Novel hybrids with MAO and A beta (1-42) self-aggregation inhibitory activities were designed and synthesized with the employment of indazole moiety and resveratrol. The biological screening results indicated that most compounds displayed potent inhibitory activity for A beta (1-42) self-aggregation, and obvious selective inhibition to MAO-B. Among these compounds, compound 6e was the most potent inhibitor not only for hMAO-B (IC50 = 1.14 mu M) but also for A beta (1-42) self-aggregation (58.9% at 20 mu M). Molecular modeling and kinetic studies revealed that compound 6e was a competitive MAO-B inhibitor, which can occupy the active site of MAO-B, and interact with A beta (1-42) via pi-pi and cation-pi stacking interactions. In addition, compound 6e had no toxicity on PC12 cells and could cross the BBB. Collectively, all these results suggested that compound 6e might be a promising multi-target lead compound worthy of further investigation. (C) 2017 Published by Elsevier Inc.
[1]Shanghai Univ Tradit Chinese Med, Expt Ctr Teaching & Learning, Shanghai 201203, Peoples R China.
[2]Shanghai Univ Tradit Chinese Med, Sch Pharm, Shanghai 201203, Peoples R China.
[3]Jiangxi Univ Tradit Chinese Med, Natl Pharmaceut Engn Ctr Solid Preparat Chinese H, Nanchang 330006, Jiangxi, Peoples R China.
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