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[Display omitted] In this present study, a series of novel (E)-2-benzylidene- N -(3-cyano-4,5,6,7-tetrahydrobenzo[ b ]thiophen-2-yl)hydrazine-1-carboxamide derivatives against α-glucosidase were designed and synthesized, and their biological activities were evaluated in vitro and in vivo. Most of the designed analogues exhibited better inhibitory activity than the marketed acarbose, especially the most potent compound 7 with an IC 50 value of 9.26 ± 1.84 μM. The direct binding of 7 and 8 with α-glucosidase was confirmed by fluorescence quenching experiments, and the kinetic and molecular docking studies revealed that 7 and 8 inhibited α-glucosidase in a non-competitive manner. Cytotoxicity bioassay indicated compounds 7 and 8 were non-toxic towards LO2 and HepG2 at 100 μM. Furthermore, both compounds were demonstrated to have in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-treated rats. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel tetrahydrobenzo[ b ]thiophen-2-yl)urea derivatives were designed and synthesized. • Tetrahydrobenzo[ b ]thiophen-2-yl)urea derivatives significantly increased α-glucosidase inhibition. • The most potent compounds 8r and 8s showed non-toxicity towards LO2 and HepG2 cells. • Compound 8r showed promising in vivo anti-hyperglycaemic activity. α-Glucosidase inhibitors, which can inhibit the digestion of carbohydrates into glucose, are one of important groups of anti-type 2 diabetic drugs. In the present study, we report our effort on the discovery and optimization of α-glucosidase inhibitors with tetrahydrobenzo[ b ]thiophen-2-yl)urea core. Screening of an in-house library revealed a moderated α-glucosidase inhibitors, 5a , and then the following structural optimization was performed to obtain more efficient derivatives. Most of these derivatives showed increased inhibitory activity against α-glucosidase than the parental compound 5a (IC 50 of 26.71 ± 1.80 μM) and the positive control acarbose (IC 50 of 258.53 ± 1.27 μM). Among them, compounds 8r (IC 50 = 0.59 ± 0.02 μM) and 8s (IC 50 = 0.65 ± 0.03 μM) were the most potent inhibitors, and showed selectivity over α-amylase. The direct binding of both compounds with α-glucosidase was confirmed by fluorescence quenching experiments. Kinetics study revealed that these compounds were non-competitive inhibitors, which was consistent with the molecular docking results that compounds 8r and 8s showed high preference to bind to the allosteric site instead of the active site of α-glucosidase. In addition, compounds 8r and 8s were not toxic (IC 50 > 100 μM) towards LO2 and HepG2 cells. Finally, the in vivo anti-hyperglycaemic activity assay results indicated that compounds 8r could significantly decrease the level of plasma glucose and improve glucose tolerance in SD rats treated with sucrose. The present study provided the tetrahydrobenzo[ b ]thiophen-2-yl)urea chemotype for developing novel α-glucosidase inhibitors against type 2 diabetes. [ABSTRACT FROM AUTHOR]