1. Benzimidazole-derived carbohydrazones as dual monoamine oxidases and acetylcholinesterase inhibitors: design, synthesis, and evaluation.
- Author
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Kumar S, Jaiswal S, Gupta SK, and Ayyannan SR
- Subjects
- Structure-Activity Relationship, Humans, Molecular Dynamics Simulation, Molecular Structure, Binding Sites, Monoamine Oxidase Inhibitors chemistry, Monoamine Oxidase Inhibitors pharmacology, Monoamine Oxidase Inhibitors chemical synthesis, Cholinesterase Inhibitors chemistry, Cholinesterase Inhibitors pharmacology, Cholinesterase Inhibitors chemical synthesis, Benzimidazoles chemistry, Benzimidazoles pharmacology, Benzimidazoles chemical synthesis, Molecular Docking Simulation, Acetylcholinesterase chemistry, Acetylcholinesterase metabolism, Monoamine Oxidase metabolism, Monoamine Oxidase chemistry, Drug Design, Hydrazones chemistry, Hydrazones pharmacology, Hydrazones chemical synthesis
- 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-(1 H -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 (IC
50 = 0.067 ± 0.018 µM), MAO-B (IC50 = 0.029 ± 0.005 µM) and AChE (IC50 = 1.37 ± 0.026 µM). 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.- Published
- 2024
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