Discovery of highly potent novel antifungal azoles by structure-based rational design |
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Authors: | Wenya Wang Chunquan Sheng Xiaoying Che Haitao Ji Yongbing Cao Zhenyuan Miao Jianzhong Yao Wannian Zhang |
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Institution: | 1. School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People’s Republic of China;2. Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, USA;3. Department of Biochemistry, Molecular Biology, and Cell Biology, and Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, IL 60208-3113, USA |
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Abstract: | On the basis of the active site of lanosterol 14α-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 MIC80 value of compounds 8c, 8i and 8n against C. albicans is 0.001 μg/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. |
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