title: Design, synthesis, and antifungal activities of novel 1H-triazole derivatives based on the structure of the active site of fungal lanosterol 14 alpha-demethylase (CYP51).
abstract: A series of fluconazole (1) analogues, compounds 3a-k, were prepared as potential antifungal agents. They were designed by computational docking experiments to the active site of the cytochrome P450 14alpha-sterol demethylase (CYP51), whose crystal structure is known. Preliminary biological tests showed that most of the target compounds exhibit significant activities against the eight most-common pathogenic fungi. Thereby, the most potent congener, 1-[(4-tert-butylbenzyl)(cyclopropyl)amino]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (3j), was found to exhibit a broad antifungal spectrum, being more active against Candida albicans, Candida tropicalis, Cryptococcus neoformans, Microsporum canis, and Trichophyton rubrum (MIC80 < 0.125 microg/ml) than the standard clinical drug itraconazole (2). The observed affinities of the lead molecules towards CYP51 indicate that a cyclopropyl residue enhances binding to the target enzyme. Our results may provide some guidance for the development of novel triazole-based antifungal lead structures.
authors.affiliation: Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Qing-Jie
authors.initials: QJ
authors.lastname: Zhao
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Hu
authors.forename: Yao-Wu
authors.initials: YW
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Song
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Cai
authors.forename: Qiu-Ye
authors.initials: QY
authors.lastname: Wu
authors.forename: Yuan-Ying
authors.initials: YY
authors.lastname: Jiang
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003577:Cytochrome P-450 Enzyme System / Q000138:chemical synthesis* / Q000378:metabolism; D015195:Drug Design; D006859:Hydrogen; D008826:Microbial Sensitivity Tests / Q000379:methods; D010088:Oxidoreductases / Q000138:chemical synthesis* / Q000378:metabolism; D058886:Sterol 14-Demethylase; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; D006859:Hydrogen; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase