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Design, synthesis, biological evaluation, and docking studies of novel (imidazol-5-yl)pyrimidine-based derivatives as dual BRAFV600E/p38α inhibitors
  The synergistic effect of dual inhibition of serine/threonine protein kinases that are involved in the same signalling pathway of the diseases can exert superior biological benefits for treatment of these diseases. In the present work, a new series of (imidazol-5-yl)pyrimidine was designed and synthesized as dual inhibitors of BRAF V600E and p38a kinases which are considered as key regulators in mitogen-activated protein kinase (MAPK) signalling pathway. The target compounds were evaluated for dual kinase inhibitory activity. The tested compounds exhibited nanomolar scale IC 50 values against BRAF V600E and low to sub-micromolar IC 50 range against p38a. Compound 20h was identified as the most potent dual BRAF V600E /p38a inhibitor with IC 50 values of 2.49 and 85 nM, respectively. Further deep investigation revealed that compound 20h possesses inhibitory activity of TNF-a production in lipopolysaccharide-induced RAW 264.7 macrophages with IC 50 value of 96.3 nM. Additionally, the target compounds efficiently frustrated the proliferation of LOX-IMVI melanoma cell line. Compound 20h showed a satisfactory antiproliferative activity with IC 50 value of 13 mM, while, compound 18f exhibited the highest cytotox-icity potency with IC 50 value of 0.9 mM. Compound 18f is 11.11-fold more selective toward LOX-IMVI melanoma cells than IOSE-80PC normal cells. The newly reported compounds represent therapeutically promising candidates for further development of BRAF V600E /p38a inhibitors in an attempt to overcome the acquired resistance of BRAF mutant melanoma.

  • Type:


  • Date:

    07 February 2021

  • Publication Status:


  • Publisher

    Elsevier BV

  • DOI:


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  • Funders:

    Historic Funder (pre-Worktribe)


Ali, E. M., El-Telbany, R. F. A., Abdel-Maksoud, M. S., Ammar, U. M., Mersal, K. I., Zaraei, S., …Oh, C. (2021). Design, synthesis, biological evaluation, and docking studies of novel (imidazol-5-yl)pyrimidine-based derivatives as dual BRAFV600E/p38α inhibitors. European Journal of Medicinal Chemistry, 215, Article 113277.



BRAFV600E, Imidazol-5-ylpyrimidine, MAPK14, Melanoma, Molecular docking, TNF-α

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