Design, synthesis, biological evaluation, and docking studies of novel (imidazol-5-yl)pyrimidine-based derivatives as dual BRAFV600E/p38α inhibitors

Eslam M.H Ali, Rania Farag A. El-Telbany, Mohammed S. Abdel-Maksoud, Usama M. Ammar, Karim I. Mersal, Sayed-Omar Zaraei, Mohammed I. El-Gamal, Se-In Choi, Kyung-Tae Lee, Hee-Kwon Kim, Kwan Hyi Lee, Chang-Hyun Oh

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1 Citation (Scopus)


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 BRAFV600E and p38α 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 IC50 values against BRAFV600E and low to sub-micromolar IC50 range against p38α. Compound 20h was identified as the most potent dual BRAFV600E/p38α inhibitor with IC50 values of 2.49 and 85 nM, respectively. Further deep investigation revealed that compound 20h possesses inhibitory activity of TNF-α production in lipopolysaccharide-induced RAW 264.7 macrophages with IC50 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 IC50 value of 13 μM, while, compound 18f exhibited the highest cytotoxicity potency with IC50 value of 0.9 μM. 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 BRAFV600E/p38α inhibitors in an attempt to overcome the acquired resistance of BRAF mutant melanoma.
Original languageEnglish
Article number113277
Number of pages16
JournalEuropean Journal of Medicinal Chemistry
Early online date7 Feb 2021
Publication statusPublished - 5 Apr 2021


  • BRAFV600E
  • imidazol-5-ylpyrimidine
  • MAPK14
  • melanoma
  • molecular docking
  • TNF-α


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