Natural scaffold, modern strategy: Coumarin hybrids as potential carbohydrate-digesting enzyme inhibitors-A decade of medicinal chemistry exploration (2015–2025)

Over the past decade (2015–2025), coumarin and its hybrid derivatives have emerged as promising scaffolds in the search for potent inhibitors of carbohydrate-digesting enzymes, particularly α-amylase (AMY) and α-glucosidase (AG), which are key pharmacological targets in controlling postprandial hyperglycemia in type-2 diabetic patients. This review compiles and critically evaluates the medicinal chemistry efforts focused on coumarin-based hybrids, highlighting their development strategies, synthesis, enzyme inhibitory potential, and structure–activity relationships (SAR). Various pharmacophoric conjugates, including thiazole, thiazolidinedione, triazole, chalcone, isatin, sulfonamide, oxadiazole, hydrazone, and cinnamic acid, have been effectively linked to the coumarin nucleus to enhance enzyme inhibitory potential. Several derivatives have exhibited superior enzyme inhibition compared to the standard drug acarbose, with favorable in vitro and in vivo profiles, low cytotoxicity, and enhanced binding interactions as supported by docking analysis. The SAR insights reveal that substitution patterns, electronic effects, and linker modifications significantly influence biological activity. The findings underscore the versatility of coumarin as a lead scaffold and deliver a robust foundation for the rational design of next-generation lead molecules targeting the two carbohydrate-digesting enzymes.