New analogs of 5-substituted-2(1H)-pyridone containing of natural amino acids as potential drugs in idiopathic pulmonary fibrosis. Investigation in silico and preliminary in vitro

The aim of our work was to analyze new functionalized analogues of 5-substituted-2(1<i>H</i>)-pyridone containing of natural amino acids derivatives as a potential drugs in idiopathic pulmonary fibrosis (IPF). The creation of connections with natural amino acids was aimed at obtaining anti-fibrotic compounds with better water solubility, increased hydrophilicity, lower toxicity and better pharmacokinetic properties. For the docking studies the corresponding grid box parameters were used: PARPγ, ALK5 andp38. During our initial research we have synthesized and performed biological <i>in vitro</i> studies for two analogues selected on the basis of molecular modeling: <b>6b</b> and <b>6f</b>. MTT test have been performed to select concentrations of PFD derivatives for subsequent analysis. We have analyzed HLA-DR and CXCR4 expression on fibroblasts and 24 h migration of TGF-β1-stimulated fibroblasts. We have also explored proliferation and production of TGF-β1 as well as IL-17 by CD3/CD28 beads-stimulated PBMCs. Preliminary studies show that the designed compounds exhibit promising potential as anti-fibrotic therapeutics. Therefore, their activity is worth further exploring.