Evaluation of novel 2-(quinoline-2-ylthio)acetamide derivatives linked to diphenyl-imidazole as α-glucosidase inhibitors: Insights from in silico, in vitro, and in vivo studies on their anti-diabetic properties

• DOI: 10.1016/j.ejmech.2024.116332
• Publication Date: 2024-03-16T05:13:26Z
• Authors: Minoo Khalili Ghomi; Milad Noori; Maryam Mirahmad; Aida Iraji; Ahmad Shahir Sadr; Navid Dastyafteh; Pooria Asili; Mahdi Gholami; Shahrzad Javanshir; Maryam Lotfi; Somayeh Mojtabavi; Mohammad Ali Fara...; Mehdi Asadi; Ensieh Nasli-Esfa...; Mahdie Palimi; Bagher Larijani; Mohammad Hadi Mes...; Mohammad Mahdavi
• Keywords: Acarbose; Quinoline; Acetamide; Imidazole; IC50; Docking (animal)

The inhibition of the α-glucosidase enzyme is crucial for targeting type 2 diabetes mellitus (DM). This study introduces a series of synthetic analogs based on thiomethylacetamide-quinoline derivatives linked to diphenyl-imidazole as highly potential α-glucosidase inhibitors. Twenty derivatives were synthesized and screened in vitro against α-glucosidase, revealing IC50 values ranging from 0.18 ± 0.00 to 2.10 ± 0.07 μM, in comparison to the positive control, acarbose. Among these derivatives, compound 10c (IC50 = 0.180 μM) demonstrated the highest potency and revealed a competitive inhibitory mechanism in kinetic studies (Ki = 0.15 μM). Docking and molecular dynamic evaluations elucidated the binding mode of 10c with the active site residues of the α-glucosidase enzyme. Moreover, in vivo assessments on a rat model of DM affirmed the anti-diabetic efficacy of 10c, evidenced by reduced fasting and overall blood glucose levels. The histopathological evaluation enhanced pancreatic islet architecture and hepatocytes in liver sections. In conclusion, novel 2-(quinoline-2-ylthio)acetamide derivatives as potent α-glucosidase inhibitors were developed. Compound 10c emerged as a promising candidate for diabetes management, warranting further investigation for potential clinical applications and mechanistic insights.