Design, synthesis and molecular modeling of phenyl dihydropyridazinone derivatives as B-Raf inhibitors with anticancer activity

  • Bioorg Chem. 2020 Oct;103:104148. doi: 10.1016/j.bioorg.2020.104148.
Mohamed G Thabit  1 ,  Amany S Mostafa  1 ,  Khalid B Selim  2 ,  Magda A A Elsayed  3 ,  Magda N A Nasr  1
Affiliations
  • 1. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 2. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: [email protected].
  • 3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University, New Dammeitta, Egypt.
PMID: 32763518 DOI: 10.1016/j.bioorg.2020.104148
Abstract

Three new series of phenyl dihydropyridazinone derivatives 4b-8i have been designed, synthesized and evaluated for their Anticancer activity against different Cancer cell lines. Nine compounds showed strong inhibitory activity, among which compound 8b exhibited potent activity against PC-3 cell line with IC50 value of 7.83 µM in comparison to sorafenib (IC50 11.53 µM). Compounds 6a, 6c, 7f-h and 8a-d were further screened for their B-Raf inhibitory activity where seven compounds 7f-h and 8a-d showed high B-Raf inhibition with ranges of IC50 values 70.65-84.14 nM and 24.97-44.60 nM, respectively when compared to sorafenib (IC50 44.05 nM). Among the tested compounds, 8b was the most potent B-Raf Inhibitor with IC50 value of 24.79 nM. Cell cycle analysis of MCF-7 cells treated with 8b showed cell cycle arrest at G2-M phase with significant apoptotic effect. Molecular modeling study was performed to understand the binding mode of the most active synthesized compounds with B-Raf enzyme.

Keywords
Antitumor; B-Raf; Cell cycle analysis; Molecular modeling; Pyridazinone.
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