Synthesis, antifungal activities and molecular docking studies of novel 2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl dithiocarbamates.
A series of 2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl dithiocarbamates as new analogs of fluconazole were synthesized and their antifungal activities were evaluated. Among these compounds, 2a-f and 3a-q exhibited higher activities than fluconazole against nearly all fungi tested except Aspergillus fumigatus. Noticeably, the in vitro biological activities of 2b, 3a, 3c, 3h-k, and 3o-q against Candida species were much better than those of fluconazole and ketoconazole. Also, 2a-d, 3a-d, 3e-f, 3h-k, 3p and 3q showed higher activities against A. fumi than fluconazole. Computational docking experiments indicated that the inhibition of CYP51 involved a coordination bond with iron of the heme group, the hydrophilic H-bonding region, the hydrophobic region, and the narrow hydrophobic cleft.
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China.
Yan
Y
Zou
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China.
Shichong
S
Yu
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China.
Renwu
R
Li
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China.
Qingjie
Q
Zhao
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China.
Xiang
X
Li
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China.
Maocheng
M
Wu
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China.
Ting
T
Huang
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China.
Xiaoxun
X
Chai
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China. Electronic address: huhonggang_fox@msn.com.
Honggang
H
Hu
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China. Electronic address: wuqy6439@sohu.com.
Qiuye
Q
Wu
D001232:Aspergillus fumigatus / Q000187:drug effects; D002175:Candida / Q000187:drug effects; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation
D002219:Carbamates
Antifungal activity; CYP51; Dithiocarbamate; SAR; Triazole