Synthesis and biological evaluation of 4-oxoquinoline-3-carboxamides derivatives as potent anti-fibrosis agents

Thirty-one 4-oxoquinoline-3-carboxamides derivatives were synthesized and evaluated for their anti-fibrotic activities by the inhibition of TGF-beta 1-induced total collagen accumulation and anti-inflammatory activities by the inhibition of LPS-stimulated TNF-alpha production. Among them, three compounds (10a, 10l and 11g) exhibited potent inhibitory effects on both TGF-beta 1-induced total collagen accumulation and LPS-stimulated TNF-a production. Furthermore, oral administrations of 10l at a dose of 20 mg/kg/day for 4 weeks effectively alleviated lung inflammation and injury, and decreased lung collagen accumulation in bleomycin-induced pulmonary fibrosis model. Histopathological evaluation of lung tissue confirmed 10l as a potential, orally active agent for the treatment of pulmonary fibrosis. (C) 2014 Elsevier Ltd. All rights reserved.