Novel tetrahydrobenzo[b]thiophen-2-yl)urea derivatives as novel α-glucosidase inhibitors: Synthesis, kinetics study, molecular docking, and in vivo anti-hyperglycemic evaluation

• Published in: Bioorganic chemistry Vol. 115; pp. 105236 - 105252
• Main Authors: Xie, Hong-Xu, Zhang, Juan, Li, Yue, Zhang, Jin-He, Liu, Shan-Kui, Zhang, Jie, Zheng, Hua, Hao, Gui-Zhou, Zhu, Kong-Kai, Jiang, Cheng-Shi
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.10.2021; Elsevier
• Subjects: alpha-Glucosidases - metabolism; Animals; Anti-hyperglycaemic activity; Biochemistry & Molecular Biology; Blood Glucose - drug effects; Cell Line; Chemistry; Chemistry, Organic; Dose-Response Relationship, Drug; Glucose Tolerance Test; Glycoside Hydrolase Inhibitors - chemical synthesis; Glycoside Hydrolase Inhibitors - chemistry; Glycoside Hydrolase Inhibitors - pharmacology; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Kinetics; Life Sciences & Biomedicine; Molecular docking; Molecular Docking Simulation; Molecular Structure; Non-competitive inhibitor; Physical Sciences; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; Tetrahydrobenzo[b]thiophen-2-yl)urea; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Type 2 diabetes; Urea - analogs & derivatives; Urea - chemistry; Urea - pharmacology; α-Glucosidase inhibitors; Tetrahydrobenzo[b]thiophen-2-yl)urea; Non-competitive inhibitor; Type 2 diabetes; α-Glucosidase inhibitors; Molecular docking; Anti-hyperglycaemic activity; DIABETES-MELLITUS; alpha-Glucosidase inhibitors; POTENT; ANALOGS; DYNAMICS; RISK
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105236

[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 (IC50 of 26.71 ± 1.80 μM) and the positive control acarbose (IC50 of 258.53 ± 1.27 μM). Among them, compounds 8r (IC50 = 0.59 ± 0.02 μM) and 8s (IC50 = 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 (IC50 > 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.