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

Shizhen Zhao; Peng Wei; Mengya Wu; Xiangqian Zhang; Liyu Zhao; Xiaolin Jiang; Chenzhou Hao; Xin Su; Dongmei Zhao; Maosheng Cheng

doi:10.1016/j.bmc.2018.04.054

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

Bioorg Med Chem. 2018 Jul 23;26(12):3242-3253. doi: 10.1016/j.bmc.2018.04.054. Epub 2018 Apr 27.

Authors

Affiliations

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.
³ 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. Electronic address: medchemzhao@163.com.

PMID: 29748145
DOI: 10.1016/j.bmc.2018.04.054

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.

Keywords: Antifungal activity; Azole antifungals; CYP51; Structure-activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antifungal Agents / chemical synthesis*
Antifungal Agents / chemistry
Antifungal Agents / pharmacology
Aspergillus fumigatus / drug effects
Aspergillus fumigatus / metabolism
Binding Sites
Candida albicans / drug effects
Candida albicans / metabolism
Catalytic Domain
Cryptococcus neoformans / drug effects
Cryptococcus neoformans / metabolism
Drug Design*
Drug Resistance, Fungal / drug effects
Drug Stability
Fluconazole / pharmacology
Fungal Proteins / antagonists & inhibitors
Fungal Proteins / metabolism*
Gas Chromatography-Mass Spectrometry
Humans
Microbial Sensitivity Tests
Molecular Docking Simulation
Protein Isoforms / antagonists & inhibitors
Protein Isoforms / metabolism
Sterol 14-Demethylase / chemistry
Sterol 14-Demethylase / metabolism*
Sterols / analysis
Structure-Activity Relationship
Triazoles / chemical synthesis
Triazoles / chemistry*
Triazoles / pharmacology

Substances

Antifungal Agents
Fungal Proteins
Protein Isoforms
Sterols
Triazoles
Fluconazole
Sterol 14-Demethylase