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

• Published in: European journal of medicinal chemistry 2015-03, Vol.93, p.308-320
• Main Authors: Khattab, Sherine N., Abdel Moneim, Shimaa A.H., Bekhit, Adnan A., El Massry, Abdel Moneim, Hassan, Seham Y., El-Faham, Ayman, Ali Ahmed, Hany Emary, Amer, Adel
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Catalytic Domain; Cattle; Chemistry Techniques, Synthetic; Drug Design; Humans; Male; Mice; Molecular Docking Simulation; Monoamine oxidase; Monoamine Oxidase - chemistry; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - chemical synthesis; Monoamine Oxidase Inhibitors - metabolism; Monoamine Oxidase Inhibitors - pharmacology; Monoamine Oxidase Inhibitors - toxicity; N-Aroylhydrazine; N′-Acetylaroylhydrazine; Quinoxalin-2(1H)-one; Quinoxalines - chemical synthesis; Quinoxalines - metabolism; Quinoxalines - pharmacology; Quinoxalines - toxicity; Schiff's base; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.02.020

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. Series 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. [Display omitted] •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.