Structural Aspects of Coumarin-heterocycle Conjugates: A New Frontier in Antidiabetic Drug Discovery

Diabetes Mellitus (DM) is a metabolic disorder that can be defined as sustained hyperglycemia, a state in which the glucose level in the blood is consistently elevated. This condition results from either the cells of the body becoming resistant to insulin or the secretion of insulin being insufficient. In recent years, hybrid drug design has shown potential for treating complex diseases, as it combines the effects of two or more pharmacophores within a single molecular structure. Coumarin and its derivatives have shown considerable attention in medicinal chemistry due to their versatility and designing of potential compounds. In recent years, coumarin derivatives have been prepared by linking the coumarin core with other pharmacophores and generating novel compounds with enhanced antidiabetic potential. In this review we have discussed various coumarin derivatives with conjugated rings, such as thiazolidinedione, benzimidazole, oxazole, and oxadiazole, their structural aspects, and structure-activity relationships for the generation of novel compounds. We also summarised the multiple mechanisms of antidiabetic action exhibited by coumarin derivatives and their conjugates, including inhibition of α-glucosidase, α-amylase, DPP-4, and aldose reductase, and the regulation of insulin sensitivity through PPAR-γ activation. The analysis of SAR revealed that the presence of electron-donating substitution in the coumarin nucleus, as well as the choice of heterocycle and the type of linker (alkyl, aryl, amides, or esters), were the major factors responsible for potency and selectivity against diabetes. The review may assist the medicinal chemist in the discovery of novel compounds as antidiabetic agents with improved efficacy, safety, and multi-target profiles.