Synthesis and Biological Evaluation of 2-Azolylmethylene-3-(2H)-benzofuranone Derivatives as Potent Monoamine Oxidases Inhibitors

IF 1.5 4区医学 Q4 CHEMISTRY, MEDICINAL

Chemical & pharmaceutical bulletin Pub Date : 2024-01-23 DOI:10.1248/cpb.c23-00763

Koichi Takao, Yuka Kubota, Kota Kurosaki, Hitoshi Kamauchi, Yoshihiro Uesawa, Yoshiaki Sugita

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Abstract

A series of 2-azolylmethylene-3-(2H)-benzofuranone derivatives, 2-indolylmethylene-3-(2H)-benzofuranone and 2-pyrrolylmethylene-3-(2H)-benzofuranone derivatives, were synthesized, and their monoamine oxidase (MAO) A and B inhibitory activities were evaluated. Compounds 1b, 3b, 6b, 7b, and 10b showed strong inhibitory activity against MAO-A, and compound 3b showed the highest potency and selectivity, with an IC₅₀ value of 21 nM and a MAO-A selectivity index of 48. Compounds 3c, 4c, 9a, 9c, 10c, 11a, and 11c showed strong inhibitory activity against MAO-B, and compound 4c showed the highest potency and selectivity, with an IC₅₀ value of 16 nM and a MAO-B selectivity index of >1100. Further analysis of these compounds indicated that compound 3b for MAO-A and compound 4c for MAO-B were competitive inhibitors, with K_i values of 10 and 6.1 nM, respectively. Furthermore, computational analyses, such as quantitative structure–activity relationship (QSAR) analysis of the 2-azolylmethylene-3-(2H)-benzofuranone derivatives conducting their pIC₅₀ values with the Molecular Operating Environment (MOE) and Mordred, and molecular docking analysis using MOE-Dock supported that the 2-azolylmethylene-3-(2H)-benzofuranone derivatives are a privileged scaffold for the design and development of novel MAO inhibitors.

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作为强效单胺氧化酶抑制剂的 2-Azolylmethylene-3-(2H)-benzofuranone 衍生物的合成与生物学评价

合成了一系列 2-偶氮亚甲基-3-(2H)-苯并呋喃酮衍生物、2-吲哚亚甲基-3-(2H)-苯并呋喃酮和 2-吡咯亚甲基-3-(2H)-苯并呋喃酮衍生物，并评估了它们对单胺氧化酶（MAO）A 和 B 的抑制活性。化合物 1b、3b、6b、7b 和 10b 对 MAO-A 具有很强的抑制活性，其中化合物 3b 的效力和选择性最高，IC50 值为 21 nM，MAO-A 选择性指数为 48。化合物 3c、4c、9a、9c、10c、11a 和 11c 对 MAO-B 具有很强的抑制活性，其中化合物 4c 的有效性和选择性最高，IC50 值为 16 nM，MAO-B 选择性指数为 1100。对这些化合物的进一步分析表明，化合物 3b 对 MAO-A 和化合物 4c 对 MAO-B 是竞争性抑制剂，Ki 值分别为 10 和 6.1 nM。此外，利用分子操作环境（MOE）和 Mordred 对 2-azolylmethylene-3-(2H)-benzofuranone 衍生物的 pIC50 值进行定量结构-活性关系（QSAR）分析，以及利用 MOE-Dock 进行分子对接分析等计算分析表明，2-azolylmethylene-3-(2H)-benzofuranone 衍生物是设计和开发新型 MAO 抑制剂的理想支架。

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来源期刊

Chemical & pharmaceutical bulletin 医学-化学综合

CiteScore

3.20

自引率

5.90%

发文量

132

审稿时长

1.7 months

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