title: Design, synthesis and structure-activity relationships of new triazole derivatives containing N-substituted phenoxypropylamino side chains.
abstract: The incidence of invasive fungal infections and resistance to antifungal agents is increasing dramatically. It is highly desirable to develop novel azoles with improved biological profiles. The structure-activity relationship (SAR) of the N-substitutions was investigated in this study. In vitro antifungal activities revealed that sterically large groups were not favored for the N-substitutions. The removal of the N-substitutions had little effect on the antifungal activity. Two compounds with free amine group (i.e.9a and 10a) showed excellent activity with broad antifungal spectrum. The SAR results were supported by molecular docking and the N-substitutions were found to be important for the conformation of the side chains. The SAR and binding mode of the azoles are useful for further lead optimization.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Shengzheng
authors.initials: S
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Jin
authors.forename: Wenya
authors.initials: W
authors.lastname: Wang
authors.forename: Lingjian
authors.initials: L
authors.lastname: Zhu
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Dong
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Chunlin
authors.initials: C
authors.lastname: Zhuang
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D005658:Fungi / Q000187:drug effects / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009584:Nitrogen / Q000737:chemistry*; D011437:Propylamines / Q000737:chemistry*; D011487:Protein Conformation; D058886:Sterol 14-Demethylase / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D011437:Propylamines; D014230:Triazoles; D058886:Sterol 14-Demethylase; D009584:Nitrogen