title: Discovery of biphenyl imidazole derivatives as potent antifungal agents: Design, synthesis, and structure-activity relationship studies.
abstract: 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 0.03125-2μg/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.
authors.affiliation: 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.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Shizhen
authors.initials: S
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Liyu
authors.initials: L
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Peng
authors.initials: P
authors.lastname: Wei
authors.affiliation: 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.
authors.forename: Chunchi
authors.initials: C
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Chenzhou
authors.initials: C
authors.lastname: Hao
authors.affiliation: Institute of BioPharmaccutical Research, Liaocheng University, 1 Hunan Road, Liaocheng 252000, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Sun
authors.affiliation: The School of Life Science and Biopharmaceutical, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: suxin1966@163.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Su
authors.affiliation: 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.
authors.forename: Maosheng
authors.initials: M
authors.lastname: Cheng
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects*; D003455:Cryptococcus neoformans / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; C029899:imidazole
keywords: Antifungal activity; Azole antifungals; CYP51; Structure-activity relationship