title: Substituted quinazolinones as kinase inhibitors endowed with anti-fibrotic properties.
abstract: Some new 3-substituted quinazolinones were synthesized and evaluated as inhibitors of kinases involved in fibrogenic process. The compounds were tested against a panel of both tyrosine and serine-threonine kinases. The profile of selectivity of some representative compounds was investigated through molecular docking studies. The most interesting compounds were also evaluated in vitro as potential agents for the treatment of fibrotic diseases. Quinazolinone derivatives reduced proliferation and expression of genes involved in the fibrogenic process in hepatic stellate cells (HSCs) and intestinal subepithelial myofibroblasts (ISEMFs). Furthermore some compounds downregulated phosphorylation of p38MAPK. Our findings provide evidences that 3-substituted quinazolinones target multiple essential pathways of the fibrogenic process.
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy. Electronic address: giovanni.marzaro@unipd.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marzaro
authors.affiliation: Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35121 Padova, Italy.
authors.forename: Ignazio
authors.initials: I
authors.lastname: Castagliuolo
authors.affiliation: Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35121 Padova, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Schirato
authors.affiliation: Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35121 Padova, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palu'
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Dalla Via
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Chilin
authors.affiliation: Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35121 Padova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Brun
mesh_terms: D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005355:Fibrosis / Q000188:drug therapy*; D062105:Molecular Docking Simulation; D052999:Quinazolinones / Q000627:therapeutic use*
chemical_list: D004791:Enzyme Inhibitors; D052999:Quinazolinones
keywords: Fibrosis; Multi kinase inhibitors; Quinazolinones; Tyrosine kinases