New azoles with potent antifungal activity: design, synthesis and molecular docking.
In response to the urgent need for novel antifungal agents with improved activity and broader spectrum, computer modeling was used to rational design novel antifungal azoles. On the basis of the active site of lanosterol 14alpha-demethylase from Candida albicans (CACYP51), a series of new azoles with substituted-phenoxypropyl piperazine side chains were rational designed and synthesized. In vitro antifungal activity assay indicates that the new azoles show good activity against most of the tested pathogenic fungi. Interestingly, the designed compounds are also active against an azole-resistant clinical strain. Compared to fluconazole and itraconazole, several compounds (such as 12i, 12j and 12n) show higher antifungal activity and broader spectrum, which are promising leads for the development of novel antifungal agents.
Che
Xiaoying
X
School of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China.
Sheng
Chunquan
C
Wang
Wenya
W
Cao
Yongbing
Y
Xu
Yulan
Y
Ji
Haitao
H
Dong
Guoqiang
G
Miao
Zhenyuan
Z
Yao
Jianzhong
J
Zhang
Wannian
W
D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology*; D020134:Catalytic Domain; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D005656:Fungal Proteins / Q000737:chemistry / Q000378:metabolism*; D005658:Fungi / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; C465525:cytochrome P-450 CYP51, Candida albicans; D003577:Cytochrome P-450 Enzyme System