Design, biological evaluation and 3D QSAR studies of novel dioxin-containing triaryl pyrazoline derivatives as potential B-Raf inhibitors

• 20 pyrazoline derivatives have been synthesized and all are novel except C1.
• Their anti-cancer activities were evaluated for the first time.
• Selectivity and cytotoxicity of representative compounds were tested.
• Molecular docking and QSAR discussions indicated breaking the limit of previous pattern to get the most potent C6.

A series of novel dioxin-containing triaryl pyrazoline derivatives C1–C20 have been synthesized. Their B-Raf inhibitory and anti-proliferation activities were evaluated. Compound C6 displayed the most potent biological activity against B-RafV600E and WM266.4 human melanoma cell line with corresponding IC50 value of 0.04 μM and GI50 value of 0.87 μM, being comparable with the positive controls and more potent than our previous best compounds. Moreover, C6 was selective for B-RafV600E from B-RafWT, C-Raf and EGFR and low toxic. The docking simulation suggested the potent bioactivity might be caused by breaking the limit of previous binding pattern. A new 3D QSAR model was built with the activity data and binding conformations to conduct visualized SAR discussion as well as to introduce new directions. Stretching the backbone to outer space or totally reversing the backbone are both potential orientations for future researches.

A series of novel dioxin-containing triaryl pyrazoline derivatives C1–C20 have been synthesized with their B-Raf inhibitory activity and anti-proliferation activity tested. Selectivity and cytotoxicity of representative compounds have been tested. The docking simulation and 3D QSAR model indicated breaking the limit of previous binding pattern.Figure optionsDownload as PowerPoint slide