title: Design and synthesis of novel benzoheterocyclic derivatives as human acrosin inhibitors by scaffold hopping.
abstract: Human acrosin is an attracting target for the development of novel male contraceptives. Scaffold hopping was used to optimize the isoxazolecarbaldehyde human acrosin inhibitors and extend their structure-activity relationships. Four kinds of scaffolds, namely benzimidazole, benzothiazole, 3H-indazole, and 5-phenyl-1H-pyrazole, were designed and synthesized. Most of the synthesized compounds showed potent human acrosin inhibitory activity and their binding modes were investigated by molecular docking. The scaffold of the compounds was found to be important for the inhibitory activity. Several compounds were more active than the positive control TLCK, suggesting that they can serve as good starting points for the discovery of novel male contraceptive agents.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Tian
authors.forename: Guangqian
authors.initials: G
authors.lastname: Han
authors.forename: Jingjing
authors.initials: J
authors.lastname: Qi
authors.forename: Canhui
authors.initials: C
authors.lastname: Zheng
authors.forename: Youjun
authors.initials: Y
authors.lastname: Zhou
authors.forename: Lili
authors.initials: L
authors.lastname: Ding
authors.forename: Juntao
authors.initials: J
authors.lastname: Zhao
authors.forename: Ju
authors.initials: J
authors.lastname: Zhu
authors.forename: Jiaguo
authors.initials: J
authors.lastname: Lv
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
mesh_terms: D000176:Acrosin / Q000037:antagonists & inhibitors*; D001562:Benzimidazoles / Q000737:chemistry; D001665:Binding Sites; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D015394:Molecular Structure
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; C031000:benzimidazole; D000176:Acrosin