toxic carrier, adjuvant, or vehicle that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof. 
     The pharmaceutical derivative may comprise a salt, ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention, although no limitation is meant thereby. 
     Compounds of the invention may be administered orally such as by means of a tabled, powder, liquid, emulsion, dispersion and the like; by inhalation; topically such as by means of a cream, ointment, salve etc; and as a suppository, although no limitation is meant thereby. 
     The compounds of the invention may be administered together with one or more drugs, including antibacterial agents such as antibiotics, for the treatment of bacterial infections. 
     In another aspect, the invention provides a compound of formula (1) when used for the treatment of a disease. 
     In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (1) when used for the treatment of a disease. 
     Methods and pharmaceutical carriers for preparation of pharmaceutical compositions are well known in the art, as set out in textbooks such as Remington&#39;s Pharmaceutical Sciences, 19th Edition, Mack Publishing Company, Easton, Pa., USA. 
     It will be clearly understood that, if a prior art publication is referred to herein, this reference does not constitute an admission that the publication forms part of the common general knowledge in the art in Australia or in any other country. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Various non-limiting embodiments of the invention will be described with reference to the following examples. Where appropriate, the following abbreviations are used. 
     Ac Acetyl 
     DTPM 5-Acyl-1,3-dimethylbarbiturate 
     DIPEA N,N-Diisopropylethylamine 
     Ph Phenyl 
     TBDMS t-Butyldimethylsilyl 
     TBDPS t-Butyldiphenylsilyl 
     Bn benzyl 
     Bz benzoyl 
     Me methyl 
     DCE 1,2-dichloroethane 
     DCM dichloromethane, methylene chloride 
     Tf trifluoromethanesulfonyl 
     Ts 4-methylphenylsulfonyl, p-toluenesulfonyl 
     DMF N,N-dimethylformamide 
     DMAP N,N-dimethylaminopyridine 
     α, α-DMT α, α-dimethoxytoluene, benzaldehyde dimethyl acetal 
     DMSO dimethylsulfoxide 
     DTT dithiothreitol 
     DMTST Dimethyl(methylthio)sulphoniumtrifluoro-methanesulphonate 
     TBAF tetra-n-butylammonium fluoride 
     Generally applicable synthetic procedures 
     A) Fmoc Removal 
     The resins were washed with dry DMF then treated with 1.5 mL of a solution of 20% v/v piperidine in DMF. The resins were shaken for 1 h and then drained and washed with DMF. The procedure was then repeated with the resins being finally washed with DMF (×3), MeOH (×3) and DCM (×3). 
     B) Cleavage from Resin (and Removal of any Boc Groups on Side Chains) 
     Each resin was treated with a solution of 10% TFA, 20% Et 3 SiH in dry DCM (1.5 ml) for 3 h, drained into a test tube and washed with DCM (2.0 ml), The samples were concentrated in vacuo on the RVC. 
     Each cleaved product was treated with a solution of saturated ammonia in methanol (1.0 ml) and left at room temperature for 2 h. The samples were again concentrated in vacuo on the RVC. 
     C) Acylation 
     Acylating mixtures were prepared by dissolving the requisite carboxylic acid (0.5 mM) in anhydrous DMF (0.5 mL) and treating this solution first with HBTU (0.5 mM) followed by DIPEA (0.5 mM). Following mixing, each solution was allowed to stand for 10 min. prior to addition of the resin bound substrate. The reaction mixture was shaken at room temperature overnight, filtered and washed with DMF (×3), MeOH (×1), DMF (×3), MeOH (×1) and DCM (×3). 
     D) Reduction of Azide 
     Equal volumes of a solution of 1,4-Dithio-DL-threitol (DTT, 0.2 M in DMF) and lithium tert-butoxide (0.2 M in DMF) were added to the resin bound substrate and the reaction mixture shaken at room temperature for 6 h. The resin was drained, washed with dry DMF (×3), dry THF (×3), dry MeOH (×3), dry DCM (×3) and dried in vacuo. 
     Synthetic Schemes 
     Synthetic schemes are given for two of the libraries synthesised as being representative of the general approach taken during monosaccharide synthesis. This is not exhaustive and variations on these approaches were used. 
     
       
                 
         
             
             
         
      
     
     Conditions: i) a) LiO t Bu (0.5 M) in DMF, 10 min. b) 1-Fluoro-2-nitrobenzene (0.5 M) in DMF, 20 min., 3 cycles ii) 5% NH 2 NH 2 ·H 2 O in DMF, 1 h iii) 4-Chloro-3-(trifluoromethyl)phenyl isocyanate (0.15 M) in DMF, o/n iv) 4-(Trifluoromethyl)benzenesulfonyl chloride (0.1 M) and DIPEA (0.2 M) in DCM, o/n v) LiO t Bu (0.2 M) and DTT (0.2 M) in DMF, 6 h vi) Aldehyde (0.2 M), NaCNBH 3  (0.175 M) in THF/MeOH/AcOH (2:2:1), o/n vii) Biphenyl-4-sulfonyl chloride (67.2 mM) and DIPEA (0.1348 M) in DCM, o/n viii) Acid (0.25 M), HBTU (0.25 M) and DIPEA (0.5 M) in DMF, o/n ix) 20% piperidine in DMF, 1 h, 2 cycles x) SnCl 2 ·2H 2 O (2.0 M) in DMF, o/n xi) 10% TFA, 20% Et 3 SiH in DCM. 
     
       
                 
         
             
             
         
      
     
     Conditions: (i) 5% NH 2 NH 2 ·H 2 O in DMF, 1.5 h (ii) 4-chloro-3-trifluoromethyl isocyanate in DMF at room temperature overnight or 4-trifluoromethyl sulphonyl chloride (2 eq) and DIPEA (4 eq) in DCM overnight (iii) DTT (0.2M) and Li-t-BuO (0.2M) in DMF at room temperature overnight (iv) 4-fluoro-3-nitro-benzotrifluoride (5 eq) or 3-chloro-4-fluoro-5-nitro-benzotrifluoride (3.5 eq) and DIPEA (0.25M) in DMF at 50° C. overnight (v) SnCl 2 ·2H 2 O (2.0M) in DMF overnight (vi) CNBr (1.0M) in DCM (vii) Amino acid (3 eq) and DIPEA (4 eq) in DMF with HBTU solution (3 eq) and shake overnight (viii) ArCH 2 Br (5 eq, 0.4M) and DIPEA (10 eq, 0.8M) in DMF at room temperature overnight (ix) Isothiocyanate (10 eq) in DMF for 4 h then drain and add DIC in DMF and shake overnight (x) 10% TFA/20% Et 3 Si/70% DCM for 3 h and treat dried product with saturated NH 3  in methanol solution for 2 h. 
     
       
                 
         
             
             
         
      
     
