c-Met/DDR1 Dual-Target Tyrosine Kinase Inhibitor Featuring an Imidazo[1,2-A]pyridine Core

Abstract

In this contribution, we report the design, synthesis, and bioactivity evaluation of a novel class of dual-target tyrosine kinases inhibitors (TKIs). By linking imidazo[1,2-a]pyridines with a commonly used cyclopropanecarboxylic acid pharmacophore fragment, a number of novel potential TKIs were synthesized. Aryl and heteroaryl side chains with different electron-withdrawing groups and electron-donating groups were introduced to the imidazo[1,2-a]pyridine ring to evaluate the inhibitory effects against Huh-7 and HepG2 tumor cells. The research results showed that compound 10a with a pyridine side-chain exhibited better in vitro inhibitory effects against Huh-7 and HepG2 cells than cabozantinib. Cell cloning and cell scratch experiments indicated that 10a significantly hampered the tumor cell proliferation and migration and exhibited comparable cytotoxicity against normal cells. Through a selectivity profile study on a 217 kinase panel, cellular-mesenchymal epithelial transition factor (c-Met) and discoidin domain receptor 1 (DDR1) were identified to be the potential targets of compound 10a.