Synthesis and in silico evaluation of 1,2,4-triazolo[1,5-a]pyridines in a solvent-free manner over cellulose-based retrievable copper catalyst

1,2,4-Triazolo[1,5-a]pyridines have emerged as potential therapeutic agents for various diseases due to their diverse biological activities, including antiparasitic and anti-inflammatory effects. Recent advances have focused on developing efficient synthetic strategies for these compounds as potential drug candidates with improved efficacy and selectivity. In this study, a cellulose-based copper-amidoxime heterogeneous catalyst was successfully synthesized and applied for the solvent-free synthesis of 1,2,4-triazolo[1,5-a]pyridine derivatives from benzonitriles and 2-aminopyridines. The nanocatalyst exhibited high catalytic activity, easy separation, and good reusability over five consecutive cycles. The nanocatalyst was characterized using FT-IR, XRD, FESEM, TEM, TGA, EDX, VSM, ICP-OES, and BET analyses. The synthesized derivatives were characterized by NMR and mass spectrometry. Molecular mechanics (MM) calculations and geometric optimization of the structures were performed using Spartan software, and the absence of imaginary frequencies confirmed the stability of the structures. Subsequently, molecular docking studies were performed using AutoDock Vina to identify optimal interactions with the target protein. Molecular dynamics (MD) simulations, structural parameter studies (RMSD, RMSF, R g ), and binding free energy calculations (MM-PBSA) confirmed that, among the synthesized compounds, 2-(naphthalen-2-yl)[1,2,4]triazolo[1,5-a]pyridine (NTP) exhibited the highest compatibility with the drug Tolmetin (TOL). Furthermore, evaluation of binding efficiency metrics, including inhibition constant ( K i ) and ligand efficiency (LE), along with ADMET (absorption, distribution, metabolism, excretion, and toxicity) and toxicity predictions, suggested that NTP could potentially serve as a promising alternative to TOL.