SAR and mechanistic pathways of oxadiazole derivatives: targeting enzymes for antidiabetic therapy.

The global prevalence of diabetes mellitus continues to rise sharply, creating an urgent need for effective strategies to manage postprandial hyperglycemia. Inhibition of the carbohydrate-hydrolysing enzymes α-glucosidase and α-amylase is a well-established approach for reducing glucose absorption and improving glycaemic control. Among the heterocyclic scaffolds investigated for antidiabetic drug discovery, oxadiazoles have attracted particular attention because of their structural versatility, balanced electronic properties, and capacity to engage enzyme active sites through hydrogen bonding, π-π stacking, hydrophobic contacts, and van der Waals interactions. Several oxadiazole derivatives also show favorable predicted pharmacokinetic profiles, supporting their potential as orally active antidiabetic agents, although systematic pharmacokinetic evaluation across the class remains limited. This review summarizes recent advances in oxadiazole derivatives as α-glucosidase and α-amylase inhibitors, with emphasis on structure activity relationships (SAR), molecular interactions, and mechanisms of enzyme inhibition. Relevant studies published between 2016 and 2024 were identified through a systematic search of PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar. The reviewed derivatives showed IC50 values ranging from 0.07 to 215 μM against α-glucosidase and from 10.60 to 92.16 μM against α-amylase, with several compounds substantially more potent than their corresponding reference inhibitors. Collectively, these findings position the oxadiazole scaffold as a promising framework for the rational design and optimization of next-generation antidiabetic agents.