title: Discovery of highly potent novel antifungal azoles by structure-based rational design.
abstract: On the basis of the active site of lanosterol 14alpha-demethylase from Candida albicans (CACYP51), a series of new azoles were designed and synthesized. All the new azoles show excellent in vitro activity against most of the tested pathogenic fungi, which represent a class of promising leads for the development of novel antifungal agents. The MIC(80) value of compounds 8c, 8i and 8n against C. albicans is 0.001 microg/mL, indicating that these compounds are more potent than fluconazole, itraconazole and voriconazole. Flexible molecular docking was used to analyze the structure-activity relationships (SARs) of the compounds. The designed compounds interact with CACYP51 through hydrophobic, van der Waals and hydrogen-bonding interactions.
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Wenya
authors.initials: W
authors.lastname: Wang
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Che
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
authors.forename: Yongbing
authors.initials: Y
authors.lastname: Cao
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; D001665:Binding Sites; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D017964:Itraconazole / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D011743:Pyrimidines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000494:pharmacology; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; D011743:Pyrimidines; D014230:Triazoles; C465525:cytochrome P-450 CYP51, Candida albicans; D017964:Itraconazole; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D065819:Voriconazole