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Bioorg Chem. 2018 Feb;76:130-139. doi: 10.1016/j.bioorg.2017.11.009. Epub 2017 Nov 15.

Design, synthesis and evaluation of resveratrol-indazole hybrids as novel monoamine oxidases inhibitors with amyloid-β aggregation inhibition.

Author information

1
Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
2
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
3
National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China. Electronic address: xiesaisainanchang@hotmail.com.
4
Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: dingyue-2001@hotmail.com.

Abstract

Novel hybrids with MAO and Aβ (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 Aβ (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 μM) but also for Aβ (1-42) self-aggregation (58.9% at 20 μM). 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 Aβ (1-42) via π-π and cation-π 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.

KEYWORDS:

Alzheimer’s disease; Aβ (1–42) aggregation; Molecular docking; Monoamine oxidase

PMID:
29172101
DOI:
10.1016/j.bioorg.2017.11.009
[Indexed for MEDLINE]

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