Pharmacological investigation of a selected triazole derivative against acetic acid-induced ulcerative colitis in mouse model.

Abstract

In this study, the pharmacological and mechanistic potential of a selected synthetic triazole derivative, 4-(4-Fluorophenyl)-3-(p-tolyl)-1H-1,2,4-triazole-5(4H)-thione (TriQ), was evaluated in an acetic acid-induced ulcerative colitis (UC) mice model using an integrated approach involving molecular docking, molecular dynamics (MD) simulations, biochemical assays, gene expression analysis, and histopathological evaluation. TriQ was selected based on the pharmacological relevance of triazole scaffolds, particularly those containing fluorophenyl and aryl substitutions, which are associated with enhanced anti-inflammatory and antioxidant properties and improved target-binding interactions. In silico analysis revealed strong binding affinities of TriQ toward key inflammatory mediators, including Nuclear Factor kappa B (NF-κB), Interleukin-6 (IL-6), and Tumor Necrosis Factor-alpha (TNF-α), stabilized through hydrogen bonding and hydrophobic interactions. MD simulations confirmed the structural stability and consistent conformational behavior of the TriQ-protein complexes over a 100 ns trajectory. In vivo administration of TriQ (5, 10, and 20 mg/kg) significantly alleviated acetic acid-induced colitis, with the highest efficacy observed at 20 mg/kg. Treatment markedly improved disease activity index and restored altered hematological and biochemical parameters, along with normalization of hepatic and renal function markers. TriQ also enhanced endogenous antioxidant defenses, including catalase (CAT), glutathione S-transferase (GST), and reduced glutathione (GSH), while suppressing oxidative stress and inflammatory mediators such as myeloperoxidase (MPO) and nitric oxide (NO). At the molecular level, TriQ significantly downregulated pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α) and upregulated heme oxygenase-1 (HO-1) expression, as confirmed by ELISA and qRT-PCR analyses. Histopathological findings demonstrated marked preservation of colonic architecture, and reduced epithelial injury. Collectively, these findings demonstrate that TriQ exerts potent anti-inflammatory and antioxidant effects primarily through modulation of the NF-κB/HO-1 signaling axis, highlighting its potential as a promising lead candidate for the development of novel anti-ulcerative colitis therapeutics.