Design and synthesis of novel 2-pyrazoline-1-ethanone derivatives as selective MAO inhibitors. Issue 3 (1st February 2015)

• Record Type: Journal Article
• Authors: Tong, Xu; Chen, Rui; Zhang, Tong-Tian; Han, Yan; Tang, Wen-Jian; Liu, Xin-Hua
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 3(2015)
• Page Start: 515
• Page End: 525
• Publication Date: 2015-02-01
• Subjects: Monoamine oxidase -- Pyrazoline -- MAOIs -- Molecular docking; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2014.12.010
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Novel 2-pyrazoline-1-ethanone derivatives as potential MAO selectivity inhibitors were designed and synthesized. Enzymatic assays revealed that compound12c exhibited strong selectivity inhibitory activity toward hMAO-A. Abstract: Thirty seven novel 2-pyrazoline-1-ethanone derivatives were designed, synthesized and evaluated as selective hMAO inhibitors. Among them, compounds7h (IC50 = 2.40 μM) and12c ( 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 compounds7h and12c 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.