Methods of treating fungal infections

Abstract

A method for treating a fungal infection is disclosed. The method includes contacting a fungus with a substituted aurone derivative.

What is claimed is:  
     
         1 . A method of preventing growth of a fungus, said method comprising contacting said fungus with a compound of formula (IA):  
       
         
           
           
               
               
           
         
       
       wherein 
 each R is independently H, OH, Br, Cl, I, amino, thiol, nitro, C 1-4  alkoxy, C 2-4  alkenyloxy, C 2-6  alkoxyalkyleneoxy, C 1-4  alkylthio, C 3-18  alkyl, or C 3-18  alkenyl; or two adjacent Rs, taken together, are a C 2-18  bivalent moiety containing at least one oxgen atom, substituted or disubstituted with A or B, or both, A being H, OH, Br, Cl, I, amino, or thiol, and B being H, C 1-10  alkyl, C 2-18  alkenyl, or C 6-18  aryl; provided that at least two Rs are not H;  
 X is C 4-10  alkyl, C 4-20  alkenyl, or a C 4-20  single, C 6-20  bridged, or C 6-20  fused ring moiety containing cycloalkyl, cycloalkenyl, aryl, heterocycle, or heteroaryl, wherein X is substituted with H, OH, Cl, Br, I, amino, cyano, nitro, alkyl, alkoxy, alkenyl, or alkenyloxy; provided that when X is a heteroaryl or heterocyclic moiety where two Rs are each OH and are meta to each other, then remaining R is H and ortho to each of the two hydroxyls, Y and Z are each O, and a ring atom of X is linked directly to the sp 2  carbon atom adjacent to X, and substituted with H, OH, Cl, Br, I, amino, cyano, alkyl, alkoxy, alkenyl, or alkenyloxy; and  
 each of Y and Z is independently selected from O, S, and NH.  
 
     
     
         2 . The method of  claim 1 , wherein X is benzyl, 2,5-dimethoxyphenyl, 2,3-dimethyl-4-methoxyphenyl, 3-benzyloxyphenyl, 3-phenoxyphenyl, 4-benzyloxy-3-methoxyphenyl, 4-[3-propenoic acid]-phenyl, 2-ethoxy-1-naphthyl, 1-(methylthio)ethyl, DL-1-phenylethyl, 4-n-pentyloxyphenyl, 1-(phenylsulfonyl)-2-pyrrolyl, 4-(3-dimethylaminopropoxy)phenyl, 3-phenylpropyl, 2,4-diethoxy-m-tolulyl, 2,6,6-trimethylcyclohexene-1-methyl, 2,5-dimethoxy-3-tetrahydrofuranyl, 4-methyl-5-imidazolyl, 4-n-pentylphenyl, 2-benzyloxy-4,5-dimethoxyphenyl, 1-pyrenyl, 3,5-dibenzyloxy-3-methoxyphenyl, 3-methyl-4-methoxyphenyl, 4-n-decyloxyphenyl, 2,4-dimethoxy-3-methylphenyl, t-butyl, 3-(4-t-butylphenoxy)phenyl, 2-n-hexyloxyphenyl, 2-(4-chlorophenylthio)phenyl, cyclopropyl, 2,6-dimethoxy-4-hydroxyphenyl, 4-benzyloxyphenyl, 2-benzyloxyphenyl, 8-hydroxy -1,1,7,7-tetramethyljulolidin-9-yl, 2,3,6,7-tetrahydro-8-hydroxyjulolidin-9-yl, 2-methoxymethyl-1-pyrrolidinyl, 5-(2-nitrophenyl)furanyl, 1,1-dimethyl-2-hydroxyethyl, 5-methylfuranyl, 5-(3-chlorophenyl)furanyl, 2,4-hexadienyl, 5-[3(trifluoromethyl)phenylfuranyl], 4,5-dimethyl-4-pentenyl, imidazolyl, ferrocenyl, 2,6-dimethylhept-5-enyl, 5-[2-(trifluoromethyl)phenyl]furanyl, 5-(hydroxy-2-nitromethyl)furanyl, 2,4-dimethyl-2,6-heptadienyl, 1-phenylethyl, 5-(2-chlorophenyl)furanyl, benzyl, 5-ethyl-2-furanyl, 5-(4-nitrophenyl)furanyl, pentamethylphenyl, 1-(methyldithio)isopropyl, 4-trifluoromethylphenyl, 3-fluoro-4-methoxyphenyl, or the X of a compound of Schemes X-1 through X-10, wherein the compounds of Schemes X-1 through X-10 have the formulae X—CHO.  
     
