Search

This 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. [ABSTRACT FROM AUTHOR]

• Starting from 2-(naphtalen-1-yl)acetic acid, eleven novel compounds (4a–k) were synthesized, featuring 2-thioxothiazolidin-4-one, targeting α-glucosidase inhibition and antimicrobial activities. • Knoevenagel reaction produced Z- isomers of 5-arylidene derivatives confirmed by spectroscopic techniques and X-ray diffraction. • Most compounds showed significant α-glucosidase inhibitory activity, with compound 4b having the lowest IC 50 value of 7.5 ± 0.5 μM, outperforming the reference drug voglibose. • Molecular docking studies revealed strong inhibition by compound 4b through key hydrogen and halogen bonds, and highlighted binding interactions for other compounds. • Significant antibacterial and antifungal activities were observed (MIC: 6.25–100 μg/mL). Compounds 4b and 4k showed the most promise for dual inhibition, suggesting antidiabetic and antibiotic uses. Eleven novel compounds, namely N -(5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)-2-(naphthalen-1-yl)acetamide 4a–k , were synthesized to exhibit dual activity against the enzyme α-glucosidase and selected strains of bacteria and fungi. They were obtained through reactions of aromatic aldehydes with 2-(naphthalen-1-yl)- N -(4-oxo-2-thioxothiazolidin-3-yl)acetamide 3 , which was prepared from reaction of thiocarbonyl- bis -thioglycolic acid and 2-(naphthalen-1-yl)acetohydrazide 2. Structural confirmation was performed using spectroscopic techniques, including FT-IR, 1H NMR, 13C NMR, and HR-ESI-MS. The Z -configuration of compounds 4a–k was identified by the downfield signal of the methylidene proton in their 1H NMR spectra. A detailed crystallographic analysis was performed for compounds 3, 4d and 4h. Evaluating α-glucosidase inhibitory activity of the compounds containing the 2-thioxothiazolidin-4-one ring (3, 4a–k) showed promising results, except for compounds 3, 4e , and 4h , which showed no activity. These compounds exhibited significant inhibitory activity, with IC 50 values ranging from 7.5 ± 0.5 μM to 290.3 ± 1.9 μM. Notably, these values are better than that of the reference drug voglibose (IC 50 = 355.8 ± 3.5 μM), indicating the potential of these compounds as effective inhibitors. Compound 4b exhibited the most pronounced activity (IC 50 = 7.5 ± 0.5 μM). Molecular docking studies demonstrated strong inhibition for compound 4b through the formation of hydrogen and halogen bonds with Asp73 and His478, respectively. Compound 4g also showed promising binding interactions, forming a hydrogen bond and fitting well within a sub-pocket. Fluorine electronegativity influenced halogen bond formation in compound 4a , while the large bromine atom hindered binding in compound 4c. Furthermore, in pursuit of investigating dual-function compounds, a series of thiazolidinone derivatives were assessed for their antibacterial and antifungal activities, with MIC values ranging from 6.25 to 100 μg/mL. Consistent with α-glucosidase inhibition, compound 3 , lacking a substituent at the fifth position of the thiazolidine ring, exhibited no activity, highlighting the significance of this position in modulating the biological activities of such compounds. Moreover, the prediction of some physicochemical properties and PAINS revealed the promising values of these compounds which allow further investigation of this series. Therefore, the molecules 4b and 4k were the most important in dual inhibitory activities. These results emphasize the promise of these synthesized derivatives as compounds with potential applications in antidiabetic and antibiotic therapies. [Display omitted] [ABSTRACT FROM AUTHOR]

• Nine novel acetamide derivatives containing a 1,2,4-triazole were designed and synthesized. • Their structure was confirmed by spectroscopic methods such as NMR, IR and HR-MS. • The crystal structure of four compounds was determined by single crystal X-ray diffraction. • Activity against enzyme α-glucosidase was evaluated. • Docking studies were conducted to analyze the interactions with the active site of the enzyme. A series of nine novel N -aryl 2-{[5-(naphthalen-1-ylmethyl)-4-phenyl-4 H -1,2,4-triazol-3-yl]thio}- N -phenylacetamide derivatives were prepared from 5-(naphthalen-1-ylmethyl)-4-phenyl-4 H -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 IC 50 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 (IC 50 = 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 IC 50 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 IC 50 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. [Display omitted] [ABSTRACT FROM AUTHOR]