Therapeutic Potential of Benzimidazoisoquinoline Derivatives in Alleviating Murine Hepatic Fibrosis
CHEMISTRY & BIODIVERSITY(2024)
Abstract
Short 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 TGF beta-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 alpha-SMA, COL1 alpha 1, PDGFR beta, and TGFRII beta 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.
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Key words
Anti-fibrotic compounds,Benzimidazoisoquinoline derivatives,CCl4- and Ethanol-induced liver disease,Hepatic fibrosis,Hepatic Stellate Cell activation
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