Antifungal agents. 11. N-substituted derivatives of 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole: synthesis, anti-Candida activity, and QSAR studies.

1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazoles were recently reported by our group as potent anti-Candida agents belonging to the antifungal azole class. In the present paper the synthesis, anti-Candida activities, and QSAR studies on a novel series of N-substituted 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole derivatives are reported. The newly synthesized azoles were tested against 12 strains of Candida albicans together with bifonazole, miconazole, itraconazole, fluconazole, and compounds 1a, 1b, 3a, 3b, and 3c used as reference drugs. In general, tested derivatives showed good antifungal activities, and the most potent compound was 1d (MIC(90) = 0.032 microg/mL), which was from 4- to 250-fold more potent than reference drugs. Catalyst software was applied to develop a quantitative pharmacophore model to be used for the rational design of new antifungal azoles. Some key interactions, as well as excluded volumes, further to the coordination bond of azole antifungals with the demethylase enzyme, are highlighted.

[1]  Pratibha Sharma,et al.  Synthesis and QSAR studies of pyrimido[4,5-d]pyrimidine-2,5-dione derivatives as potential antimicrobial agents. , 2004, Bioorganic & medicinal chemistry letters.

[2]  I. Kuntz,et al.  Computer-assisted design of selective imidazole inhibitors for cytochrome p450 enzymes. , 2004, Journal of medicinal chemistry.

[3]  R. Chandra,et al.  Optically active antifungal azoles: synthesis and antifungal activity of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-[2-[4-aryl-piperazin-1-yl]-ethyl]-tetrazol-2-yl/1-yl)-1-[1,2,4]-triazol-1-yl-butan-2-ol. , 2004, Bioorganic & medicinal chemistry.

[4]  Anton J. Hopfinger,et al.  4D-QSAR Analysis of a Series of Antifungal P450 Inhibitors and 3D-Pharmacophore Comparisons as a Function of Alignment , 2003, J. Chem. Inf. Comput. Sci..

[5]  N. Gow,et al.  Antifungal agents: mechanisms of action. , 2003, Trends in microbiology.

[6]  J. Krysiński,et al.  Quantitative structure-activity relationships study of a series of imidazole derivatives as potential new antifungal drugs. , 2002, Acta Poloniae Pharmaceutica - Drug Research.

[7]  Sean Ekins,et al.  Pharmacophore modeling of cytochromes P450. , 2002, Advanced drug delivery reviews.

[8]  D. Sanglard,et al.  Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. , 2002, The Lancet. Infectious diseases.

[9]  R. Costi,et al.  Analytical and semipreparative enantiomeric separation of azole antifungal agents by high-performance liquid chromatography on polysaccharide-based chiral stationary phases. Application to in vitro biological studies. , 2002, Journal of chromatography. A.

[10]  T. Poulos,et al.  Crystal structure of cytochrome P450 14α-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[11]  David J. Schuller,et al.  Crystal Structure of a Thermophilic Cytochrome P450 from the Archaeon Sulfolobus solfataricus * , 2000, The Journal of Biological Chemistry.

[12]  M. Botta,et al.  Chiral azole derivatives. 4. Enantiomers of bifonazole and related antifungal agents: synthesis, configuration assignment, and biological evaluation. , 2000, The Journal of organic chemistry.

[13]  S. Ablordeppey,et al.  Systemic antifungal agents against AIDS-related opportunistic infections: current status and emerging drugs in development. , 1999, Current medicinal chemistry.

[14]  Jon A. Erickson,et al.  A comparative molecular field analysis study of obtusifoliol 14α-methyl demethylase inhibitors † , 1999 .

[15]  J. Perfect,et al.  Formation of Azole-Resistant Candida albicans by Mutation of Sterol 14-Demethylase P450 , 1999, Antimicrobial Agents and Chemotherapy.

[16]  M. Ghannoum.  Future of antimycotic therapy , 1997 .

[17]  T. Theophanides,et al.  Molecular modeling of azole antifungal agents active against Candida albicans. 1. A comparative molecular field analysis study. , 1996, Journal of medicinal chemistry.

[18]  V. Andriole,et al.  Efficacy of UK-109496, a new azole antifungal agent, in an experimental model of invasive aspergillosis , 1996, Antimicrobial agents and chemotherapy.

[19]  A. Retico,et al.  Antifungal agents. 9. 3-Aryl-4-[alpha-(1H-imidazol-1-yl)arylmethyl]pyrroles: a new class of potent anti-Candida agents. , 1995, Journal of medicinal chemistry.

[20]  Steven L. Teig,et al.  Chemical Function Queries for 3D Database Search , 1994, J. Chem. Inf. Comput. Sci..

[21]  A. Retico,et al.  Antifungal agents. VIII. Synthesis and antifungal activities of bipyrryl analogues of bifonazole. , 1994, Il Farmaco.

[22]  M. Artico,et al.  Synthesis of Biologically Active Azoles via TosMIC , 1993 .

[23]  A. Retico,et al.  Antifungal agents. III. Naphthyl and thienyl derivatives of 1H-imidazol-1-yl-4-phenyl-1H-pyrrol-3-ylmethane. , 1993, Farmaco.

[24]  C. Beck-Sague,et al.  Secular trends in the epidemiology of nosocomial fungal infections in the United States, 1980-1990. National Nosocomial Infections Surveillance System. , 1993, The Journal of infectious diseases.

[25]  R. Costi,et al.  Novel in vitro Highly Active Antifungal Agents with Pyrrole and Imidazole Moieties. , 1992 .

[26]  A. Retico,et al.  Antifungal agents. 1. Synthesis and antifungal activities of estrogen-like imidazole and triazole derivatives , 1992 .

[27]  P. Troke,et al.  Activity of UK-49,858, a bis-triazole derivative, against experimental infections with Candida albicans and Trichophyton mentagrophytes , 1985, Antimicrobial Agents and Chemotherapy.

[28]  R. Bannatyne,et al.  Susceptibility of Candida albicans to Miconazole , 1978, Antimicrobial Agents and Chemotherapy.

[29]  M. Artico,et al.  Antifungal estrogen-like imidazoles. Synthesis and antifungal activities of thienyl and 1H-pyrrolyl derivatives of 1-aryl-2-(1H-imidazol-1-yl)ethane , 1997 .

[30]  J Deisenhofer,et al.  Structure and function of cytochromes P450: a comparative analysis of three crystal structures. , 1995, Structure.

[31]  A. Retico,et al.  Antifungal agents. 5. Chloro and amino derivatives of 1,2-diaryl-1-(1H-imidazol-1-yl)ethane with potent antifungal activities , 1993 .

[32]  M. Richardson.  Opportunistic and pathogenic fungi. , 1991, The Journal of antimicrobial chemotherapy.

[33]  Y. Koltin.  Chapter 15. Targets for Antifungal Drug Discovery , 1990 .

[34]  M. Plempel,et al.  Antimycotic efficacy of bifonazole in vitro and in vivo. , 1983, Arzneimittel-Forschung.