Synthesis, biological evaluation and 3D-QSAR studies of novel 4,5-dihydro-1H-pyrazole niacinamide derivatives as BRAF inhibitors

A new series of novel 4,5-dihydropyrazole derivatives containing niacinamide moiety were designed, synthesized and evaluated for biological activities as potential V600E mutant BRAF kinase (BRAFV600E) inhibitors. Among these compounds, 27e ((5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)6-methylpyridin-3-yl methanone) showed the most potent agent against BRAF and WM266.4 human melanoma cell line with IC50 value of 0.20 μM and GI50 value of 0.89 μM. Docking simulation was performed to insert compound 27e into the crystal structure of BRAF to determine the probable binding model. QSAR model was also built to provide a reliable tool for rational design of novel BRAF inhibitors.