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

Ali, Eslam M.H and El-Telbany, Rania Farag A. and Abdel-Maksoud, Mohammed S. and Ammar, Usama M. and Mersal, Karim I. and Zaraei, Sayed-Omar and El-Gamal, Mohammed I. and Choi, Se-In and Lee, Kyung-Tae and Kim, Hee-Kwon and Lee, Kwan Hyi and Oh, Chang-Hyun (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. 113277. ISSN 0223-5234 (

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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.


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