Benzimidazole-derived carbohydrazones as dual monoamine oxidases and acetylcholinesterase inhibitors: design, synthesis, and evaluation
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Date
2024
Authors
Journal Title
Journal of Biomolecular Structure and Dynamics
Journal ISSN
Volume Title
Publisher
Taylor and Francis Ltd.
Abstract
A series of novel benzimidazole-derived carbohydrazones was designed, synthesized and evaluated for their dual inhibition potential against monoamine oxidases (MAOs) and acetylcholinesterase (AChE) using multitarget-directed ligand approach (MTDL). The investigated compounds have exhibited moderate to excellent in�vitro MAOs/AChE inhibitory activity at micromolar to nanomolar concentrations. Compound 12, 2-(1H-Benzo[d]imidazol-1-yl)-N'-[1-(4-hydroxyphenyl) ethylidene]acetohydrazide has emerged as a lead dual MAO-AChE inhibitor by exhibiting superior multi-target activity profile against MAO-A (IC50 = 0.067 � 0.018 �M), MAO-B (IC50 = 0.029 � 0.005 �M) and AChE (IC50 = 1.37 � 0.026 �M). SAR studies suggest that the site A (hydrophobic ring) and site C (semicarbazone linker) modifications attempted on the semicarbazone-based MTDL resulted in a significant enhancement in the MAO-A/B inhibitory potential and a drastic decrease in the AChE inhibitory activity. Further, molecular docking and dynamics simulation experiments disclosed the possible molecular interactions of inhibitors inside the active site of respective enzymes. Also, computational prediction of drug-likeness and ADME parameters of test compounds revealed their drug-like characteristics. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.
Description
Keywords
acetylcholinesterase, Benzimidazole, carbohydrazones, dual inhibitors, molecular dynamics, monoamine oxidase