Design, synthesis and biological evaluation of novel human monoamine oxidase B inhibitors based on a fragment in an X-ray crystal structure. Issue 8 (15th April 2019)

• Record Type: Journal Article
• Authors: Cheng, Kai; Li, Shiyu; Lv, Xiao; Tian, Yongbin; Kong, Haiyan; Huang, Xufeng; Duan, Yajun; Han, Jihong; Xie, Zhouling; Liao, Chenzhong
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 8(2019)
• Page Start: 1012
• Page End: 1018
• Publication Date: 2019-04-15
• Subjects: hMAO-B -- Isatin -- Isoform selectivity -- Fragment-based drug design -- Structure activity relationship; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.02.008
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Novel reversible selective hMAO-B inhibitors were designed from a fragment, isatin. Five different scaffolds were designed and many compounds were synthesized. Compound A3 demonstrated very high potency and isoform selectivity against hMAO-B. Our results may challenge our understanding of molecular interactions. Abstract: Herein we report our efforts of developing reversible selective hMAO-B inhibitors based on isatin, a fragment in an X-ray crystal structure. Five different scaffolds were designed and many compounds were synthesized. Among them, compound A3 demonstrated very high potency and isoform selectivity against hMAO-B, 11 and 13 times more potent (IC50 = 3 nM) and 23.64 and 6.8 times more selective than the marked drugs, selegiline and safinamide. However, the endeavors to modify the polar 3-one group of isatin, that is in a hydrophobic environment in the binding site of hMAO-B, to small nonpolar hydrophobic groups did not bring about improved hMAO-B inhibitors, which may challenge our understanding of molecular interactions and molecular recognition in biological systems.