Bridging the gap in Alzheimer's therapy: strategic design and SAR evolution of coumarin-based hybrids as potent MTDLs

Due to their multitargeting potential, coumarin-based hybrid molecules represent a new and valuable drug development strategy for the treatment of Alzheimer's disease (AD). This review summarizes recent advances in the design, synthesis, and evaluation of coumarin hybrids as multi-target-directed ligands (MTDLs) for AD. This review covers various coumarin hybrid classes, including those incorporating triazole, thiazole, quinoline, chalcone, and other pharmacophores, highlighting their diverse mechanisms of action, such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, amyloid-beta (Aβ) aggregation prevention, BACE-1 inhibition, MAO-B modulation, antioxidant activity, and metal ion chelation. Structure-activity relationship (SAR) studies have identified key structural features for optimal activity, including linker length, substitution patterns, and physicochemical properties influencing CNS penetration. Molecular docking and dynamics simulations reveal information about drug-target interactions and demonstrate the ability to engage multiple targets. Coumarin hybrids are already showing ecological in vivo efficacy in animal models, and also the desired safety window and metabolic stability make them potential clinical candidates. Future research directions include incorporating emerging therapeutic targets, advanced computational design, and a focus on the microbiome-gut-brain axis to develop more effective and disease-modifying AD therapeutics.