Synthesis of 2-phenyl-1H-imidazo[4,5-b]pyridine as type 2 diabetes inhibitors and molecular docking studies

A series of imidazo[4,5-b]pyridines (3–32) was synthesized and evaluated for their ability to inhibit Baker’s yeast α-glucosidase enzyme. The IC50 values for all compounds were in the range of 13.5–93.7 µM with compound 15, a 2,4-dihydroxy-substituted analog, displayed the most potent activity potential. Structure–activity relationship strongly suggested the presence of hydroxyl group at aromatic side chain as the main contributing factor towards the inhibitory potential. Findings also suggested that compounds having hydroxyl groups at ortho and para positions are able to inhibit α-glucosidase enzyme efficiently. This experimental observation was further supported by docking studies carried out on human intestinal maltase-glucoamylase enzyme (PDB ID: 3TOP). The –NH– group of imidazo-pyridine of compound 15 formed H-bond with Asp1526, while both hydroxyls of catechol formed H-bond with Asp1279. Imidazo-pyridine ring was well stabilized by π–π stacking with Phe1560, and other hydrophobic interactions involving side chain of Pro1159, Tyr1167, Asp1157, Met1421, Trp1369, Pro1318, and Lys1460. The catechol ring also forms several hydrophobic interactions with Phe1560, Trp1523, Trp1418, His1584, Try1251, Ile1218 and Trp1355.