Exploring new selective 3-benzylquinoxaline-based MAO-A inhibitors: Design, synthesis, biological evaluation and docking studies

•A series of quinoxalinyl hydrazones and hydrazides were synthesized.•The compounds were evaluated in vitro as inhibitors of the two monoamine oxidase isoforms, MAO-A and MAO-B.•Most of the compounds showed a potent and selective MAO-A inhibitory activity where 4e and 9g were the most potent derivatives.•Molecular modeling studies were performed to rationalize the recognition of all inhibitors with respect to hMAO-A.

In this investigation, we searched for novel MAO-A inhibitors using a 3-benzylquinoxaline scaffold based on our earlier findings. Series of N′-(3-benzylquinoxalin-2-yl)acetohydrazide, 4a, N′-(3-benzylquinoxalin-2-yl)benzohydrazide derivatives 4b–f, N′-[2-(3-benzyl-2-oxoquinoxalin-1(2H)-yl)acetyl]benzohydrazide derivatives 7a–d, (9H-fluoren-9-yl)methyl 1-[2-(2-(3-benzyl-2-oxoquinoxalin-1(2H)-yl)acetyl)-hydrazinyl]-2-ylcarbamate derivatives 8a–c, 2-(3-benzyl-2-oxoquinoxalin-1(2H)-yl)-N′-benzylidene acetohydrazide derivatives 9a–h, and ethyl 2-(3-benzyl-2-oxoquinoxalin-1(2H)-yl)acetate derivatives 10a–e were synthesized and evaluated in vitro as inhibitors of the two monoamine oxidase isoforms, MAO-A and MAO-B. Most of the compounds showed a selective MAO-A inhibitory activity in the nanomolar or low micromolar range. Compounds 4e and 9g were the most potent derivatives with high MAO-A selectivity and their molecular docking studies were performed in order to rationalize the obtained biological result.

Graphical abstractSeries of 3-benzylquinoxalinyl hydrazones and hydrazides were synthesized and were evaluated in vitro as inhibitors of the two monoamine oxidase isoforms, MAO-A and MAO-B. Most of the compounds showed a potent and selective MAO-A inhibitory activity especially 4e and 9g derivatives.Figure optionsDownload full-size imageDownload as PowerPoint slide