Design, synthesis and evaluation of novel 2-(1H-imidazol-2-yl) pyridine Sorafenib derivatives as potential BRAF inhibitors and anti-tumor agents

• Two series of Sorafenib derivatives were designed and synthesized.
• Most compounds were identified as potent BRAF inhibitors.
• Most compounds displayed potent antiproliferative activity.
• Two compounds (CLW14 and CLW27) showed good in vivo activities.

A series of 2-(1H-imidazol-2-yl) pyridine derivatives (CLW01–CLW31) have been designed and synthesized, and they were screened for BRAF kinase inhibitory activity. Besides, their biological activities were evaluated in vitro and in vivo. All the compounds were reported for the first time, and compounds CLW14 and CLW27 displayed the most potent antiproliferative activity against cell line A375 in vitro, with IC50 values of 4.26 and 2.93 μM, respectively, which were comparable with the positive control Sorafenib. Those two compounds were further evaluated for the in vivo efficacy using an A375 xenograft nude mice model. The results showed that the growth of A375 cancer cells xenografts was suppressed by factors of 35.68% and 42.50% (percent tumor growth inhibition values) after intragastric (ig) administration of compound CLW14 and CLW27 at concentration of 50 mg/kg. Thus they may be promising lead compounds to be developed as an alternative for current Sorafenib therapy.

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