Design, synthesis and biological evaluation of (1,3-diphenyl-1H-pyrazol-4-yl) methyl benzoate derivatives as potential BRAFV600E inhibitors

Abstract

A series of (1,3-diphenyl-1H-pyrazol-4-yl) methyl benzoate derivatives (6a–10d) were designed, synthesized and evaluated as BRAF^V600E inhibitors. Biological evaluation assays indicated that compound 10a showed the most potent inhibitory activity against A375, WM266.4 and BRAF^V600E in vitro with IC₅₀ values of 1.36 μM, 0.94 μM and 0.11 μM respectively compared with the positive compound vemurafenib. Furthermore, compound 10a showed highly selective BRAF^V600E inhibitory activity in vitro. A docking simulation displayed that compound 10a could tightly bind the crystal structure of BRAF^V600E at the active site. 3D-QSAR would provide a guideline to design and optimize more potent and positive BRAF^V600E inhibitors based on the (1,3-diphenyl-1H-pyrazol-4-yl) methyl benzoate derivatives skeleton.