Synthesis and biological evaluation of sulfonamide derivatives containing imidazole moiety as ALK5 inhibitors

Four series of sulfonamide derivatives (13a–b, 14a–d, 15a–b, and 16a–d) were synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) inhibitory activities. Of these, compounds 13b (IC₅₀ = 0.130 μM) and 15a (IC₅₀ = 0.130 μM) showed the highest inhibitory activities against ALK5 kinase, with activities similar to the positive control LY-2157299. Notably, we discovered that introduction of sulfonamide group at the 2-position of the central imidazole ring significantly increased ALK5 inhibitory activity. Compounds 13b and 15a did not show toxicity in A549 cells up to the maximum concentration of 50 μM, and effectively inhibited TGF-β1-induced Smad-signaling and cell motility in A549 cells. The results indicate that compounds 13b and 15a are worth of further development as anticancer agents.