Design, synthesis and evaluation of benzoheterocycle analogues as potent antifungal agents targeting CYP51

Publication date: 23 July 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 12
Author(s): Shizhen Zhao, Peng Wei, Mengya Wu, Xiangqian Zhang, Liyu Zhao, Xiaolin Jiang, Chenzhou Hao, Xin Su, Dongmei Zhao, Maosheng Cheng
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.

Graphical abstract

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