title: Synthesis, biological evaluation and 3D-QSAR studies of novel 4,5-dihydro-1H-pyrazole niacinamide derivatives as BRAF inhibitors.
abstract: A series of novel 4,5-dihydropyrazole derivatives containing niacinamide moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. Results of the bioassays against BRAF(V600E) and WM266.4 human melanoma cell line showed several compounds to be endowed potent activities with IC(50) and GI(50) value in low micromolar range, among which compound 27e, (5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)6-methylpyridin-3-yl methanone (IC(50)=0.20 μM, GI(50)=0.89 μM) was bearing the best bioactivity comparable with the positive control Sorafenib. Docking simulation was performed to determine the probable binding model and 3D-QSAR model was built to provide more pharmacophore understanding that could use to design new agents with more potent BRAF(V600E) inhibitory activity.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
authors.forename: Cui-Yun
authors.initials: CY
authors.lastname: Li
authors.forename: Qing-Shan
authors.initials: QS
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.forename: Xiao-Guang
authors.initials: XG
authors.lastname: Sun
authors.forename: Ran
authors.initials: R
authors.lastname: Wei
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Gong
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009536:Niacinamide / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D014407:Tumor Cells, Cultured
chemical_list: D047428:Protein Kinase Inhibitors; D009536:Niacinamide; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf