Design and synthesis of novel 1,2,3-triazole linked hybrids: Molecular docking, MD simulation, and their antidiabetic efficacy as α-Amylase inhibitors

Novel 1,2,3-triazole linked coumarin and cinnamic acid analogs were designed, synthesized, characterized, and evaluated for their ability to inhibit the alpha-amylase enzyme in order to treat diabetes. Porcine pan-creatic alpha-amylase isoenzyme II was used in the investigation and analysis of in silico molecular docking and molecular dynamic simulations. The server PreADME/toxicity was used to predict pharmacokinetics and pharmacodynamics properties. In vitro and in silico results revealed that compounds 7d, 7e and 7f showed excellent antidiabetic activity with IC50 in the range of 0.133-0.192 mu M and percentage inhibi-tions in the range of 88.22 +/- 1.43 to 98.87 +/- 2.63%, respectively, indicating their better potency than the standard acarbose. Furthermore, synthesized compounds were docked into the active sites of the porcine pancreatic alpha-amylase isoenzyme II to evaluate binding affinity and hybrid most potent 7f was lodged in the active site via many strong hydrogen and hydrophobic interactions. Through a 100-ns dynamic simulation research, stability and binding interactions between the promising hybrid 7f and the active residues of the investigated alpha-amylase isoenzyme II were confirmed. The biological assessments, ADMET, molecular docking, and MD simulations of synthesized analogs allude to the possibility of using hybrids 7d, 7e, and 7f in the development of new antidiabetic therapeutics.(c) 2023 Elsevier B.V. All rights reserved.