     Conditions: (i) 5% NH 2 NH 2 ·H 2 O in DMF, 1.5 h (ii) 4-fluoro-3-nitro-benzotrifluoride or 3-chloro-4-fluoro-5-nitro-benzotrifluoride (0.25M) and DIPEA (0.25M) in DMF at 50° C. overnight (iii) DTT (1.2M) and triethylamine (2.7M) in DMF at room temperature overnight (iv) Amino acid (3 eq) and DIPEA (4 eq) in DMF with HBTU solution (3 eq) and shake overnight (v) SnCl 2 ·2H 2 O (2.15M) in DMF overnight (vi) p-toluene sulfonic acid monohydrate in trimethylorthoformate (for benzimidazole), 1,1-carbonyldiimidazole (0.5M) in DCM (for benzimidazolone), 1,1-thiocarbonyldiimidazole (0.5M) in THF (for thiobenzimidazole), CNBr (0.5M) in DCM (for iminobenzimidazole) (vii) 10% TFA/20% Et 3 Si/70% DCM for 3 h (viii) Saturated NH 3  in methanol solution for 2 h 
     EXPERIMENTAL 
     General Resin Preparation Common to Each Library 
     Preparation of TCA Resin 
     To Wang resin (20 g, loading: 0.9 mmol/g, 18.0 mmol, dried over P 2 O 5  overnight) was added dry DCM (200 ml) and dry trichloroacetonitrile (0.32 mol, 17.7 equiv.). The resin suspension was cooled in an ice water bath and gently stirred for 15 min. DBU (13.4 mmol, 0.74 equiv.) was then added dropwise over 15 min. The resulting suspension was then gently stirred at 0° C. with occasional shaking for 1 h to give a dark brown suspension. The resin was then filtered in the glove box and washed with dry DMF (×3), dry THF (×3) and dry DCM (×3). The resin was then dried on the high vac over KOH overnight. 
     Loading of TG Building Block onto TCA Resin 
     TCA resin (19.6 g, 15.6 mmol) was washed in the glove box with dry THF (×4). A solution of the appropriate building block (46.9 mmol, 3 equiv.) in dry DCM (75 ml) was added to the resin, which was shaken for 3 min. BF 3 ·OEt 2  (11.0 mmol, 0.7 equiv.) was then added and the resin was shaken for a further 10 min. The resin was drained and washed with dry DCM (×5). The combined filtrate was washed with sat NaHCO 3  (500 ml), dried (MgSO 4 ) and the solvent was removed in vacuo to give the recovered building block. 
     The resin was washed further with dry THF (×4) and dry DCM (×4) and dried in vacuo overnight. 
     Removal of Para-Chlorobenzoate Group at 3 Position 
     The resin bound substrate (22.2 g) was treated with a solution of NaOMe (30 mM) in dry THF (310 ml) and dry MeOH (62 ml). The resin was shaken overnight, filtered in the glove box and washed with dry THF (×3), dry THF/acetic acid/dry MeOH (8:1:1, ×5), dry THF (×3) and dry DCM (×3). The resin was dried in vacuo overnight. 
     Library Production 
     TG 23 
     Note: Resin with an SMe group at the anomeric position, as well as hydrogen, was used for this library. 
     Alkylation at 3 Position with Methyl Iodide 
     The resin bound substrate was washed in the glove box with dry DMF (×3). A solution of lithium tert-butoxide in dry DMF (0.25 M) was added and the resin was shaken for 10 min. and drained. A solution of methyl iodide in dry DMF (0.25 M) was added and the resin was shaken for 20 min. The resin was then filtered and washed with dry DMF (×3). This cycle was performed an additional two times. The resin was finally washed in the glove box with dry DMF (×3), dry THF/dry MeOH/acetic acid (8:1:1, ×5), dry THF (×3), dry MeOH (×3) and dry DCM (×3). The resin was then dried on the high vac overnight. 
     Urea Formation 
     The resin bound substrate was treated with a solution of DIPEA in dry DMF (0.36 M) and shaken at room temperature for 30 min. The resin was drained, washed with dry DMF (×3) and treated with a solution of the isocyanate in dry DMF (0.15 M). The resin was shaken at room temperature overnight, drained and washed with DMF (×3) and DCM (×3). 
     Sulfonamide Formation 
     The resin bound substrate was treated with a solution the sulfonyl chloride (0.1 M) and DIPEA (0.2 M) in dry DCM and shaken at room temperature for 2. The resin was drained, washed with dry DCM (×3), MeOH (×3) and DCM (×3). 
     TG24 
     Fluoride Displacement at 3 Position 
     The resin bound substrate was washed in the glove box with dry DMF (×3). A solution of lithium tert-butoxide in dry DMF (0.5 M) was added and the resin was shaken for 10 min. and drained. A solution of 1-fluoro-2-nitrobenzene in dry DMF (0.5 M) was added and the resin was shaken for 20 min. The resin was then filtered and washed with dry DMF (×3). This cycle was repeated twice. The resin was washed in the glove box with dry DMF (×3), dry THF/dry MeOH/acetic acid (8:1:1, ×3), dry THF (×3), dry MeOH (×3) and dry DCM (×3). The resin was then dried on the high vac overnight. 
     Removal of DTPM Group at 2 Position 
     The resin bound substrate was treated with a solution of 5% hydrazine hydrate in DMF and shaken at room temperature for 1 h. The resin was drained, washed with DMF (×5) and DCM (×3) and dried in vacuo. 
     Urea Formation at 2 Position 
     The resin bound substrate was washed in the glove box with dry DMF (×3). A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate in dry DMF (0.15 M, 1.9 equiv.) was added and the resin was shaken at room temperature overnight. The resin was filtered in the glove box, washed with dry DMF (×3) and dry DCM (×3) and dried in vacuo. Compounds with a free hydroxyl at the 3-position were subsequently treated in the following manner: the resin was then swollen in dry THF and treated with a solution of NaOMe in dry MeOH (0.3 M). The resin was heated at 70° C. and under nitrogen for 4 h, allowed to cool, transferred into a solid phase vessel with dry THF and washed with dry THF (×3), dry MeOH (×3) and dry DCM (×3). The resin was then dried on the high vac overnight. 
     Sulfonamide Formation at 2 Position 
     The resin bound substrate was treated in the glove box with a solution of 4-(trifluoromethyl)-benzenesulfonyl chloride (0.11 M, 2 eq) and DIPEA (0.22 M, 4 eq) in dry DCM. The resin was shaken at room temperature overnight, filtered, washed in the glove box with dry DCM (×3), dry MeOH (×3) and dry DCM (×3) and dried in vacuo. 
     Reductive Amination at 4 Position 
     A solution of aldehyde (0.2 M) and sodium cyanoborohydride (0.175 M) in dry THF/dry MeOH/acetic acid (2:2:1) was added to each resin bound substrate. The resins were shaken at room temperature overnight, filtered and washed with THF/MeOH (1:3, ×3), DMF/MeOH (1:3, ×3), DCM/MeOH (1:3, ×3) and DCM (×3). 
     Sulfonamide Formation at 4 Position 
     To each resin bound substrate was added a solution of biphenyl-4-sulfonyl chloride (76.2 mM) and DIPEA (0.135 M) in dry DCM. The resins were shaken at room temperature overnight, filtered and washed with DCM (×3), MeOH (×3) and DCM (×3). 
     Reduction of Aromatic Nitro Group with Tin Chloride 
     Each resin bound substrate was washed with DMF (×2), then treated with a solution of SnCl 2 ·2H 2 O in DMF (2.0 M) and shaken at room temperature overnight. The resins were filtered and washed with DMF (×3), DMF/MeOH (1:1, ×3), DMF (×3), DMF/MeOH (1:1, ×3) and DCM (×3). 
     TG25 
     Fluoride Displacement at 3 Position 
     The resin bound substrate was washed in the glove box with dry DMF (×3). A solution of lithium tert-butoxide in dry DMF (0.5 M) was added and the resin was shaken for 10 min. and drained. A solution of 1-fluoro-2-nitrobenzene in dry DMF-(0.5 M) was added and the resin was shaken for 20 min. The resin was then filtered and washed with dry DMF (×3). This cycle was performed an addition two times. The resin was finally washed in the glove box with dry DMF (×3), dry THF/dry MeOH/acetic acid (8:1:1, ×5), dry THF (×3), dry MeOH (×3) and dry DCM (×3). The resin was then dried on the high vac overnight. 
     Removal of DTPM Group at 2 Position 
     The resin bound substrate was treated with a solution of 5% hydrazine hydrate in DMT and shaken at room temperature for 1 h. The resin was drained, washed with DMF (×5) and DCM (×3) and dried in vacuo. 
     Urea Formation at 2 Position 
     The resin bound substrate was washed in the glove box with dry DMF (×3). A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate in dry DMF (0.15 M, 1.9 equiv.) was added and the resin was shaken at room temperature overnight. The resin was filtered in the glove box, washed with dry DMF (×3) and dry DCM (×3) and dried in vacuo. Compounds with a free hydroxyl at the 3-position were subsequently treated in the following manner: the resin was then swollen in dry THF and treated with a solution of NaOMe in dry MeOH (0.3 M). The resin was heated at 70° C. and under nitrogen for 4 h, allowed to cool, transferred into a solid phase vessel with dry THF and washed with dry THF (×3), dry MeOH (×3) and dry DCM (×3). The resin was then dried on the high vac overnight. 
     Sulfonamide Formation at 2 Position 
     The resin bound substrate was treated in the glove box with a solution of 4-(trifluoromethyl)-benzenesulfonyl chloride (0.11 M, 2 eq) and DIPEA (0.22 M, 4 eq) in dry DCM. The resin was shaken at room temperature overnight, filtered, washed in the glove box with dry DCM (×3), dry MeOH (×3) and dry DCM (×3) and dried in vacuo. 
     Triazole Formation from Alkynes at 4 Position 
     To each resin bound substrate was added a solution of the alkyne in dry toluene (0.44 M). The resins were heated in test tubes in a graphite bath at 100° C. overnight, allowed to cool, transferred into solid phase tubes in the Bohdan Block with toluene and washed with toluene (×3), THF (×3) and DCM (×3). The resins were dried in vacuo for 2 h. The reaction was repeated. 
     Triazole Formation from β-Ketoesters at 4 Position 
     To each resin bound substrate was added a solution of the β-ketoester in dry DMF (0.5 M) followed by a solution of NaOEt in EtOH (0.5 M). The resins were heated in test tubes in a graphite bath at 100° C. overnight, allowed to cool, transferred into solid phase tubes in the Bohdan Block with DMF and washed with DMF (×3), DMF/MeOH (1:1, ×3), DMF (×3), DMF/MeOH (1:1, ×3) and DCM (×3). The resins were dried in vacuo for 2 h. The reaction was repeated for the biphenyl derivatives. 
