Design, synthesis and biological evaluation of novel human monoamine oxidase B inhibitors based on a fragment in an X-ray crystal structure.


School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China. Electronic address: [Email]


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.


Fragment-based drug design,Isatin,Isoform selectivity,Structure activity relationship,hMAO-B,

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