Design, synthesis and activity of novel sorafenib analogues bearing chalcone unit

Abstract Two series of sorafenib derivatives ( N -methylpicolinamide-4-oxy) chalcones ( 5a – o , 7a – e ) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR and BRAF kinases. The results indicated that all the compounds showed moderate to good antitumor activity, and the compound 5c showed well cytotoxic activity against HepG2, MCF-7 and PC-3 cell lines with IC 50 values of 0.56 ± 0.83 μM, 3.88 ± 1.03 μM and 3.15 ± 0.81 μM, which were 1.03–6.14-fold more active than sorafenib (3.44 ± 1.50 μM, 3.18 ± 1.43 μM, 3.24 ± 0.45 μM), respectively. The compound 5b showed good activity on VEGFR-2/KDR kinase, and its IC 50 value was 0.72 μM. Structure–activity relationships (SARs) and docking studies indicated that replacement of urea group of sorafenib by chalcone ketones improved the cytotoxic activity, and the results suggested that halogen [3-Br, 4-F] and methoxy (substituted on C-3,4,5 or C-2,3,4 position) substitution was benefit for the activity.