     Each resin was then swollen in THF and then treated with a solution of lithium hydroxide monohydrate in water (1.5 M). The resins were shaken on a Merrifield shaker (reactions were not successful when performed using the Bohdan block presumable due to insufficient mixing) at room temperature overnight, drained and washed with THF (×3), MeOH (×3), THF (×3), MeOH (×3) and DCM (×3). 
     Triazole Formation from 4-Biphenylacetonitrile at 4 Position 
     To the resin bound substrate was added a solution of 4-biphenylacetonitrile in dry DMF (0.5 M) followed by a solution of NaOEt in EtOH (0.5 M). The resin was heated in a test tube in a graphite bath at 100° C. overnight, allowed to cool, transferred into solid phase tubes in the Bohdan Block with DMF and washed with DMF (×3), DMF/MeOH (1:1, ×3), DMF (×3), DMF/MeOH (1:1, ×3) and DCM (×3). The resin was dried in vacuo for 2 h. 
     TG26 
     DTPM Removal 
     The resin bound substrate was treated with a solution of 5% hydrazine hydrate in DMF and shaken at room temperature for 1.5 h. The resin was drained, washed with DMF (×5) and DCM (×3) and dried in vacuo. 
     Urea Formation 
     The resin bound substrate was washed with dry DMF and then the 4-chloro-3-trifluoromethyl isocyanate in DMF added and the reaction shaken overnight. The resin was drained and washed with DMF, MeOH and DCM. 
     Compounds with a free hydroxyl at the 3-position were subsequently treated in the following manner: The resin bound substrate was shaken for 3 h with a NaOMe solution (0.15M) made by dissolving 260 mg of Na metal in MeOH (15 mL) and mixing with THF (65 mL). The resin was washed with THF (×3), MeOH (×3) and DCM (×3) and dried under vacuum. 
     Sulphonamide Formation 
     The resin bound substrate was washed with dry DCM (×3) and DIPEA (4 eq, 0.3M) in DCM added. 4-Trifluoromethyl sulfonylchloride (2 eq, 0.15M) was taken up in DCM and also added to the resin and shaken overnight. The resin was drained and washed with DCM (×3), MeOH (×3) and DCM (×3). 
     Fluoride Displacement at the 4-Position 
     Resin bound substrates were treated with a solution of either 4-fluoro-3-nitro-benzotrifluoride (5.40 mmol, 5 eq) or 3-chloro-4-fluoro-5-nitro-benzotrifluoride (3.75 mmol, 3.5 eq) and DIPEA (5.4 mmol) in DMF (15 mL) at 50° C. overnight without shaking. The resins were then transferred into fritted vessels and drained and washed with dry DMF (×3), dry MeOH (×3), dry DCM (×3) and dried in vacuo. 
     Tin (II) Chloride Nitro Reduction 
     Each resin bound substrate was washed with DMF (×2), then treated with a solution of SnCl 2 ·2H 2 O in DMF (2.0 M) and shaken at room temperature overnight. The resins were drained and washed with DMF (×3), DMF/MeOH (1:1, ×3), DMF (×3), DMF/MeOH (1:1, ×3) and DCM (×3). 
     Cyclisation to the 4-iminobenzimidazole 
     Resin bound substrated was washed with anhydrous DCM then treated with cyanogen bromide (1M in DCM) overnight. After this time, the resins were then drained and washed with DCM (×3), MeOH (×3) and DCM (×3). 
     Acylation of the Iminobenzimidazole (Anhydride/DIC Method) 
     A solution was made up of each amino acid (1.6 mmol) and DIC (0.125 mL) in DMF (3.8 mL). This was stirred for one hour and then one solution was added to each resin bound substrate and the reaction mixture was shaken overnight. The resins were drained and washed with DMF (×3), MeOH (×3) and DCM (×3). 
     The resin bound substrates were subsequently treated with a solution of sodium methoxide 0.1 M in THF/MeOH (5:1) overnight then drained and washed with THF (×3), MeOH (×3), THF (×3) and DCM (×3). 
     Alkylation of the Iminobenzimidazole 
     Each resin bound substrate was treated with a solution containing a substituted aryl bromide (5 eq, 0.4M) and DIPEA (10 eq, 0.8M) in DMF. The solutions were shaken overnight. The resins were drained and washed with DMF (×3), MeOH (×3) and DCM (×3). 
     Cyclisation with the Aromatic Isothiocyanates 
     Resin bound substrate was treated with a solution of an aromatic isothiocyanates (3.08 mmol, 10 eq) in DMF for 4 h and then drained. Following this treatment, a solution of DIC (3.08 mmol, 10 eq) in DMF was added and the reaction mixture was shaken overnight. The resins were then drained and washed with DMF (×3), MeOH (×3) and DCM (×3). 
     Cyclisation with Decyl Isothiocyanate 
     The decyl isothiocyanate (6.16 mmol, 20 eq) and DIPEA (9.24 mmol, 30 eq) were taken up in DMF and added to each of the resin bound substrates. The resins were shaken overnight and then drained and washed with DMF (×3). A solution of DIC (20 eq, 1.54M) in DMF was added to each resin and the mixture shaken overnight. The resins were then drained and washed with DMF (×3), MeOH (×3) and DCM (×3). 
     TG27 
     DTPM Removal 
     The resin bound substrate was treated with a solution of 5% hydrazine hydrate in DMF and shaken at room temperature for 1.5 h. The resin was drained, washed with DMF (×5) and DCM (×3) and dried in vacuo. 
     Fluoride Displacement at the 2-Position 
     Resin bound substrates were treated with a solution of either 4-fluoro-3-nitro-benzotrifluoride (5.40 mmol, 5 eq) or 3-chloro-4-fluoro-5-nitro-benzotrifluoride (3.75 mmol, 3.5 eq) and DIPEA (5.4 mmol) in DMF (15 mL) at 50° C. overnight without shaking. The resins were then transferred into fritted vessels and drained and washed with dry DMF (×3), dry MeOH (×3), dry DCM (×3) and dried in vacuo. 
     Tin (II) Chloride Reduction 
     Resin bound substrate was washed with DMF (×2), then treated with a solution of SnCl 2 .2H 2 O in DMF (2.0 M) and shaken at room temperature overnight. The resins were filtered and washed with DMF (×3), DMF/MeOH (1:1, ×3), DMF (×3), DMF/MeOH (1:1, ×3) and DCM (×3). 
     Cyclisation to the Benzimidazole 
     Resin bound substrate was washed with THF (×3). p-toluenesulfonic acid monohydrate (catalytic) in trimethyl orthoformate and added to each of the resins. After shaking overnight the resins were drained and washed with THF (×3), MeOH (×3) and DCM (×3). 
     Cyclisation to the Benzimidazolone 
     Resin bound substrate was washed with DCM (×3). 1,1-carbonyldiimidazole (0.1M) in DCM and added to each of the resins. After shaking overnight the resins were drained and washed with DCM (×3), MeOH (×3) and DCM (×3). 
     Cyclisation to the Thiobenzimidazoleone 
     Resin bound substrate was washed with THF (×3). 1,1-thiocarbonyldiimidazole (0.5M) in THF and added to each of the resins. After shaking overnight the resins were drained and washed with THF (×3), MeOH (×3) and DCM (×3). 
     Cyclisation to the Iminobenzimidazoleone 
     Resin bound substrate was washed with DCM (×3). A 0.5M solution of cyanogen bromide was added to each of the resins. After shaking overnight the resins were drained and washed with DCM (×3), MeOH (×3) and DCM (×3). 
     At this point the (benzimidazolone and thiobenzimidazole) resins were treated with a sodium methoxide in THF/MeOH solution (0.04M) to remove any 3-position carbamates/thiocarbamates which may have formed. The resins were then drained and washed with THF (×3), MeOH (×3), THF (×3) and DCM (×3). 
     TG29 
     Urea Formation 
     Resin bound substrate was drained, washed with dry DMF (×3) and treated with a solution of an isocyanate in dry DMF (0.15 M). The resin was shaken at room temperature overnight, drained and washed with DMF (×3) and DCM (×3). 
     Thiourea Formation 
     Resin bound substrate was drained, washed with dry DMF (×3) and treated with a solution of an isothiocyanate in dry DMF (0.15 M). The resin was shaken at room temperature overnight, drained and washed with DMF (×3) and DCM (×3). 
     Examples of the kind of molecules synthesised are shown below. ACL00016124 has been shown to have an MIC of 1 μg/mL against  S. Aureus  in the absence of serum. ACL00016116 has shown MIC&#39;s of 4 μg/mL and 16 μg/mL against  S. Aureus  in the absence and presence (5% horse serum) of serum, respectively. Finally, ACL00016105 has demonstrated MIC values from 2-4 μg/mL, against  S. Aureus, S. Aureus  MRSA,  E. Faecium, E. Faecium  VanB and  E. Faecalis  in the absence of serum. 
     Biological Test Methods 
     Antibacterial testing was undertaken at a number of contract research organizations, and methods and procedures for the culture and testing of antibacterials are well documented in the scientific and technical literature. The following general procedures are provided as examples of the methods applied. 
     Testing was conducted to determine the in vitro antimicrobial activity of a series of compounds synthesised by Alchemia Pty Ltd. The antimicrobial activity of each compound was determined at a single concentration (128 μg/mL) in Mueller Hinton (MH) broth against the ATCC type strain of  Staphylococcus aureus . Compounds that demonstrate activity at this level were then subjected to MIC determination in  S. aureus  in MH broth in the absence of serum and in the presence of 5% heat inactivated horse serum. Compounds showing activity at concentrations up to 32-64 μg/mL in the presence/absence of serum were then tested for MIC activity against a standard set of 5 microorganisms comprising of ATCC type strains of MRSA,  Enterococcus faecalis, Enterococcus faecium , VRE and  Escherichia coli . CLSI (formerly NCCLS) microbroth dilution technique was used. 
     Procedures 
     Test Solution Preparation 
     Each compound is initially dissolved in 100 μL of DMSO. Each solution is then diluted further in 0.9 mL of sterile MH broth to give a total volume of 1 mL (1000 μg/mL) This stock solution is then further diluted in MH broth to give a test solution with final concentration of 128 μg/mL using the following formula:
 
