New cycloalkyl[b]thiophenylnicotinamide-based α-glucosidase inhibitors as promising anti-diabetic agents: Synthesis, in silico study, in vitro and in vivo evaluations

In the present study, a series of cycloalkyl[b]thiophenylnicotinamide derivatives against α-glucosidase were synthesized, and evaluated for their in vitro and in vivo anti-diabetic potential. Most of the synthetic analogues exhibited superior α-glucosidase inhibitory effects than the standard drug a...

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Published in:Bioorganic & medicinal chemistry letters 2023-01, Vol.79, p.129069-129069, Article 129069
Main Authors: Wang, Kai-Ming, Ge, Yong-Xi, Zhang, Jie, Chen, Yi-Tong, Zhang, Nai-Yu, Gu, Jin-Song, Fang, Lei, Zhang, Xin-Lei, Zhang, Juan, Jiang, Cheng-Shi
Format: Article
Language:English
Subjects:
Acarbose
alpha-Glucosidases
Animals
Glycoside Hydrolase Inhibitors - pharmacology
Hypoglycemic Agents - pharmacology
Molecular Docking Simulation
Rats
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Summary:In the present study, a series of cycloalkyl[b]thiophenylnicotinamide derivatives against α-glucosidase were synthesized, and evaluated for their in vitro and in vivo anti-diabetic potential. Most of the synthetic analogues exhibited superior α-glucosidase inhibitory effects than the standard drug acarbose (IC  = 258.5 μM), in which compound 11b with cyclohexyl[b]thiophene core demonstrated the highest activity with an IC value of 9.9 μM and showed higher selectivity towards α-glucosidase over α-amylase by 7.4-fold. Fluorescence quenching experiment confirmed the direct binding of 11b with α-glucosidase, kinetics study revealed that 11b was a mixed-type inhibitor, and its binding mode was analyzed using molecular docking. Moreover, analogs compounds 6a-9b, 11b, 12b did not show in vitro cytotoxicity against LO2 and HepG2 cells. Finally, compound 11b exhibited in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-loaded rats.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2022.129069