Therapeutic Potential of Benzimidazoisoquinoline Derivatives in Alleviating Murine Hepatic Fibrosis

Abstract

AbstractShort Title: Benzimidazoisoquinoline derivatives as potent antifibrotics Hepatic fibrosis is a pathological condition of liver disease with an increasing number of cases worldwide. Therapeutic strategies are warranted to target the activated hepatic stellate cells (HSCs), the collagen‐producing cells, an effective strategy for controlling the disease progression. Benzimidazoisoquinoline derivatives were synthesized as hybrid molecules by the combination of benzimidazoles and isoquinolines to evaluate their anti‐fibrotic potential using an in‐vitro and in‐vivo model of hepatic fibrosis. A small library of benzimidazoisoquinoline derivatives (1–17 and 18–21) was synthesized from 2‐aryl benzimidazole and acetylene functionalities through C−H and N−H activation. Compounds (10 and its recently synthesized derivatives 18–21) depicted a significant decrease in PDGF‐BB and/or TGFβ‐induced proliferation (1.7–1.9 ‐fold), migration (3.5–5.0 ‐fold), and fibrosis‐related gene expressions in HSCs. These compounds could revert the hepatic damage caused by chronic exposure to hepatotoxicants, ethanol, and/or carbon tetrachloride as evident from the histological, biochemical, and molecular analysis. Anti‐fibrotic effect of the compounds was supported by the decrease in the malondialdehyde level, collagen deposition, and gene expression levels of fibrosis‐related markers such as α‐SMA, COL1α1, PDGFRβ, and TGFRIIβ in the preclinical models of hepatic fibrosis. In conclusion, the synthesized benzimidazoisoquinoline derivatives (compounds 18, 19, 20, and 21) possess anti‐fibrotic therapeutic potential against liver fibrosis.