Benzimidazole-derived carbohydrazones as dual monoamine oxidases and acetylcholinesterase inhibitors: design, synthesis, and evaluation

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 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

Keywords:

• Benzimidazole
• carbohydrazones
• dual inhibitors
• monoamine oxidase
• acetylcholinesterase
• molecular dynamics

Acknowledgements

SK is grateful to the Indian Institute of Technology (Banaras Hindu University), Varanasi, for providing Teaching Assistantship. The authors thankfully acknowledge SAIF/CIL, Central Drug Research Institute (CDRI), Lucknow, for providing mass spectra, and Dr. Sairam Krishnamurthy, Pharmaceutical Engineering and Technology, IIT (BHU), Varanasi, for his support in the pharmacological screening. The support and the resources provided by ‘PARAM Shivay Facility’ under the National Supercomputing Mission, Government of India, at the Indian Institute of Technology, Varanasi, are gratefully acknowledged.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.