Bis-1,2,4-triazole derivatives as potential antioxidants for pneumonia therapy.

This study investigates the antioxidant and predicted anti‑virulence potential of six novel bis‑1,2,4‑triazole derivatives for pneumonia therapy. All compounds were synthesized and evaluated in vitro against the DPPH radical; the half‑maximal inhibitory concentrations (IC₅₀) ranged from 45.1 to 108.7 µg/mL, with compounds 2 and 6 showing the lowest values and approaching the efficacy of ascorbic acid. The structural motifs of a flexible hexyl chain in compound 2 and a para‑nitrophenyl group in compound 6 appear to enhance radical‑scavenging potency. Molecular docking across the series yielded predicted binding affinities to pneumococcal virulence factors neuraminidase A (NanA) and pneumolysin (Ply) between − 5.6 and − 8,. kcal/mol; compounds 2 and 6 exhibited the most favourable docking scores (up to − 8.1 kcal/mol) and formed multiple stabilising hydrogen bonds and hydrophobic contacts within the active sites. All compounds were compared with ascorbic acid in statistical analyses, and the IC₅₀ values of 2 and 6 were significantly different (p < 0.05) from the reference. In silico ADMET profiling of the entire series indicated high gastrointestinal absorption, low predicted toxicity, absence of hERG inhibition, and minimal CYP450 inhibition, supporting their drug‑likeness. To our knowledge this is the first report evaluating bis‑1,2,4‑triazoles as dual antioxidant and anti‑virulence agents for pneumonia; the findings justify further optimisation and biological testing, including cytotoxicity assays in A549 cells and in vivo pneumonia models.