Discovery of biphenyl imidazole derivatives as potent antifungal agents: Design, synthesis, and structure-activity relationship studies

被引：47

作者：

Zhao, Dongmei ^{[1
]}

Zhao, Shizhen ^{[1
]}

Zhao, Liyu ^{[1
]}

Zhang, Xiangqian ^{[1
]}

Wei, Peng ^{[1
]}

Liu, Chunchi ^{[1
]}

Hao, Chenzhou ^{[1
]}

Sun, Bin ^{[3
]}

Su, Xin ^{[2
]}

Cheng, Maosheng ^{[1
]}

机构：

[1] Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Minist Educ, Key Lab Struct Based Drug Design & Discovery, 103 Wenhua Rd, Shenyang 110016, Peoples R China

[2] Shenyang Pharmaceut Univ, Sch Life Sci & Biopharmaceut, 103 Wenhua Rd, Shenyang 110016, Peoples R China

[3] Liaocheng Univ, Inst BioPharmaccut Res, 1 Hunan Rd, Liaocheng 252000, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2017年 / 25卷 / 02期

关键词：

Antifungal activity; CYP51; Structure-activity relationship; Azole antifungals; CANDIDA-ALBICANS; BIOLOGICAL EVALUATION; AZOLE ANTIFUNGALS; FUNGAL-INFECTIONS; MECHANISMS; MICROSOMES; RESISTANCE; INHIBITORS; DRUGS;

D O I：

10.1016/j.bmc.2016.11.051

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Fungal infections have became a serious medical problem due to their high incidence and mortality. We describe the discovery and structure-activity relationships studies (SARs) of a series of novel biphenyl imidazole derivatives with excellent antifungal activities against Candida albicans and Cryptococcus neoformans. The most promising compounds 12f-g and 19a-b exhibited excellent activity with minimum inhibitory concentration (MIC) values in the range of 0.03125-2 mu g/mL. Preliminary mechanism studies showed that the potent antifungal activity of compound 12g stemed from inhibition of CYP51 in Candida albicans. Furthermore, compounds 12g and 19b exhibited low inhibition profiles for various human cytochrome P450 isoforms. The SARs and binding mode established in this study will be useful for further lead optimization. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：750 / 758

页数：9

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