Synthesis, in silico and pharmacological evaluation of 2-pyridin-acetamides as tyrosine kinase inhibitors

A new synthesis of 2-pyridineacetamides was developed starting from pyran-2-one N-functionalized amidines. Secondary amines reacted in a sealed tube with the above-mentioned amidines and, by nucleophilic attack on pyran-2-one nucleus and thermal rearrangement, afforded exclusively the desired 2-pyridineacetamide derivatives. Such compounds have been pharmacologically tested on smooth muscular cells proliferation and resulted active with an IC50 ranging from 40 to 0.7 µM. With the aid of molecular modeling tools a potential mechanism of action has been proposed. The pharmacological activity seems to be due to tyrosine kinase receptors inhibition. In silico experiments shows a notable selectivity toward the epidermal derived growth factor receptor kinase (EGFRK) and the platelet derived growth factor receptor kinase (PDGFRK) if compared with the vascular endothelial derived growth factor receptor kinase (VEGFRK) and the fibroblast derived growth factor receptor kinase (FGFRK). The predicted potency of the 2-pyridineacetamides described in the present study is comparable to that of known EGFRK inhibitor TarcevaTM. Preliminary pharmacological experiments conducted on rat's aorta smooth muscular cells confirm the observed computational results.