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

Abstract

In search of potent inhibitors of α-glucosidase, we have synthesized amide coupled adamantane derived 1,2,3-triazoles (4a-4f, 6a-6f, and 8a-8f) using Click reaction. After establishing their structure using spectral studies, all the molecular hybrids were assayed for α-glucosidase inhibition assay. Compounds 6c (IC50 = 8.30 ± 0.33 μM) and 6b (IC50 = 14.0 ± 0.16 μM) demonstrated promising inhibition of α-glucosidase in comparison to reference used (Acarbose, IC50 = 13.50 ± 0.32 μM). The role of various covalent linkers between triazole and phenyl ring has been established using structure activity relationship (SAR). The most probable mode of inhibition was studied by docking the most active compound 6c and Acarbose within the protein target (PDB ID: 3L4U).  Further, 100 ns dynamics simulations were conducted to gain a detailed understanding of the complex stability. Binding energy for both the simulated complexes was calculated using MMGBSA and MMPBSA analysis, where compound 6c and Acarbose demonstrates a ΔGbind of -15.74 kcal/mol, and -46.37 kcal/mol. All compounds fit in the Lipinski rules of five, when ADME studies was carried out. This study paves the way for developing small molecule based α-glucosidase inhibitors as potential lead molecules using these frameworks.