Synthesis, molecular docking, and biological evaluation of novel triazole derivatives as antifungal agents.
Twenty-eight novel triazole derivatives (compounds 1a-v, 2a-f) have been synthesized for structure-activity relationship studies as antifungal agents. The compounds were designed on the basis of the structure of fluconazole and molecular modeling of the active site of the cytochrome P450 14α-demethylase (CYP51). All of them are reported for the first time. Their chemical structures are characterized by (1) H NMR, (13) C NMR, LC-MS, and elemental analysis. The antifungal activities have been evaluated in vitro by measuring the minimal inhibitory concentrations (MICs). Compounds 1a-v exhibited higher activity against nearly all fungi tested except Aspergillus fumigatus (A. fum) than fluconazole (FCZ). The computational molecular docking experiments indicated that the inhibition of CYP51 involves a coordination bond with iron of the heme group, a hydrophilic H-bonding region, a hydrophobic region, and a narrow hydrophobic binding cleft.
Department of Organic Chemistry, College of Pharmacy, Second Military Medical University, Guohe Road 325, Shanghai, China.
Zhongjun
Z
Guan
Xiaoyun
X
Chai
Shichong
S
Yu
Honggang
H
Hu
Yuanying
Y
Jiang
Qingguo
Q
Meng
Qiuye
Q
Wu
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003198:Computer Simulation; D015195:Drug Design; D015725:Fluconazole / Q000737:chemistry / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D000935:Antifungal Agents; D014230:Triazoles; D015725:Fluconazole