0.5 ml stock in 3.4 ml MH broth
 
     The test solutions are prepared on the same day as initial testing is performed. Remaining stock and test solutions are then stored in labelled containers at −20° C. 
     Test Organisms 
     The same series of organisms were tested for all compounds. These include ATCC strains: 
       Staphylococcus aureus  ATCC 25923 (fully susceptible) 
       Staphylococcus aureus  (MRSA) ATCC 33591 
       Enterococcus faecalis  ATCC 29212 
       Enterococcus faecium  ATCC 35667 
       Escherichia coli  ATCC 25922 
       Enterococcus faecalis  ATCC 51299 (VRE) 
     Each test organism was subcultured from the −70° C. deep freezer onto horse blood agar. The plates were streaked to obtain isolated colonies and incubated at 35° C. in non-CO 2  incubator for 24 hours. A second subculture was carried out onto horse blood agar. For each test organism, 1-2 colonies were selected from an 18-24 hour culture and inoculated into 2 ml sterile MH broth. The turbidity was adjusted to 0.5 McFarland standard. 
     A 1:10 dilution in MH broth (200 μL in 2 ml MH) of the 0.5 McFarland control was prepared. 5 μL of this diluted solution was used to inoculate the trays. 
     MICs to vancomycin for each test organism were determined in a single series of testing as a means of confirming the test organisms were reacting within defined. MIC parameters. 
     Activity Against  S. Aureus    
     100 μL of test solution was added to each well. The final row on each tray had sterile MH broth only added (positive control). 5 μL of test organism solution was added to each well including the final row. The final well on each row had no organism solution added (negative control). The plate was then sealed and incubated at 35° C. in a non-CO 2  incubator for 18-24 hours. The plates were examined for growth after the incubation time. 
     MIC Against  S. aureus    
     Each compound that showed activity against  S. aureus  (inhibition of growth in the well) was tested further to determine the actual MIC. 100 μL of sterile MH broth was added in columns 2-12. 200 μL of test solution was added in column 1. 100 μL was transferred in column 2 giving a ½ dilution. 100 μL from column 2 was then transferred to column 3 (¼ dilution). This dilution was carried on until column 12. A second tray containing the same test solution was inoculated in a similar manner using sterile MH broth with 5% heat inactivated horse serum. 5 μL of organism solution was then added to each well. The plates were then sealed and incubated at 35° C. in a non-CO 2  incubator for 18-24 hours. The plates were examined for growth after the incubation time. 
     MIC Levels Against 5 Organisms 
     Each compound that showed activity at MIC level at 32 or less in sterile MH broth and at MIC level of 64 or less in the presence of serum was tested to determine full MIC against 5 microorganisms. The trays were prepared in a similar way as mentioned above and incubated at 35° C. in a non-CO 2  incubator for 18-24 hours. The plates were examined for growth after the incubation time. 
     After 18-24 hour incubation 5 μL from each well was then inoculated onto horse blood agar and incubated for 18-24 hours at 35° C. in a non-CO 2  incubator. 
     Plate Examination 
     If the test organism is sensitive to the compound in the broth the growth will be inhibited. Similarly, if the organism grows on the antibiotic containing medium then it is resistant to this particular antibiotic. 
     The organisms were scored as follows: 
     “No Growth”=Sensitive (S) 
     “Growth”=Resistant (R) 
     “Scant growth”=SG 
     All the results were recorded electronically on spreadsheets. 
     HPLC Separation 
     All compounds were separated on a Zorbax C18(4.6×50 mm) column. 
     The liquid phase used was H 2 O— Acetonitrile in the gradients described below. 
     5% acetonitrile from 0-1 min then gradient to 100% acetonitrile at 7 min and hold until 12 min for TG 23, 24, 27 and 29. 
     5% acetonitrile from 0-1 min then gradient to 30% acetonitrile at 3 min, gradient to 60% acetonitrile at 11 min and gradient to 100% acetonitrile at 12 min and hold until 15 min for TG 25 
     5% acetonitrile from 0-1 min then gradient to 100% H 2 O at 7 min and hold until 12 min for TG 26 compounds apart from AL00016098 and AL00016114 which used 5% acetonitrile from 0-1 min then gradient to 40% acetonitrile at 3 min, gradient to 70% acetonitrile at 11 min and gradient to 100% acetonitrile at 12 min and hold until 15 min. 
     Key to Building Blocks for Tables 1 and 2 
     
       
         
               
             
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Compounds of formula (1) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 RT: retention time/minutes 
               
               
                   
                 M + H: mass ion + 1 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Biological activity of compounds of formula (1) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 “++”: MIC (μg/mL): MIC ≦ 16 
               
               
                   
                 “+”: MIC (μg/mL): 64 ≧ MIC &gt; 16 
               
               
                   
                 “−”: MIC (μg/mL): MIC &gt; 64 
               
               
                   
                 Blank: not determined 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Compounds of formula (1) 
               
             
          
           
               
                 Compound Number 
                 R1 
                 R2 
                 R3 
                 R4 
                 RT 
                 M + H 
               
               
                   
               
             
          
           
               
                 1 
                 X1 
                 X3 
                 X9 
                 X10 
                 5.27 
                 564 
               
               
                 2 
                 X1 
                 X8 
                 X9 
                 X10 
                 5.23 
                 552 
               
               
                 3 
                 X1 
                 X3 
                 X9 
                 X22 
                 4.78 
                 550 
               
               
                 4 
                 X1 
                 X7 
                 X9 
                 X12 
                 4.18 
                 595 
               
               
                 5 
                 X1 
                 X8 
                 X9 
                 X16 
                 6.04 
                 540 
               
               
                 6 
                 X1 
                 X7 
                 X9 
                 X16 
                 5.93 
                 540 
               
               
                 7 
                 X2 
                 X7 
                 X9 
                 X16 
                 6.29 
                 586 
               
               
                 8 
                 X1 
                 X7 
                 X81 
                 X16 
                 6.23 
                 554 
               
               
                 9 
                 X1 
                 X6 
                 X9 
                 X10 
                 5.26 
                 586 
               
               
                 10 
                 X2 
                 X7 
                 X9 
                 X10 
                 5.22 
                 598 
               
               
                 11 
                 X1 
                 X7 
                 X81 
                 X10 
                 5.43 
                 566 
               
               
                 12 
                 X1 
                 X6 
                 X9 
                 X11 
                 5.7 
                 620 
               
               
                 13 
                 X1 
                 X8 
                 X9 
                 X11 
                 5.32 
                 586 
               
               
                 14 
                 X1 
                 X7 
                 X9 
                 X11 
                 5.38 
                 586 
               
               
                 15 
                 X2 
                 X7 
                 X9 
                 X11 
                 5.58 
                 632 
               
               
                 16 
                 X1 
                 X7 
                 X81 
                 X11 
                 5.63 
                 600 
               
               
                 17 
                 X1 
                 X6 
                 X9 
                 X12 
                 4.27 
                 629 
               
               
                 18 
                 X1 
                 X8 
                 X9 
                 X12 
                 4.12 
                 595 
               
               
                 19 
                 X2 
                 X7 
                 X9 
                 X12 
                 4.37 
                 641 
               
               
                 20 
                 X1 
                 X7 
                 X81 
                 X12 
                 4.33 
                 609 
               
