Synthesis and bioevaluation study of novel N-methylpicolinamide and thienopyrimidine derivatives as selectivity c-Met kinase inhibitors.

Four series of N -methylpicolinamide moiety and thienopyrimidine moiety bearing pyridazinone were designed and synthesized and evaluated for the IC 50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Three compounds ( 35 , 39 and 43 ) showed more active than positive control Foretinib against A549, HepG2 and MCF-7 cell lines. The most promising compound 43 showed superior activity against A549, HepG2 and MCF-7, with the IC 50 values of 0.58 ± 0.15 µM, 0.47 ± 0.06 µM and 0.74 ± 0.12 µM, which were 3.73–5.39-fold more activity than Foretinib, respectively. The experiments of enzyme-based showed that 43 restrain the c-Met selectively, with the IC 50 values of 16 nM, which showed equal activity to Foretinib (14 nM) and better than the compound 5 (90 nM). Moreover, AO and Annexin V/PI staining and docking studies were carried out. [ABSTRACT FROM AUTHOR]