Coumarin derivatives as antidiabetic agents: a comprehensive review on mechanistic insights, structure-activity relationships, in silico studies, and challenges.

Abstract

In recent years, coumarin has been structurally modified by combining it with heterocyclic or other active pharmacophores such as thiazolidinedione, hydrazone, triazole, cinnamic acid, aza group, oxadiazole, sulfonamide, and piperidinyl to influence molecular targets related to diabetes, such as aldose reductase (ALR2), α-glucosidase, α-amylase, dipeptidyl peptidase-4 (DPP-4), peroxisome proliferator-activated receptor alpha (PPAR-α), peroxisome proliferator-activated receptor gamma (PPAR-γ), and protein tyrosine phosphatase 1B (PTP1B). This review provides a structured overview of the structure-activity relationship (SAR) of coumarin-based derivatives, focusing on their substitution patterns and functional relationships, which affect potency, selectivity, and efficacy. In silico analysis revealed key binding interactions between coumarin derivatives and the catalytic sites of different druggable enzyme targets. More progressive insights, including quantitative structure-activity relationship (QSAR) and machine learning, have been discussed, which have contributed to addressing the selectivity, solubility, safety, and stability challenges of these compounds. Moreover, this review highlighted coumarin hybrids as targeted candidates for future antidiabetic therapies.