Synthesis and in Silico Evaluation of Novel Triazolone-Derived Naphthalene-2-Sulfonates, Evaluation of Potential Antiproliferative Agents and Enzyme Inhibitory Activities

Abstract

This study reports the synthesis and biological evaluation of four novel N-acetyl-derived heterocyclic compounds, namely 2-((1-acetyl-3-substituted-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)iminomethyl)-phenyl-naphthalene-2-sulfonates. The compounds were synthesized via acetylation reactions using acetic anhydride and were fully characterized by IR, 1H NMR, 1 3C NMR, elemental analysis, and HR-MS techniques. The anticancer activities of the synthesized compounds were evaluated in the concentration range of 1.563-200 mu M against HepG2 (hepatocellular carcinoma) and U87 (glioblastoma) cell lines, showing significant cytotoxic effects. Enzyme inhibition assays demonstrated potent inhibitory activities against alpha-glucosidase, alpha-amylase, acetylcholinesterase (AChE), and glutathione S-transferase (GST), with IC50 values ranging from 1.4 to 2.9 mu M. Molecular docking studies, performed using DFT-optimized geometries, supported the experimental findings and revealed strong and specific interactions with the target proteins. Among the studied derivatives, compound 2a exhibited the highest affinity toward alpha-glucosidase, 2d showed superior binding to alpha-amylase and AChE, while 2c demonstrated enhanced interaction with GST. Compound 2b displayed promising anticancer potential, forming stable complexes with proteins associated with the HepG2 and U87 cell lines.