title: New azoles with potent antifungal activity: design, synthesis and molecular docking.
abstract: 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.
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Che
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.forename: Wenya
authors.initials: W
authors.lastname: Wang
authors.forename: Yongbing
authors.initials: Y
authors.lastname: Cao
authors.forename: Yulan
authors.initials: Y
authors.lastname: Xu
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Dong
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
mesh_terms: 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
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; C465525:cytochrome P-450 CYP51, Candida albicans; D003577:Cytochrome P-450 Enzyme System