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[Display omitted] • Novel 2-phenyl-1 H -benzo[ d ]imidazole-based α-glucosidase inhibitors were identified. • Some of derivatives significantly increased α-glucosidase inhibition. • The non-competitive inhibitors 15o and 22d did not have cytotoxicity towards LO2 cells. • Compound 15o showed significant in vivo anti-hyperglycaemic activity. In the present study, a series of 2-phenyl-1 H -benzo[ d ]imidazole-based α-glucosidase inhibitors were synthesized and evaluated for their in vitro and in vivo anti-diabetic potential. Screening of an in-house library revealed a moderated α-glucosidase inhibitor, 6a with 3-(1 H -benzo[ d ]imidazol-2-yl)aniline core, and then the structural optimization was performed to obtain more efficient derivatives. Most of these derivatives showed increased activity than 6a , and the most promising inhibitors were found to be compounds 15o and 22d with IC 50 values of 2.09 ± 0.04 and 0.71 ± 0.02 µM, respectively. Fluorescence quenching experiment confirmed the direct binding of compounds 15o and 22d with α-glucosidase. Kinetic study revealed that both compounds were non-competitive inhibitors, that was consistent with the result of molecular docking studies where they located at the allosteric site of the enzyme. Cell viability evaluation demonstrated the non-cytotoxicity of 15o and 22d against LO2 cells. Furthermore, the in vivo pharmacodynamic study revealed that compound 15o showed significant hypoglycemic activity and improved oral sucrose tolerance, comparable to the positive control acarbose. [ABSTRACT FROM AUTHOR]