2. Academic Validation
  3. Design, synthesis and biological evaluation of novel 5-phenyl-1H-pyrazole derivatives as potential BRAF(V600E) inhibitors

Design, synthesis and biological evaluation of novel 5-phenyl-1H-pyrazole derivatives as potential BRAF(V600E) inhibitors

  • Bioorg Med Chem. 2014 Nov 1;22(21):6201-8. doi: 10.1016/j.bmc.2014.08.029.
Shu-Fu Wang 1,  Yin-Ling Zhu 1,  Ping-Ting Zhu 1,  Jigar A Makawana 1,  Ya-Liang Zhang 1,  Meng-Yue Zhao 1,  Peng-Cheng Lv 1,  Hai-Liang Zhu 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China. Electronic address: zhuhl@nju.edu.cn.
PMID: 25267006 DOI: 10.1016/j.bmc.2014.08.029
Abstract

A series of novel 5-phenyl-1H-pyrazole derivatives (5 a-5 u) containing niacinamide moiety were synthesized and evaluated for biological activity as potential BRaf(V600E) inhibitors. Among them, compound 5h exhibited the most potent inhibitory activity with an IC50 value of 0.33 μM for BRaf(V600E). Antiproliferative assay results indicated that compound 5h has better antiproliferative activity against WM266.4 and A375 in vitro with IC50 value of 2.63 and 3.16 μM, respectively, being comparable with the positive control vemurafenib. Molecular docking of 5h into the BRaf(V600E) active site was performed to determine the probable binding mode. Furthermore, molecular docking and 3D QSAR study by means of DS 3.5 (Discovery Studio 3.5, Accelrys, Co. Ltd) explored the binding modes and the structure and activity relationship (SAR) of these derivatives.

Keywords

3D-QSAR; BRAF(V600E) inhibitor; Molecular docking; Niacinamide; Pyrazole.

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