Synthesis, structure and α-glucosidase inhibitor activity evaluation of some acetamide derivatives starting from 2-(naphthalen-1-yl) acetic acid, containing a 1,2,4-triazole

Abstract

A series of nine novel N-aryl 2-{[5-(naphthalen-1-ylmethyl)-4-phenyl-4H-1,2,4-triazol-3-yl]thio}-N-phenylacetamide derivatives were prepared from 5-(naphthalen-1-ylmethyl)-4-phenyl-4H-1,2,4-triazole-3-thiol which was obtained from 2-(naphthalen-1-yl)acetohydrazide synthesized starting from 2-(naphthalen-1-yl)acetic acid. The structures of these heterocyclic compounds were confirmed by IR, 1H NMR, 13C NMR and HR-MS spectra. Additionally, the crystal structures of four compounds (3, 5a, 5c, and 5i) were determined using X-ray diffraction. Compound 3 and a series of acetamide derivatives that contain the 1,2,4-triazole heterocycle 5a-i were evaluated for their ability to inhibit the enzyme α-glucosidase. All compounds demonstrated good inhibition activity with IC50 values ranging from 0.11 ± 0.04 µM to 21.89 ± 1.28 µM, and were found to be more active than the positive control Voglibose (IC50 = 35.12 ± 1.69 µM). Among these compounds, compound 5b possessing a 2-methyl group on the N-phenylacetamide moiety, was found to be the most potent inhibitor in this series of derivatives with an IC50 value of 0.11 ± 0.04 µM. Conversely, compound 5a, which lacks a substituent on the N-phenylacetamide moiety, showed the lowest activity with an IC50 value of 21.89 ± 1.28 µM. To gain insights into the mechanism of how these compounds affect the enzyme α-glucosidase, molecular docking studies were conducted to analyze the interactions of these compounds with the active site of the enzyme. The results indicate that compounds 3 and 5a-i can bind to the binding pocket of the enzyme, and compound 5b was found to have stronger binding through the formation of hydrogen bonds with residue Arg404.