In silico design, chemistry and biological activity of thiazole-based azetidinone Schiff bases as potential anti-Alzheimer agents

Abstract

Neurodegenerative disorders remain a critical challenge due to their complex pathology and limited therapeutic options. In this context, we report the computer-aided design, synthesis and comprehensive evaluation of novel heterocycles, rationally developed based on the pharmacophoric features of the clinically used acetylcholinesterase inhibitor Donepezil for Alzheimer’s disease (AD). These compounds were meticulously characterised using advanced spectroscopic techniques such as FTIR, HRMS, ¹³C NMR and ¹H NMR. Molecular docking studies were conducted against acetylcholinesterase (AChE), human peroxiredoxin and tyrosinase enzymes, revealing favourable binding interactions and predicted affinities. The synthesized compound 6c showed docking score − 8.82 kcal/mol and formed significant interactions with key active-site residues with AChE. In vitro, Ellman's assay confirmed potent enzyme inhibition of compound 6c IC₅₀ (5.54 ± 1.12 µM), highlighting its therapeutic promise. The MTT assay was conducted to assess the cell viability of the synthesised compounds, and cellular studies in SH-SY5Y neuroblastoma cells demonstrated AChE inhibition (55.12%), indicating potential neuroprotective effects. In vivo cognitive assessments in wistar rats using Y-Maze and Novel object recognition paradigms exhibited improvements in memory and learning, further supported by biochemical analyses showing enhanced activities of AChE, catalase, and superoxide dismutase (SOD). Histopathological examination of brain tissues corroborated the neuroprotective efficacy of these thiazole-based azetidinone Schiff bases. Collectively, this multidisciplinary approach establishes the thiazole azetidinone Schiff base derivative 6c as a prospective applicant for the advancement of novel therapeutics targeting AD.