Design,synthesis and evaluation of benzoheterocycle analogues as potent antifungal agents targeting CYP51 |
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| Authors: | Shizhen Zhao Peng Wei Mengya Wu Xiangqian Zhang Liyu Zhao Xiaolin Jiang Chenzhou Hao Xin Su Dongmei Zhao Maosheng Cheng |
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| Institution: | 1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China;2. The School of Life Science and Biopharmaceutical, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China |
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| Abstract: | To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compound 1, a series of benzoheterocycle analogues were designed, synthesized and evaluated for their in vitro antifungal activity. The most promising compounds 13s and 14a exhibited excellent antifungal activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. albicans strains, that was superior or comparable to those of the reference drugs fluconazole and voriconazole. GC–MS analyses suggested that the novel compound 13s might have a similar mechanism to fluconazole by inhibiting fungal lanosterol 14α-demethylase (CYP51). Furthermore, compounds 13s and 14a exhibited low inhibition profiles for various human cytochrome P450 isoforms as well as excellent blood plasma stability. |
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| Keywords: | Antifungal activity Azole antifungals CYP51 Structure-activity relationship |
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