Novel Benzimidazole–Isatin Hybrids as Potential Therapeutics for Alzheimer’s Disease: Design, Microwave-Assisted Synthesis, and Structure–Activity Relationship

Abstract Objective: A novel series of benzimidazole–isatin hybrid compounds was designed and synthesized to evaluate their inhibitory activity against acetylcholinesterase (AChE) and establish comprehensive structure–activity relationships (SAR). Methods: Target hybrids and intermediate precursors were synthesized using both conventional heating and microwave-assisted protocols. Structural elucidation of all synthesized compounds was unequivocally performed using 1H, 13C NMR, high-resolution mass spectrometry (HRMS), and elemental analysis. Results and Discussion: Biological evaluation revealed that integration of the isatin scaffold significantly enhanced AChE inhibitory potency compared with that of the isatin-free intermediate precursors. Notably, several hybrid derivatives displayed superior inhibitory activity relative to the reference drug galantamine (IC50 = 56.4 ± 0.7 µM). SAR analysis demonstrated that electron-withdrawing substituents on the benzyl moiety, in synergy with halogenation on the isatin ring, substantially boosted AChE inhibition. Conclusions: This study underscores microwave irradiation as a highly efficient and superior synthetic approach, establishing benzimidazole–isatin hybrids—most notably compound Vi—as promising pharmacophoric scaffolds for drug development targeting Alzheimer’s disease.