Studying the Structure and Evaluating α‐Glucosidase Inhibition of Novel Acetamide Derivatives Incorporating 4‐Ethyl‐4H‐1,2,4‐Triazole Starting from 2‐(Naphthalen‐1‐yl)Acetic Acid

Abstract

AbstractThis research aims to create innovative compounds that incorporate 1,2,4‐triazole and exhibit α‐glucosidase inhibitory potential. Similar to our previously reported series of N‐aryl 2‐{[5‐(naphthalen‐1‐ylmethyl)‐4‐phenyl‐4H‐1,2,4‐triazol‐3‐yl]thio}acetamide compounds, we explore here 4‐ethyl instead of 4‐phenyl as substituent. The synthesis process effectively yielded these compounds, with the highest yield reaching up to 91 % for compound N‐phenyl‐2‐{[5‐(naphthalen‐1‐ylmethyl)‐4‐ethyl‐4H‐1,2,4‐triazol‐3‐yl]thio}acetamide 5 a. Their structures were validated through various spectroscopic techniques such as IR, 1H‐NMR, 13C‐NMR, and HR‐MS spectra, and for compounds 3, 5 d, and 5 e by X‐ray diffraction. In vitro experiments revealed that only compound 5 g, marked by a 3‐hydroxy substitution on the N‐phenylacetamide moiety, demonstrated higher α‐glucosidase inhibitory potential (IC50=158.4±3.4 μM) compared to the positive control, acarbose (IC50=351.3±1.8 μM). Molecular docking studies also coincide with in vitro assay by uncovering a strong hydrogen bond with residue Asp1526 along with other hydrophobic interactions of compound 5 g in the α‐glucosidase binding pocket. Compound 5 g showed a free binding energy of −9.7 kcal/mol, contrasting with acarbose (−8.0 kcal/mol). Despite the modest biological activity, this research underscores the simplicity and convenience of the procedure for synthesizing 1,2,4‐triazole‐based compounds, and contributes a key feature to the structure‐activity relationship of the triazole scaffold in the α‐glucosidase pocket.