title: Design, synthesis, and biological evaluation of novel triazole derivatives as inhibitors of cytochrome P450 14alpha-demethylase.
abstract: Based on the results of computational docking to the active site of the cytochrome P450 14alpha-demethylase (CYP51), a series of 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols as analogs of fluconazole were designed, synthesized, and evaluated as antifungal agents. The MIC(80) values indicate that compounds 1a-n exhibited higher activity against nearly all fungi tested except Aspergillus fumigatus than fluconazole, while compounds 2a-f, 3a-f showed no activity or only moderate activity against all fungi tested. Noticeably, the MIC value of compounds 1a, 1b and 1g is 64 times lower than that of fluconazole against Microsporum gypseum in vitro. And compounds 1a, 1b and 2b showed 128 times higher activity (with the MIC(80) value of 0.0039 microg/mL) than that of fluconazole against Candida albicans and also showed higher activity than that of the other positive controls. Computational docking experiments indicated that the inhibition of CYP51 involves a coordination bond with iron of the heme group, the hydrophilic H-bonding region, the hydrophobic region, and the narrow hydrophobic cleft. In addition, the activity of the compounds would be enhanced when the side chains were shorter.
authors.affiliation: Department of Organic Chemistry, College of Pharmacy, Second Military Medical University, Guohe Road 325, Shanghai 200433, People's Republic of China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Chai
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Honggang
authors.initials: H
authors.lastname: Hu
authors.forename: Shichong
authors.initials: S
authors.lastname: Yu
authors.forename: Qingyan
authors.initials: Q
authors.lastname: Sun
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Dan
authors.forename: Yuanying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Qiuye
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D058886:Sterol 14-Demethylase; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D014230:Triazoles; D058886:Sterol 14-Demethylase