Synthesis, in vitro antiproliferative activity, and kinase inhibitory effects of pyrazole-containing diarylureas and...

Twenty pyrazole-containing diarylureas and diarylamides were designed and synthesized. They were tested for in vitro antiproliferative activity over a 58-cancer cell line panel at the NCI, USA. The diarylurea derivatives 1b-e and 1g exerted the strongest antiproliferative activity. Among them, compound 1e possessing 3,5-bis(trifluoromethyl)phenyl terminal ring and 3`-methoxy-5`-chlorophenyl ring attached to the central pyrazole ring was the most potent. Its IC₅₀ values were in sub-micromolar range against most of the tested cell lines. It showed superior potency than sorafenib, a reference diarylurea drug, over all the tested cell lines. It was also extremely selective towards cancer cells than non-cancerous cells (IC₅₀ against RAW 264.7 macrophages was higher than 100 μM). At molecular level, compound 1e selectively inhibited V600E mutated B-RAF kinase (IC₅₀ = 0.39 μM). It also stimulated caspase 3/7 enzymes in RPMI-8226 leukemia cells (2.79 fold increase at 10 μM concentration, EC₅₀ = 1.52 μM). So compound 1e may kill cancer cells through induction of apoptosis. This promising candidate can be considered further for development of new efficient anticancer agents.