Design, synthesis, and anti-fibrotic evaluation of novel sulfonamide-embedded 1,2,4-triazinone derivatives in TGF-β-activated hepatic stellate cells (LX-2).

Authors

Ahmed M El-Saghier, Souhaila S Enaili, Asmaa Abdul-Baset, Mounir A A Mohamed, Amany M Hamed

Published in

RSC medicinal chemistry. Jul 02, 2026. Epub Jul 02, 2026.

Abstract

Background: hepatic fibrosis is a progressive liver disorder driven by activation of hepatic stellate cells (HSCs) and excessive extracellular matrix (ECM) deposition. α-Smooth muscle actin (α-SMA) is a hallmark of HSC activation and a critical therapeutic target. Despite the clinical use of silybin, there is a need for more potent anti-fibrotic agents. This study describes the synthesis of novel sulfonamide-embedded 1,2,4-triazinone derivatives designed to suppress hepatic stellate cell activation and extracellular matrix accumulation associated with liver fibrosis. Methods: the cytotoxicity of compounds 3-12 was assessed using the MTT assay to determine nontoxic concentrations for subsequent studies. Anti-fibrotic activity of compounds 4-6 was evaluated at sub-cytotoxic doses (0.5-10 μM) by measuring ECM markers, hyaluronic acid (HA), laminin (LN), and collagen I (Col I), and α-SMA expression using Western blot normalized to β-actin. Silybin was used as a positive control. Dose-response curves were generated to determine IC₅₀ values. Results: compounds 4-6 were non-cytotoxic at the tested concentration of 5 μM, as determined by the MTT assay, and significantly inhibited ECM deposition in TGF-β1-activated LX-2 cells. Compound 4 exhibited the highest potency, reducing HA, LN, and Col I by 69.2 ± 0.1%, 73.5 ± 0.6%, and 76.8 ± 0.3%, respectively, with IC₅₀ values of 2.8 ± 0.3 μM (HA), 2.4 ± 0.2 μM (LN), and 2.1 ± 0.2 μM (Col I). Compounds 5 and 6 showed moderate inhibition, while silybin exerted comparatively weaker effects. Western blot analysis confirmed marked suppression of α-SMA by compounds 4-6, with the strongest effect observed for compound 4, consistent with ECM inhibition results. Conclusion: novel compounds, particularly compound 4, effectively suppress HSC activation and ECM accumulation at non-cytotoxic concentrations, outperforming silybin. These findings highlight their potential as promising anti-fibrotic therapeutics for liver fibrosis.

PMID:
42396220
Bibliographic data and abstract were imported from PubMed on 03 Jul 2026.

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