Design, Synthesis, and Antifibrotic Evaluation of Silicon-Incorporated Alkyl Hydrazide Analogs of Tubastatin A: HDAC3 Selective Inhibitor for Ameliorating Liver Fibrosis

Abstract Liver fibrosis remains a significant therapeutic challenge, with limited effective treatments and few clinically viable HDAC inhibitors despite their antifibrotic potential. Here, we report the design of silicon-incorporated alkyl hydrazide analogs of tubastatin-A to develop selective HDAC3 inhibitors via cap and zinc-binding motif optimization. These compounds were evaluated for HDAC-selectivity and antifibrotic activity in TGF-β-induced HSC-LX2 and HHSEC models, where 6b exhibited potent and selective HDAC3 inhibition (IC50-22 nM) with respect to HDAC5, HDAC6, HDAC8 along with robust antifibrotic activity, supported by molecular docking. ADMET studies indicated a favourable pharmacokinetic profile, permeability, microsomal stability, and a promising safety profile. Further validation in a CCl4-induced hepatic-fibrosis model, 6b demonstrated significant in-vivo efficacy by reducing AST/ALT levels, fibrotic marker expression and improving histopathology, outperforming tubastatin-A and nintedanib. Mechanistically, 6b significantly inhibited TGF-β/Smad signaling, likely through modulation of histone-acetylation patterns. Collectively, these findings identify 6b as a promising lead candidate for hepatic fibrosis.