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

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 deriva-tives that contain the 1,2,4-triazole heterocycle 5a-i were evaluated for their ability to inhibit the en-zyme alpha-glucosidase. All compounds demonstrated good inhibition activity with IC50 values ranging from 0.11 +/- 0.04 mu M to 21.89 +/- 1.28 mu M, and were found to be more active than the positive control Vogli -bose (IC50 = 35.12 +/- 1.69 mu M). 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 deriva-tives with an IC50 value of 0.11 +/- 0.04 mu M. 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 mu M. To gain insights into the mechanism of how these compounds affect the enzyme alpha-glucosidase, molecular dock-ing 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.(c) 2023 Elsevier B.V. All rights reserved.

Automated summary

A series of novel N-aryl 2-{[5-(naphthalen-1-ylmethyl)-4-phenyl-4H-1,2,4-triazol-3-yl]thio}-N- phenylacetamide derivatives were synthesized and characterized. These compounds showed good inhibition activity against alpha-glucosidase, with compound 5b being the most potent inhibitor. Molecular docking studies revealed the interactions between these compounds and the active site of the enzyme.