Adamantane-Appended 1,2,3-Triazole Hybrids: Synthesis and α-Glucosidase Inhibition Studies through Experimental and In Silico Approach.

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 (IC50 = 8.30 ± 0.33 μM) and 6b (IC50 = 14.0 ± 0.16 μM) exhibit promising inhibition of α-glucosidase in comparison to reference used (Acarbose, IC50 = 13.50 ± 0.32 μM). Five hybrids show better activity than precursor alkyne (IC50 = 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 ΔGbind 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.