Design and synthesis of pyrrole–5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones with C-3′ side chains as potent Met kinase inhibitors

Pyrrole–5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones of scaffold 4 with various C-3′ side chains were designed as potent Met kinase inhibitors. Structural optimization led to compounds 10, 20, and 22–24 which demonstrated subnanomolar IC50 values in the biochemical assay. The potent compound 20 inhibited Met with IC50 value of 0.37 nM and the proliferation of MKN45 cells with IC50 of 0.22 μM. It suppressed Met autophosphorylation with the downstream signaling through Gab-1, PLC-γ, FAK, Akt, STAT3, and ERK in cell. Complete inhibition of STAT3 and ERK phosphorylation was observed in MKN45 cells treated with 20 at the concentration of 100 nM. A computation simulation study was performed to reveal the interaction of 20 with Met.