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

Sherine N Khattab; Shimaa A H Abdel Moneim; Adnan A Bekhit; Abdel Moneim El Massry; Seham Y Hassan; Ayman El-Faham; Hany Emary Ali Ahmed; Adel Amer

doi:10.1016/j.ejmech.2015.02.020

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

Eur J Med Chem. 2015 Mar 26:93:308-20. doi: 10.1016/j.ejmech.2015.02.020. Epub 2015 Feb 16.

Authors

Sherine N Khattab¹, Shimaa A H Abdel Moneim¹, Adnan A Bekhit², Abdel Moneim El Massry³, Seham Y Hassan¹, Ayman El-Faham⁴, Hany Emary Ali Ahmed⁵, Adel Amer⁶

Affiliations

¹ Department of Chemistry, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
³ Department of Chemistry, Faculty of Science, Alexandria University, Alexandria 21321, Egypt; Department of Chemistry, Rabigh College of Science and Art, King Abdulaziz University, Saudi Arabia.
⁴ Department of Chemistry, Faculty of Science, Alexandria University, Alexandria 21321, Egypt; Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, 11451 Riyadh, Saudi Arabia.
⁵ Pharmacognosy and Pharmaceutical Chemistry Department, Pharmacy College, Taibah University, Al-Madinha Al-Munawaraha, Saudi Arabia; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
⁶ Department of Chemistry, Faculty of Science, Alexandria University, Alexandria 21321, Egypt; Department of Chemistry, College of Science, Taibah University, Al-Madinha Al-Munawaraha, Saudi Arabia. Electronic address: adel.amer@alex-sci.edu.eg.

PMID: 25707011
DOI: 10.1016/j.ejmech.2015.02.020

Abstract

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.

Keywords: Amino acids; Monoamine oxidase; N-Aroylhydrazine; N′-Acetylaroylhydrazine; Quinoxalin-2(1H)-one; Schiff's base.

MeSH terms

Animals
Catalytic Domain
Cattle
Chemistry Techniques, Synthetic
Drug Design*
Humans
Male
Mice
Molecular Docking Simulation*
Monoamine Oxidase / chemistry
Monoamine Oxidase / metabolism*
Monoamine Oxidase Inhibitors / chemical synthesis*
Monoamine Oxidase Inhibitors / metabolism
Monoamine Oxidase Inhibitors / pharmacology*
Monoamine Oxidase Inhibitors / toxicity
Quinoxalines / chemical synthesis*
Quinoxalines / metabolism
Quinoxalines / pharmacology*
Quinoxalines / toxicity
Stereoisomerism
Structure-Activity Relationship

Substances

Monoamine Oxidase Inhibitors
Quinoxalines
Monoamine Oxidase