               
                 21 
                 X1 
                 X6 
                 X9 
                 X13 
                 4.38 
                 629 
               
               
                 22 
                 X1 
                 X8 
                 X9 
                 X13 
                 4.18 
                 595 
               
               
                 23 
                 X1 
                 X7 
                 X9 
                 X13 
                 4.27 
                 595 
               
               
                 24 
                 X2 
                 X7 
                 X9 
                 X13 
                 4.28 
                 641 
               
               
                 25 
                 X1 
                 X7 
                 X81 
                 X13 
                 4.32 
                 609 
               
               
                 26 
                 X1 
                 X6 
                 X9 
                 X17 
                 4.78 
                 631 
               
               
                 27 
                 X1 
                 X8 
                 X9 
                 X17 
                 4.72 
                 597 
               
               
                 28 
                 X1 
                 X7 
                 X9 
                 X17 
                 4.68 
                 597 
               
               
                 29 
                 X2 
                 X7 
                 X9 
                 X17 
                 5.12 
                 643 
               
               
                 30 
                 X1 
                 X7 
                 X81 
                 X17 
                 4.93 
                 611 
               
               
                 31 
                 X1 
                 X6 
                 X9 
                 X14 
                 5.77 
                 560 
               
               
                 32 
                 X1 
                 X8 
                 X9 
                 X14 
                 5.53 
                 526 
               
               
                 33 
                 X1 
                 X7 
                 X9 
                 X14 
                 5.58 
                 526 
               
               
                 34 
                 X2 
                 X7 
                 X9 
                 X14 
                 5.79 
                 572 
               
               
                 35 
                 X1 
                 X7 
                 X81 
                 X14 
                 5.84 
                 540 
               
               
                 36 
                 X1 
                 X8 
                 X9 
                 X15 
                 5.18 + 4.68 
                 526 
               
               
                 37 
                 X1 
                 X7 
                 X9 
                 X15 
                 4.71 + 5.23 
                 526 
               
               
                 38 
                 X1 
                 X7 
                 X81 
                 X15 
                 5.27 
                 540 
               
               
                 39 
                 X1 
                 X6 
                 X9 
                 X19 
                 5.18 
                 570 
               
               
                 40 
                 X1 
                 X8 
                 X9 
                 X19 
                 5.02 
                 536 
               
               
                 41 
                 X1 
                 X7 
                 X9 
                 X19 
                 4.98 
                 536 
               
               
                 42 
                 X2 
                 X7 
                 X9 
                 X19 
                 5.17 
                 582 
               
               
                 43 
                 X1 
                 X7 
                 X81 
                 X19 
                 5.23 
                 550 
               
               
                 44 
                 X1 
                 X6 
                 X9 
                 X18 
                 5.32 
                 602 
               
               
                 45 
                 X1 
                 X8 
                 X9 
                 X18 
                 5.13 
                 568 
               
               
                 46 
                 X1 
                 X7 
                 X9 
                 X18 
                 5.12 
                 568 
               
               
                 47 
                 X2 
                 X7 
                 X9 
                 X18 
                 5.33 
                 614 
               
               
                 48 
                 X1 
                 X7 
                 X81 
                 X18 
                 5.37 
                 582 
               
               
                 49 
                 X1 
                 X3 
                 X9 
                 X21 
                 4.82 
                 584 
               
               
                 50 
                 X1 
                 X3 
                 X9 
                 X23 
                 5.27 
                 524 
               
               
                 51 
                 X1 
                 X3 
                 X9 
                 X24 
                 4.63 
                 567 
               
               
                 52 
                 X1 
                 X3 
                 X9 
                 X25 
                 5.22 
                 600 
               
               
                 53 
                 X1 
                 X7 
                 X9 
                 X21 
                 4.68 
                 571 
               
               
                 54 
                 X1 
                 X7 
                 X9 
                 X22 
                 4.42 
                 537 
               
               
                 55 
                 X1 
                 X7 
                 X9 
                 X23 
                 4.93 
                 511 
               
               
                 56 
                 X1 
                 X7 
                 X9 
                 X24 
                 4.67 
                 554 
               
               
                 57 
                 X1 
                 X7 
                 X9 
                 X25 
                 5.28 
                 587 
               
               
                 58 
                 X1 
                 X3 
                 X20 
                 X21 
                 5.27 
                 675 
               
               
                 59 
                 X1 
                 X3 
                 X20 
                 X22 
                 5.08 
                 641 
               
               
                 60 
                 X1 
                 X3 
                 X20 
                 X23 
                 5.72 
                 615 
               
               
                 61 
                 X1 
                 X3 
                 X20 
                 X24 
                 5.64 
                 658 
               
               
                 62 
                 X1 
                 X3 
                 X20 
                 X25 
                 5.42 
                 691 
               
               
                 63 
                 X1 
                 X7 
                 X20 
                 X21 
                 5.14 
                 662 
               
               
                 64 
                 X1 
                 X7 
                 X20 
                 X22 
                 4.87 
                 628 
               
               
                 65 
                 X1 
                 X7 
                 X20 
                 X23 
                 5.43 
                 602 
               
               
                 66 
                 X1 
                 X7 
                 X20 
                 X24 
                 5.37 
                 645 
               
               
                 67 
                 X1 
                 X7 
                 X20 
                 X25 
                 5.38 
                 678 
               
               
                 68 
                 X1 
                 X3 
                 X20 
                 X16 
                 6.18 
                 643 
               
               
                 69 
                 X1 
                 X3 
                 X20 
                 X10 
                 5.43 
                 655 
               
               
                 70 
                 X1 
                 X3 
                 X20 
                 X12 
                 4.67 
                 698 
               
               
                 71 
                 X1 
                 X3 
                 X20 
                 X12 
                 4.88 
                 698 
               
               
                 72 
                 X1 
                 X3 
                 X20 
                 X13 
                 4.52 
                 698 
               
               
                 73 
                 X1 
                 X3 
                 X20 
                 X17 
                 5.6 
                 700 
               
               
                 74 
                 X1 
                 X3 
                 X20 
                 X17 
                 6.18 
                 700 
               
               
                 75 
                 X1 
                 X3 
                 X20 
                 X17 
                 5.58 
                 700 
               
               
                 76 
                 X1 
                 X7 
                 X20 
                 X16 
                 5.33 
                 630 
               
               
                 77 
                 X1 
                 X7 
                 X20 
                 X10 
                 4.47 
                 642 
               
               
                 78 
                 X1 
                 X7 
                 X20 
                 X12 
                 4.68 
                 685 
               
               
                 79 
                 X1 
                 X7 
                 X20 
                 X12 
                 4.47 
                 685 
               
               
                 80 
                 X1 
                 X7 
                 X20 
                 X13 
                 5.53 
                 685 
               
               
                 81 
                 X1 
                 X7 
                 X20 
                 X17 
                 1 
                 687 
               
               
                 82 
                 X1 
                 X3 
                 X9 
                 X16 
                 6.04 
                 552 
               
               
                 83 
                 X1 
                 X4 
                 X9 
                 X16 
                 5.72 
                 518 
               
               
                 84 
                 X1 
                 X5 
                 X9 
                 X16 
                 5.78 
                 518 
               
               
                 85 
                 X1 
                 X77 
                 X9 
                 X16 
                 5.78 
                 534 
               
               
                 86 
                 X1 
                 X74 
                 X9 
                 X16 
                 5.88 
                 518 
               
               
                 87 
                 X1 
                 X75 
                 X9 
                 X16 
                 5.99 
                 534 
               
               
                 88 
                 X1 
                 X76 
                 X9 
                 X16 
                 5.97 
                 534 
               
               
                 89 
                 X1 
                 X78 
                 X9 
                 X16 
                 4.47 
                 373 
               
               
                 90 
                 X1 
                 X5 
                 X9 
                 X10 
                 4.97 
                 530 
               
               
                 91 
                 X1 
                 X77 
                 X9 
                 X10 
                 5.13 
                 546 
               
               
                 92 
                 X1 
                 X74 
                 X9 
                 X10 
                 5.08 
                 530 
               
               
                 93 
                 X1 
                 X75 
                 X9 
                 X10 
                 5.18 
                 546 
               
               
                 94 
                 X1 
                 X78 
                 X9 
                 X10 
                 3.82 
                 385 
               
               
                 95 
                 X1 
                 X5 
                 X9 
                 X12 
                 4.42 
                 573 
               
               
                 96 
                 X1 
                 X74 
                 X9 
                 X12 
                 4.47 
                 573 
               
               
                 97 
                 X1 
                 X75 
                 X9 
                 X12 
                 4.53 
                 589 
               
               
                 98 
                 X1 
                 X76 
                 X9 
                 X12 
                 4.47 
                 589 
               
