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.