Synthesis of new clioquinol derivatives as potent α-glucosidase inhibitors; molecular docking, kinetic and structure–activity relationship studies

• Published in: Bioorganic chemistry 2022-02, Vol.119, p.105506-105506, Article 105506
• Main Authors: Wali, Shoukat, Atia-tul-Wahab, Ullah, Saeed, Khan, Maria Aqeel, Hussain, Shahid, Shaikh, Muniza, Atta-ur-Rahman, Choudhary, M. Iqbal
• Format: Article
• Language: English
• Subjects: alpha-Glucosidases - metabolism; Antidiabetic agents; Cells, Cultured; Clioquinol - chemical synthesis; Clioquinol - chemistry; Clioquinol - pharmacology; Clioquinol derivatives; Diabetes mellitus; Dose-Response Relationship, Drug; Enzyme inhibition; 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; Molecular Docking Simulation; Molecular Structure; Postprandial hyperglycemia; Structure-Activity Relationship; α-Glucosidase Inhibition
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105506

[Display omitted] •A series of of new clioquinol derivatives 2a-11a were synthesized.•The synthetic compounds were evaluated for α-glucosidase inhibitory activity with IC50 between 43.86 and 325.81 µM.•Kinetic studies of compounds 2a-11a indicated mode of inhibitions.•Docking studies on compounds 4a, 10a, and 11a revealed the predicted binding pose and their interactions with a-glucosidase. Diabetes mellitus is a chronic metabolic disorder with increasing prevalence and long-term complications. The aim of this study was to identify α-glucosidase inhibitory compounds with potential anti-hyperglycemic activity. For this purpose, a series of new clioquinol derivatives 2a-11a was synthesized, and characterized by various spectroscopic techniques. The enzyme inhibitory activities of the resulting derivatives were assessed using an in-vitro mechanism-based assay. All the tested compounds 2a-11a of the series showed a significant α-glucosidase inhibition with IC50 values 43.86–325.81 µM, as compared to the standard drug acarbose 1C50: 875.75 ± 2.08 µM. Among them, compounds 4a, 5a, 10a, and 11a showed IC50 values of 105.51 ± 2.41, 119.24 ± 2.37, 99.15 ± 2.06, and 43.86 ± 2.71 µM, respectively. Kinetic study of the active analogues showed competitive, non-competitive, and mixed-type inhibitions. Furthermore, the molecular docking study was performed to elucidate the binding interactions of most active analogues with the various sites of α-glucosidase enzyme. The results indicate that these compounds have the potential to be further studied as new anti-diabetic agents.