Cyanoacetohydrazide linked to 1,2,3-triazole derivatives: a new class of α-glucosidase inhibitors

Abstract

In this work, a novel series of cyanoacetohydrazide linked to 1,2,3-triazoles (9a–n) were designed and synthesized to be evaluated for their anti-α-glucosidase activity, focusing on the fact that α-glucosidase inhibitors have played a significant role in the management of type 2 diabetes mellitus. All synthesized compounds except 9a exhibited excellent inhibitory potential, with IC50 values ranging from 1.00 ± 0.01 to 271.17 ± 0.30 μM when compared to the standard drug acarbose (IC50 = 754.1 ± 0.5 μM). The kinetic binding study indicated that the most active derivatives 9b (IC50 = 1.50 ± 0.01 μM) and 9e (IC50 = 1.00 ± 0.01 μM) behaved as the uncompetitive inhibitors of α-glucosidase with Ki = 0.43 and 0.24 μM, respectively. Moreover, fluorescence measurements were conducted to show conformational changes of the enzyme after binding of the most potent inhibitor (9e). Calculation of standard enthalpy (ΔHm°) and entropy (ΔSm°) values confirmed the construction of hydrophobic interactions between 9e and the enzyme. Also, docking studies indicated desired interactions with important residues of the enzyme which rationalized the in vitro results.

New solid phase methodology for the synthesis of biscoumarin derivatives: experimental and in silico approaches

“…α-glucosidase enzyme catalyzes the hydrolysis of starch to simple sugars which leads to an increase in blood glucose levels. α-glucosidase inhibitors can be ideal and effective anti-diabetic agents [ 51 – 53 ]. Docking studies of the mentioned compounds were carried out with gold docking software using different score fitness functions including chem score, gold score, ChemPLP, and the best accuracy with the lowest RMSD was seen in the ChemScore fitness function.…”

Design, synthesis, and in silico studies of quinoline-based-benzo[d]imidazole bearing different acetamide derivatives as potent α-glucosidase inhibitors

“…Ligands were prepared by OPLS_2005 force field using EPIK at a target pH of 7.0 ± 2. The grid box was generated for each binding site using entries with a box size of 25 Å, all derivatives were docked on binding sites using induced-fit docking, reporting 10 poses per ligand to form the final complex 9 , 37 .…”

“…α-Glucosidase (EC 3.2.1.20) is a catalytic hydrolase enzyme present on the brush border of the small intestine which hydrolyzes oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides at their non-reducing ends 7 – 10 . The produced monosaccharides especially glucose enter the bloodstream, resulting in postprandial hyperglycemia thus causing diabetes 11 – 13 .…”

Design, synthesis, and molecular docking studies of diphenylquinoxaline-6-carbohydrazide hybrids as potent α-glucosidase inhibitors

“…The α-glucosidase inhibitory effects of diphenylquinoxaline-6-carbohydrazide hybrids 7a–o were determined by previously reported method [ 51 ]. In this protocol, 20 μL of enzyme solution (α-glucosidase from Saccharomyces cerevisiae, EC3.2.1.20, 20 U/mg), 20 μL of test compounds 7a–o with various concentrations, and 135 μL of potassium phosphate buffer were added and incubated in the 96-well plate for 10 min at 37 ◦ C. Later on, 25 μL of the substrate (p-nitrophenyl glucopyranoside, 4 mM) was added to each well of the plate, and incubation was continued for 20 min at 37 ◦ C. Next, absorbance was measured at 405 nm by spectrophotometer (Gen5, Power wave xs2, BioTek, USA), and the IC 50 value for each tested compound was calculated by taking advantage of the nonlinear regression curve [ 52 , 53 ].…”