               
                 99 
                 X1 
                 X78 
                 X9 
                 X12 
                 3.47 
                 428 
               
               
                 100 
                 X1 
                 X3 
                 X9 
                 X13 
                 4.38 
                 607 
               
               
                 101 
                 X1 
                 X4 
                 X9 
                 X13 
                 4.22 
                 573 
               
               
                 102 
                 X1 
                 X5 
                 X9 
                 X13 
                 4.28 
                 573 
               
               
                 103 
                 X1 
                 X77 
                 X9 
                 X13 
                 4.27 
                 589 
               
               
                 104 
                 X1 
                 X74 
                 X9 
                 X13 
                 4.33 
                 573 
               
               
                 105 
                 X1 
                 X76 
                 X9 
                 X13 
                 4.43 
                 589 
               
               
                 106 
                 X1 
                 X78 
                 X9 
                 X13 
                 3.22 
                 428 
               
               
                 107 
                 X1 
                 X3 
                 X9 
                 X17 
                 5.33 
                 609 
               
               
                 108 
                 X1 
                 X4 
                 X9 
                 X17 
                 5.07 
                 575 
               
               
                 109 
                 X1 
                 X5 
                 X9 
                 X17 
                 4.97 
                 575 
               
               
                 110 
                 X1 
                 X77 
                 X9 
                 X17 
                 5.12 
                 591 
               
               
                 111 
                 X1 
                 X74 
                 X9 
                 X17 
                 5.07 
                 575 
               
               
                 112 
                 X1 
                 X4 
                 X9 
                 X15 
                 5.37 
                 504 
               
               
                 113 
                 X1 
                 X5 
                 X9 
                 X15 
                 5.43 
                 504 
               
               
                 114 
                 X1 
                 X77 
                 X9 
                 X15 
                 5.48 
                 520 
               
               
                 115 
                 X1 
                 X74 
                 X9 
                 X15 
                 5.54 
                 504 
               
               
                 116 
                 X1 
                 X75 
                 X9 
                 X15 
                 5.57 
                 520 
               
               
                 117 
                 X1 
                 X76 
                 X9 
                 X15 
                 5.69 
                 520 
               
               
                 118 
                 X1 
                 X78 
                 X9 
                 X15 
                 4.18 
                 359 
               
               
                 119 
                 X1 
                 X3 
                 X9 
                 X19 
                 5.07 
                 548 
               
               
                 120 
                 X1 
                 X5 
                 X9 
                 X19 
                 4.88 
                 514 
               
               
                 121 
                 X1 
                 X77 
                 X9 
                 X19 
                 4.87 
                 530 
               
               
                 122 
                 X1 
                 X74 
                 X9 
                 X19 
                 4.92 
                 514 
               
               
                 123 
                 X1 
                 X75 
                 X9 
                 X19 
                 5.03 
                 530 
               
               
                 124 
                 X1 
                 X76 
                 X9 
                 X19 
                 5.13 
                 530 
               
               
                 125 
                 X1 
                 X78 
                 X9 
                 X19 
                 3.68 
                 369 
               
               
                 126 
                 X1 
                 X3 
                 X9 
                 X18 
                 5.23 
                 580 
               
               
                 127 
                 X1 
                 X4 
                 X9 
                 X18 
                 5.08 
                 546 
               
               
                 128 
                 X1 
                 X5 
                 X9 
                 X18 
                 5.02 
                 546 
               
               
                 129 
                 X1 
                 X77 
                 X9 
                 X18 
                 5.13 
                 562 
               
               
                 130 
                 X1 
                 X74 
                 X9 
                 X18 
                 5.17 
                 546 
               
               
                 131 
                 X1 
                 X75 
                 X9 
                 X18 
                 5.13 
                 562 
               
               
                 132 
                 X1 
                 X78 
                 X9 
                 X18 
                 3.87 
                 401 
               
               
                 133 
                 X1 
                 X3 
                 X9 
                 X80 
                 5.54 
                 629 
               
               
                 134 
                 X1 
                 X4 
                 X9 
                 X80 
                 5.23 
                 595 
               
               
                 135 
                 X1 
                 X5 
                 X9 
                 X80 
                 5.33 
                 595 
               
               
                 136 
                 X1 
                 X77 
                 X9 
                 X80 
                 5.27 
                 611 
               
               
                 137 
                 X1 
                 X74 
                 X9 
                 X80 
                 5.33 
                 595 
               
               
                 138 
                 X1 
                 X75 
                 X9 
                 X80 
                 5.37 
                 611 
               
               
                 139 
                 X1 
                 X76 
                 X9 
                 X80 
                 5.48 
                 611 
               
               
                 140 
                 X1 
                 X78 
                 X9 
                 X80 
                 4.22 
                 450 
               
               
                 141 
                 X1 
                 X3 
                 X9 
                 X79 
                 5.33 
                 544 
               
               
                 142 
                 X1 
                 X4 
                 X9 
                 X79 
                 5.02 
                 510 
               
               
                 143 
                 X1 
                 X5 
                 X9 
                 X79 
                 5.13 
                 510 
               
               
                 144 
                 X1 
                 X77 
                 X9 
                 X79 
                 5.07 
                 526 
               
               
                 145 
                 X1 
                 X74 
                 X9 
                 X79 
                 5.1 
                 510 
               
               
                 146 
                 X1 
                 X75 
                 X9 
                 X79 
                 5.17 
                 526 
               
               
                 147 
                 X1 
                 X76 
                 X9 
                 X79 
                 5.33 
                 526 
               
               
                 148 
                 X1 
                 X78 
                 X9 
                 X79 
                 3.82 
                 365 
               
               
                 149 
                 X1 
                 X65 
                 X9 
                 X10 
                 5.01 
                 528 
               
               
                 150 
                 X1 
                 X67 
                 X9 
                 X10 
                 5 
                 544 
               
               
                 151 
                 X1 
                 X63 
                 X9 
                 X10 
                 4.17 
                 527 
               
               
                 152 
                 X1 
                 X61 
                 X9 
                 X10 
                 4.87 
                 512 
               
               
                 153 
                 X1 
                 X66 
                 X9 
                 X10 
                 5.21 
                 562 
               
               
                 154 
                 X1 
                 X68 
                 X9 
                 X10 
                 5.39 
                 578 
               
               
                 155 
                 X1 
                 X64 
                 X9 
                 X10 
                 4.67 
                 561 
               
               
                 156 
                 X1 
                 X62 
                 X9 
                 X10 
                 5.28 
                 546 
               
               
                 157 
                 X1 
                 X65 
                 X9 
                 X12 
                 4.18 
                 571 
               
               
                 158 
                 X1 
                 X67 
                 X9 
                 X12 
                 4.17 
                 587 
               
               
                 159 
                 X1 
                 X63 
                 X9 
                 X12 
                 3.53 
                 570 
               
               
                 160 
                 X1 
                 X61 
                 X9 
                 X12 
                 4.12 
                 555 
               
               
                 161 
                 X1 
                 X66 
                 X9 
                 X12 
                 4.34 
                 605 
               
               
                 162 
                 X1 
                 X68 
                 X9 
                 X12 
                 4.43 
                 621 
               
               
                 163 
                 X1 
                 X64 
                 X9 
                 X12 
                 4.07 
                 604 
               
               
                 164 
                 X1 
                 X62 
                 X9 
                 X12 
                 4.33 
                 589 
               
               
                 165 
                 X1 
                 X65 
                 X9 
                 X16 
                 5.63 
                 516 
               
               
                 166 
                 X1 
                 X67 
                 X9 
                 X16 
                 5.84 
                 532 
               
               
                 167 
                 X1 
                 X63 
                 X9 
                 X16 
                 4.63 
                 515 
               
               
                 168 
                 X1 
                 X61 
                 X9 
                 X16 
                 5.68 
                 500 
               
               
                 169 
                 X1 
                 X66 
                 X9 
                 X16 
                 6.14 
                 550 
               
               
                 170 
                 X1 
                 X68 
                 X9 
                 X16 
                 6.34 
                 566 
               
               
                 171 
                 X1 
                 X64 
                 X9 
                 X16 
                 5.38 
                 549 
               
               
                 172 
                 X1 
                 X62 
                 X9 
                 X16 
                 6.13 
                 534 
               
               
                 173 
                 X1 
                 X65 
                 X9 
                 X15 
                 5.27 
                 502 
               
               
                 174 
                 X1 
                 X67 
                 X9 
                 X15 
                 5.32 
                 518 
               
               
                 175 
                 X1 
                 X63 
                 X9 
                 X15 
                 4.33 
                 501 
               
               
                 176 
                 X1 
                 X61 
                 X9 
                 X15 
                 5.32 
                 486 
               
               
                 177 
                 X1 
                 X66 
                 X9 
                 X15 
                 5.72 
                 536 
               
