Designing, Synthesis and Characterisation of Novel Benzimidazole derivatives as Multi- Targeted anti-Alzheimer’s agent integrated with computational screening

According to the cholinergic hypothesis, along with senile plaques, neurofibrillary tangles, and widespread neuronal loss, cholinergic abnormalities are the main features of Alzheimer's disease (AD). Multi-target-directed ligands (MTDLs) targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and also amyloid-β receptors represent a promising therapeutic strategy for AD. Benzimidazole derivatives are known for their diverse biological activities, including anti-Alzheimer's properties. New benzimidazole derivatives with substituted aryl/alkyl amides and benzyl groups at the N-1 position were strategically designed based on the literature study. In total, a library of 52 molecules was generated, which was screened based on their ADMET profile and binding affinity for AChE, BChE, and amyloid-β proteins. To bridge theoretical design with experimental application, a highly sustainable synthetic protocol was performed for the highest-scoring derivatives. During synthesis, TLC analysis confirmed the successful completion of reactions. The characterisation was done based on their physicochemical properties i.e. melting points, and solubility etc. and also from their IR, 1H-NMR and 13C-NMR spectral studies. The results suggest that some benzimidazole-containing analogues have strong potential as anti-Alzheimer’s agents, warranting further experimental validation through in vitro and in vivo studies. In conclusion, the study provides a rigorous, pre-validated computational blueprint and a ready-to-use synthetic protocol to accelerate the development of novel therapeutics for Alzheimer's disease.