Synthesis of novel triazole derivatives as inhibitors of cytochrome P450 14alpha-demethylase (CYP51).
A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substitutedphenyl)-piperazin-1-yl]-propan-2-ols have been designed and synthesized on the basis of the structure-activity relationships and antimycotic mechanism of azole antifungal agents. Their structures were confirmed by elemental analysis, IR, MS and (1)H NMR. Results of preliminary antifungal tests against eight human pathogenic fungi (Candida albicans, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton rubrum, Fonsecaea compacta, and Microsporum gypseum) in vitro showed that all title compounds exhibited activity against fungi tested to some extent. Among the compounds tested, all compounds showed higher activity against C. albicans than fluconazole in vitro. Compounds 3, 6-8, 28, 29, and 32 exhibited the same activities against C. albicans as voriconazole (with the MIC value of 0.0152microg/mL). Compounds 3, 6, and 7 showed higher activity against C. parapsilosis than all five positive controls.
Sun
Qing-Yan
QY
Department of Organic Chemistry, College of Pharmacy, Second Military Medical University, Guohe Road 325, Shanghai 200433, People's Republic of China. sqy_2000@163.com
Xu
Jian-Ming
JM
Cao
Yong-Bing
YB
Zhang
Wan-Nian
WN
Wu
Qiu-Ye
QY
Zhang
Da-Zhi
DZ
Zhang
Jun
J
Zhao
Hui-Qing
HQ
Jiang
Yuan-Ying
YY
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000138:chemical synthesis* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D014230:Triazoles; D003577:Cytochrome P-450 Enzyme System