               
                 178 
                 X1 
                 X68 
                 X9 
                 X15 
                 5.88 
                 552 
               
               
                 179 
                 X1 
                 X64 
                 X9 
                 X15 
                 5.13 
                 535 
               
               
                 180 
                 X1 
                 X62 
                 X9 
                 X15 
                 5.78 
                 520 
               
               
                 181 
                 X1 
                 X65 
                 X9 
                 X17 
                 4.83 
                 573 
               
               
                 182 
                 X1 
                 X67 
                 X9 
                 X17 
                 4.77 
                 589 
               
               
                 183 
                 X1 
                 X63 
                 X9 
                 X17 
                 4.18 
                 572 
               
               
                 184 
                 X1 
                 X61 
                 X9 
                 X17 
                 4.77 
                 557 
               
               
                 185 
                 X1 
                 X66 
                 X9 
                 X17 
                 5.03 
                 607 
               
               
                 186 
                 X1 
                 X68 
                 X9 
                 X17 
                 4.97 
                 623 
               
               
                 187 
                 X1 
                 X64 
                 X9 
                 X17 
                 4.83 
                 606 
               
               
                 188 
                 X1 
                 X62 
                 X9 
                 X17 
                 4.77 
                 591 
               
               
                 189 
                 X1 
                 X69 
                 X9 
                 X10 
                 5.77 
                 532 
               
               
                 190 
                 X1 
                 X70 
                 X9 
                 X10 
                 6.77 
                 566 
               
               
                 191 
                 X1 
                 X69 
                 X9 
                 X12 
                 7.77 
                 575 
               
               
                 192 
                 X1 
                 X70 
                 X9 
                 X12 
                 8.77 
                 609 
               
               
                 193 
                 X1 
                 X69 
                 X9 
                 X16 
                 9.77 
                 520 
               
               
                 194 
                 X1 
                 X70 
                 X9 
                 X16 
                 10.77 
                 554 
               
               
                 195 
                 X1 
                 X69 
                 X9 
                 X15 
                 11.77 
                 506 
               
               
                 196 
                 X1 
                 X70 
                 X9 
                 X15 
                 12.77 
                 540 
               
               
                 197 
                 X1 
                 X69 
                 X9 
                 X17 
                 13.77 
                 577 
               
               
                 198 
                 X1 
                 X70 
                 X9 
                 X17 
                 14.77 
                 611 
               
               
                 199 
                 X1 
                 X71 
                 X9 
                 X10 
                 15.77 
                 502 
               
               
                 200 
                 X1 
                 X72 
                 X9 
                 X10 
                 16.77 
                 536 
               
               
                 201 
                 X1 
                 X71 
                 X9 
                 X12 
                 17.77 
                 545 
               
               
                 202 
                 X1 
                 X72 
                 X9 
                 X12 
                 18.77 
                 579 
               
               
                 203 
                 X1 
                 X71 
                 X9 
                 X16 
                 19.77 
                 490 
               
               
                 204 
                 X1 
                 X72 
                 X9 
                 X16 
                 20.77 
                 524 
               
               
                 205 
                 X1 
                 X71 
                 X9 
                 X15 
                 21.77 
                 476 
               
               
                 206 
                 X1 
                 X72 
                 X9 
                 X15 
                 22.77 
                 510 
               
               
                 207 
                 X1 
                 X71 
                 X9 
                 X17 
                 23.77 
                 547 
               
               
                 208 
                 X1 
                 X3 
                 X9 
                 X27 
                 5.33 + 5.48 
                 588 
               
               
                 209 
                 X1 
                 X3 
                 X9 
                 X27 
                 5.42 
                 588 
               
               
                 210 
                 X1 
                 X7 
                 X9 
                 X27 
                 7.98 + 8.63 
                 575 
               
               
                 211 
                 X1 
                 X7 
                 X9 
                 X27 
                 8.09 + 8.84 
                 575 
               
               
                 212 
                 X1 
                 X3 
                 X20 
                 X27 
                 9.68 
                 679 
               
               
                 213 
                 X1 
                 X3 
                 X20 
                 X27 
                 10.57 
                 679 
               
               
                 214 
                 X1 
                 X7 
                 X20 
                 X27 
                  9.52 + 10.06 
                 666 
               
               
                 215 
                 X1 
                 X3 
                 X9 
                 X26 
                 8.02 + 8.76 
                 580 
               
               
                 216 
                 X1 
                 X3 
                 X9 
                 X26 
                 8.72 
                 580 
               
               
                 217 
                 X1 
                 X7 
                 X9 
                 X26 
                 7.27 + 8.09 
                 567 
               
               
                 218 
                 X1 
                 X7 
                 X9 
                 X26 
                 7.98 
                 567 
               
               
                 219 
                 X1 
                 X3 
                 X20 
                 X26 
                 9.2 
                 671 
               
               
                 220 
                 X1 
                 X3 
                 X20 
                 X26 
                 9.91 
                 671 
               
               
                 221 
                 X1 
                 X7 
                 X20 
                 X26 
                 9.01 + 9.63 
                 658 
               
               
                 222 
                 X1 
                 X7 
                 X20 
                 X26 
                 9.54 
                 658 
               
               
                 223 
                 X1 
                 X3 
                 X9 
                 X31 
                 7.45 
                 632 
               
               
                 224 
                 X1 
                 X7 
                 X9 
                 X31 
                 6.15 + 6.57 
                 619 
               
               
                 225 
                 X1 
                 X3 
                 X9 
                 X29 
                 6.32 + 6.67 
                 590 
               
               
                 226 
                 X1 
                 X7 
                 X9 
                 X29 
                 5.26 
                 577 
               
               
                 227 
                 X1 
                 X7 
                 X9 
                 X28 
                 7.8 
                 590 
               
               
                 235 
                 X1 
                 X3 
                 X9 
                 X53 
                 6.68 
                 793 
               
               
                 236 
                 X1 
                 X3 
                 X9 
                 X55 
                 5.23 
                 777 
               
               
                 237 
                 X1 
                 X3 
                 X9 
                 X57 
                 5.63 
                 791 
               
               
                 238 
                 X1 
                 X3 
                 X9 
                 X59 
                 5.54 
                 791 
               
               
                 239 
                 X1 
                 X7 
                 X9 
                 X53 
                 6.68 
                 780 
               
               
                 240 
                 X1 
                 X7 
                 X9 
                 X55 
                 5.32 
                 764 
               
               
                 241 
                 X1 
                 X7 
                 X9 
                 X57 
                 5.67 
                 778 
               
               
                 242 
                 X1 
                 X7 
                 X9 
                 X59 
                 5.78 
                 778 
               
               
                 243 
                 X1 
                 X3 
                 X9 
                 X33 
                 6.23 
                 678 
               
               
                 244 
                 X1 
                 X3 
                 X9 
                 X35 
                 6.23 
                 712 
               
               
                 245 
                 X1 
                 X3 
                 X9 
                 X37 
                 5.03 
                 720 
               
               
                 246 
                 X1 
                 X3 
                 X9 
                 X41 
                 5.57 
                 658 
               
               
                 247 
                 X1 
                 X3 
                 X9 
                 X43 
                 5.39 
                 692 
               
               
                 248 
                 X1 
                 X3 
                 X9 
                 X45 
                 5.52 
                 714 
               
               
                 249 
                 X1 
                 X3 
                 X9 
                 X51 
                 5.53 
                 750 
               
               
                 250 
                 X1 
                 X3 
                 X9 
                 X47 
                 5.27 
                 734 
               
               
                 251 
                 X1 
                 X3 
                 X9 
                 X49 
                 6.29 
                 708 
               
               
                 252 
                 X1 
                 X3 
                 X9 
                 X34 
                 6.53 
                 712 
               
               
                 253 
                 X1 
                 X3 
                 X9 
                 X36 
                 6.49 
                 746 
               
               
                 254 
                 X1 
                 X3 
                 X9 
                 X38 
                 5.28 
                 754 
               
               
                 255 
                 X1 
                 X3 
                 X9 
                 X42 
                 5.82 
                 692 
               
               
                 256 
                 X1 
                 X3 
                 X9 
                 X44 
                 5.83 
                 726 
               
               
                 257 
                 X1 
                 X3 
                 X9 
                 X46 
                 8.04 
                 748 
               
               
                 258 
                 X1 
                 X3 
                 X9 
                 X52 
                 5.74 
                 784 
               
               
                 259 
                 X1 
                 X3 
                 X9 
                 X48 
                 5.74 
                 768 
               
               
                 260 
                 X1 
                 X3 
                 X9 
                 X50 
                 5.67 
                 742 
               
               
                 261 
                 X1 
                 X3 
                 X9 
                 X50 
                 5.78 
                 742 
               
               
                 262 
                 X1 
                 X7 
                 X9 
                 X33 
                 5.93 
                 665 
               
               
                 263 
                 X1 
                 X7 
                 X9 
                 X35 
                 5.88 
                 699 
               
               
                 264 
                 X1 
                 X7 
                 X9 
                 X37 
                 4.77 
                 707 
               
               
                 265 
                 X1 
                 X7 
                 X9 
                 X41 
                 4.83 
                 645 
               
               
                 266 
                 X1 
                 X7 
                 X9 
                 X43 
                 5.37 
                 679 
               
               
                 267 
                 X1 
                 X7 
                 X9 
                 X45 
                 5.23 
                 701 
               
               
                 268 
                 X1 
                 X7 
                 X9 
                 X51 
                 5.27 
                 737 
               
               
                 269 
                 X1 
                 X7 
                 X9 
                 X47 
                 4.93 
                 721 
               
               
                 270 
                 X1 
                 X7 
                 X9 
                 X49 
                 6.28 
                 695 
               
               
                 271 
                 X1 
                 X7 
                 X9 
                 X34 
                 6.24 
                 699 
               
               
                 272 
                 X1 
                 X7 
                 X9 
                 X36 
                 6.48 
                 733 
               
               
                 273 
                 X1 
                 X7 
                 X9 
                 X38 
                 4.98 
                 741 
               
               
                 274 
                 X1 
                 X7 
                 X9 
                 X42 
                 5.32 
                 679 
               
               
                 275 
                 X1 
                 X7 
                 X9 
                 X44 
                 5.53 
                 713 
               
               
                 276 
                 X1 
                 X7 
                 X9 
                 X46 
                 5.72 
                 735 
               
               
                 277 
                 X1 
                 X7 
                 X9 
                 X52 
                 5.43 
                 771 
               
               
                 278 
                 X1 
                 X7 
                 X9 
                 X48 
                 5.47 
                 755 
               
               
                 279 
                 X1 
                 X7 
                 X9 
                 X50 
                 1 
                 729 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Biological activity of compounds of formula (1) 
               
             
          
           
               
                   
                   
                 
                   S. Aureus 
                 
                   
                 
                   E. Faecium 
                 
                   
               
               
                 Com- 
                 
                   S. Aureus 
                 
                 33591 
                 
                   E. Faecium 
                 
                 51299 
                 
                   E. Fecalis 
                 
               
               
                 pound 
                 25923 
                 MRSA 
                 35667 
                 VanB 
                 29212 
               
               
                 number 
                 activity 
                 activity 
                 activity 
                 activity 
                 activity 
               
               
                   
               
             
          
           
               
                 7 
                 + 
                 + 
                 − 
                 − 
                 − 
               
               
                 8 
                 + 
                 − 
                 − 
                 − 
                 − 
               
               
                 12 
                 + 
               
               
                 26 
                 + 
               
               
                 27 
                 + 
               
               
                 29 
                 ++ 
               
               
                 30 
                 + 
               
               
                 50 
                 + 
                 + 
                 + 
                 − 
                 + 
               
               
                 62 
                 + 
                 ++ 
                 − 
                 − 
                 − 
               
               
                 69 
                 + 
                 − 
                 − 
                 − 
                 − 
               
               
                 70 
                 + 
                 ++ 
                 + 
                 − 
                 + 
               
               
                 71 
                 ++ 
                 ++ 
                 ++ 
                 + 
                 + 
               
               
                 72 
                 ++ 
               
               
                 73 
                 ++ 
                 ++ 
                 ++ 
                 + 
                 ++ 
               
               
                 74 
                 + 
                 + 
                 + 
                 + 
                 − 
               
               
                 75 
                 ++ 
               
               
                 79 
                 + 
                 + 
                 − 
                 − 
                 − 
               
               
                 88 
                 + 
                 + 
                 + 
                 + 
                 + 
               
               
                 107 
                 ++ 
                 ++ 
                 + 
                 + 
                 + 
               
               
                 108 
                 + 
                 + 
                 − 
                 − 
                 − 
               
               
                 109 
                 ++ 
                 + 
                 − 
                 − 
                 − 
               
               
                 153 
                 + 
                 + 
                 − 
                 − 
                 + 
               
               
                 155 
                 + 
                 + 
                 − 
                 − 
                 − 
               
               
                 156 
                 + 
                 − 
                 + 
                 − 
                 − 
               
               
                 161 
                 + 
                 + 
                 − 
                 − 
                 + 
               
               
                 163 
                 + 
                 + 
                 − 
                 − 
                 + 
               
               
                 169 
                 + 
                 + 
                 + 
                 + 
                 + 
               
               
                 170 
                 − 
                 ++ 
                 + 
                 ++ 
                 − 
               
               
                 171 
                 + 
                 + 
                 − 
                 − 
                 − 
               
               
                 172 
                 + 
                 + 
                 − 
                 − 
                 − 
               
               
                 177 
                 + 
                 + 
                 + 
                 − 
                 − 
               
               
                 178 
                 + 
                 − 
                 − 
                 − 
                 − 
               
               
                 179 
                 + 
                 − 
                 − 
                 − 
                 − 
               
               
                 181 
                 + 
                 ++ 
                 + 
                 + 
                 + 
               
               
                 182 
                 ++ 
                 ++ 
                 ++ 
                 ++ 
                 ++ 
               
               
                 183 
                 + 
                 − 
                 ++ 
                 − 
                 − 
               
               
                 185 
                 + 
                 ++ 
                 ++ 
                 + 
                 ++ 
               
               
                 186 
                 ++ 
                 + 
                 − 
                 − 
                 + 
               
               
                 187 
                 ++ 
                 ++ 
                 + 
                 ++ 
                 ++ 
               
               
                 188 
                 + 
                 + 
                 − 
                 + 
                 + 
               
               
                 197 
                 ++ 
                 + 
                 + 
                 + 
                 + 
               
               
                 198 
                 + 
                 + 
                 + 
                 + 
                 + 
               
               
                 200 
                 − 
                 + 
                 − 
                 − 
                 − 
               
               
                 202 
                 + 
                 + 
                 + 
                 − 
                 − 
               
               
                 207 
                 + 
                 + 
                 + 
                 + 
                 + 
               
               
                 236 
                 − 
                 ++ 
                 ++ 
                 + 
                 ++ 
               
               
                 237 
                 − 
                 ++ 
                 − 
                 − 
                 ++ 
               
               
                 238 
                 − 
                 ++ 
                 − 
                 − 
                 ++ 
               
               
                 240 
                 ++ 
                 ++ 
                 − 
                 − 
                 ++ 
               
               
                 241 
                 ++ 
                 ++ 
                 ++ 
                 + 
                 ++ 
               
               
                 242 
                 ++ 
                 ++ 
                 ++ 
                 − 
                 ++ 
               
               
                 246 
                 ++ 
                 ++ 
                 + 
                 + 
                 ++ 
               
               
                 247 
                 ++ 
                 ++ 
                 − 
                 ++ 
                 ++ 
               
               
                 248 
                 ++ 
                 ++ 
                 ++ 
                 ++ 
                 ++ 
               
               
                 249 
                 ++ 
                 ++ 
                 ++ 
                 ++ 
                 ++ 
               
               
                 251 
                 ++ 
                 ++ 
                 ++ 
                 ++ 
                 ++ 
               
               
                 252 
                 + 
                 − 
                 − 
                 − 
                 + 
               
               
                 253 
                 − 
                 − 
                 − 
                 − 
                 + 
               
               
                 254 
                 ++ 
                 ++ 
                 − 
                 − 
                 − 
               
               
                 255 
                 ++ 
                 ++ 
                 − 
                 + 
                 ++ 
               
               
                 256 
                 − 
                 − 
                 − 
                 ++ 
                 ++ 
               
               
                 258 
                 ++ 
               
               
                 259 
                 ++ 
               
               
                 261 
                 ++ 
               
               
                 262 
                 + 
               
               
                 263 
                 ++ 
               
               
                 264 
                 ++ 
               
               
                 265 
                 + 
               
               
                 266 
                 ++ 
               
               
                 267 
                 ++ 
               
               
                 268 
                 ++ 
               
               
                 269 
                 ++ 
               
               
                 270 
                 ++ 
               
               
                 271 
                 ++ 
               
               
                 272 
                 ++ 
               
               
                 273 
                 ++ 
               
               
                 274 
                 ++ 
               
               
                 275 
                 ++ 
               
               
                 276 
                 + 
               
               
                 277 
                 + 
               
               
                 278 
                 ++ 
               
               
                 279 
                 ++ 
               
               
                   
               
             
          
         
       
     
     FIG. 1: Sidearms for Table 1. 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
     It should be appreciated that various other changes and modifications can be made to the specification without departing from the spirit and scope of the invention.