title: Design and synthesis of novel 2-pyrazoline-1-ethanone derivatives as selective MAO inhibitors.
abstract: Thirty seven novel 2-pyrazoline-1-ethanone derivatives were designed, synthesized and evaluated as selective hMAO inhibitors. Among them, compounds 7h (IC50=2.40 μM) and 12c (IC50=2.00 μM) exhibited best inhibitory activity and selectivity against hMAO-A, surpassing that of the positive control Clorgyline (IC50=2.76 μM). Based on selective activity of hMAO-A, SAR analysis showed that the order of N1 substituent contribution was bromo (3)>piperidinyl (4)>morpholinyl (5)>imidazolyl (6), and compounds with electron-withdrawing substituents (-F, -Cl) at C3 or C5 phenyl ring of 2-pyrazoline nucleus dedicated stronger MAO-A inhibitory activity. Molecular docking showed that compounds 7h and 12c were nicely bound to hMAO-A via two hydrogen bonds (SER209, GLU216), one Pi-Pi interaction and three hydrogen bonds (SER209, GLU216, TYR69), one Sigma-Pi interaction, respectively. In addition, the substituent at C3 position of 2-pyrazoline with the N1 acetyl has little effect on MAO-A inhibitory activity. These data support further studies to assess rational design of more efficiently selective hMAO inhibitors in the future.
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Xu
authors.initials: X
authors.lastname: Tong
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Tong-Tian
authors.initials: TT
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Han
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, PR China. Electronic address: ahmupharm@126.com.
authors.forename: Wen-Jian
authors.initials: WJ
authors.lastname: Tang
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: xhliuhx@163.com.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Liu
mesh_terms: D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008996:Monoamine Oxidase Inhibitors; D011720:Pyrazoles; D008995:Monoamine Oxidase
keywords: MAOIs; Molecular docking; Monoamine oxidase; Pyrazoline