Nath_2026_Mol.Divers__

Alzheimer's disease is a progressive neurodegenerative illness i.e., characterized by cognitive decline, memory impairment, cholinergic dysfunction, oxidative stress, Abeta aggregation, tau hyperphosphorylation and neuroinflammation. Due to multifactorial nature of AD, conventional single-target therapeutic approaches exhibit limited clinical success. Hence, development of multifunctional small molecules emerged as a promising strategy for management of Alzheimer's diseases i.e., capable to modulate multiple pathological pathways simultaneously. Among various heterocyclic pharmacophores, isatin (1H-indole-2,3-dione) gained considerable attention due to its structural versatility, synthetic accessibility and broad spectrum of biological effects. Recent studies demonstrated that isatin-derived molecules possess significant inhibitory activity against acetylcholinesterase, butyrylcholinesterase, monoamine oxidase-A/B, beta-secretase and amyloid aggregation pathways. Furthermore, hybridization of isatin core with pharmacologically active moieties like triazoles, coumarins, tacrine, benzylamine, piperazine, quinoline, hydrazones and melatonin afford more promising multitarget-directed ligands with improved BBB permeability, antioxidant potential and improved neuroprotective properties. Also, docking, MD simulation and ADMET analyses validated favorable binding interactions and drug-likeness characteristics of many isatin analogues. This review comprehensively summarizes recent advances in design, synthesis, biological evaluation, docking investigations and SAR studies of isatin-based anti-Alzheimer agents. In addition, key emphasis is placed on SAR trends which is responsible for promoted potency and selectivity including electron-withdrawing substitutions, linker optimization, hydrophobic interactions and dual-site binding with catalytic as well as peripheral anionic sites of target enzymes. Integration of hybrid isatin scaffolds with complementary pharmacophore combined with advanced in silico modeling and preclinical evaluation may pave the way for next-generation multifunctional therapeutics with improved efficacy and safety in treatment of Alzheimer's disease.