GA: Inspired from biological activity backgrounds of adamantane (Saxagliptin, antidiabetic drug) and 1,2,3-triazoles, a new library of adamantane-appended 1,2,3-triazole is synthesized and evaluated for its antidiabetic potential. Various linkers are added to elucidate structure–activity relations.

In search of potent inhibitors of α-glucosidase, adamantane-appended 1,2,3-triazoles (4a-4f, 6a-6f, and 8a-8f) are synthesized using Click reaction. After establishing their structure using spectral studies, all the molecular hybrids are assayed for α-glucosidase inhibition. Compounds 6c (IC ₅₀ = 8.30 ± 0.33 μM) and 6b (IC ₅₀ = 14.0 ± 0.16 μM) exhibit promising inhibition of α-glucosidase in comparison to reference used (Acarbose, IC ₅₀ = 13.50 ± 0.32 μM). Five hybrids show better activity than precursor alkyne (IC ₅₀ = 19.57 ± 0.013 μM). The role of various covalent linkers between triazole and phenyl ring has been established using structure–activity relationship. The most probable mode of inhibition is studied by docking the most active compound 6c and Acarbose within the protein target (PDB ID: 3L4U). Compounds 2, 6c, and Acarbose show a docking score of −5.048, −6.14, and −12.118, respectively. Further, molecular dynamics simulations for 100 ns are performed to gain a detailed understanding of the complex stability. Binding energy for both the simulated complexes is calculated using MMGBSA and MMPBSA analysis, where, compound 6c exhibits a ΔG _bind of −15.74 kcal mol⁻¹. All the compounds follow Lipinski rules of five. This study paves the way for developing small-molecule-based α-glucosidase inhibitors as potential lead molecules using these hybrid frameworks.