     
         3 . The method of  claim 2 , wherein said compound is one of formulae (I), (II), (III), or (IV):  
       
         
           
           
               
               
           
         
       
       wherein 
 V is a bivalent C 2-18  moiety containing at least one oxygen atom and substituted with A, B, or both;  
 each of W and W′ is independently selected from the values for A, cyano, nitro, C 1-4  alkoxy, C 2-4  alkenyloxy, C 2-6  alkyloxyalkyleneoxy, C 2-7  carboxyalkyloxy, C 7-15  arylalkoxy, and C 1-4  alkylthio;  
 R a  is H, C 3-18  alkyl, C 3-18  alkenyl, C 5-18  cyclohexenyl, or C 6-18  aryl; and  
 each of R b  and R c  is independently selected from H and C 1-4  alkyl.  
 
     
     
         4 . The method of  claim 3 , wherein said compound is of the formula Q=(CHX), where Q is selected from the Qs of the compounds of Schemes Q-1 through Q-11, wherein the compounds of Schemes Q-1 through Q-11 have the formula Q-H 2 .  
     
     
         5 . The method of  claim 1 , wherein said compound has an IC 50  of less than 50 micrograms per milliliter against at least one pathogenic strain of Candida or Aspergillus.  
     
     
         6 . The method of  claim 3 , wherein V contains between 1 and 3 rings.  
     
     
         7 . The method of  claim 3 , wherein V is selected from the following formulae:  
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 3 , wherein V is selected from the following formulae:  
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 3 , wherein R a  is selected from H, prop-2-enyl, cinnamyl, 2-methylprop-2-enyl, but-2-enyl, 3-methylbut-2-enyl, 3,7-dimethylocta-2,6-dienyl, (cyclohexenyl)methyl, 3,7,11-trimethyldodeca-2,6,10-trienyl, and benzyl.  
     
     
         10 . The method of  claim 2 , wherein said compound is of formula (III), and each of Y and Z is independently selected from O and S.  
     
     
         11 . The method of  claim 1 , wherein said compound is selected from S01, S02, S03, S04, S05, S06, S08, S09, S10, S11, S12, S13, S14, S15, S16, S17, S18, and S19.  
     
     
         12 . The method of  claim 2 , wherein each of W and W′ is independently selected from H, OH, methoxy, methoxymethyleneoxy, and carboxymethoxy.  
     
     
         13 . The method of  claim 12 , wherein Y and Z are O, and at least one of W and W′ is OH.  
     
     
         14 . The method of  claim 2 , wherein X is a heterocyclic or heteroaryl moiety.  
     
     
         15 . The method of  claim 1 , wherein X is selected from C 4-10  alkyl, C 4-20  alkenyl, and a C 4-20  single, C 6-20  bridged, or C 6-20  fused ring moiety containing cycloalkyl, cycloalkenyl, or aryl.  
     
     
         16 . The method of  claim 15 , wherein X is a nonaromatic moiety containing cycloalkyl, cycloalkenyl, alkyl, or alkenyl.  
     
     
         17 . The method of  claim 1 , wherein said compound is selected from S17 and S19.  
     
     
         18 . The method of  claim 15 , wherein X is an aryl moiety.  
     
     
         19 . The method of  claim 1 , wherein said compound is selected from S12 and S02.  
     
     
         20 . The method of  claim 1 , wherein said fungus is of a Candida species.  
     
     
         21 . The method of  claim 1 , wherein said fungus is resistant to at least one azole antifungal agent.  
     
     
         22 . The method of  claim 21 , wherein said azole antifungal agent is fluconazole.  
     
     
         23 . The method of  claim 1 , wherein said fungus is of an Aspergillus species.  
     
     
         24 . The method of  claim 1 , wherein said fungus is selected from the group consisting of  C. albicans, C. glabrata, C. krusei, C. tropicalis, C. parapsilosis, A. fumigatus,  or  A. niger.    
     
     
         25 . A method for treating a fungal infection, said method comprising administering to a patient a pharmaceutical composition containing a compound selected from the following formulae: