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

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

Authors

Eslam M.H. Ali

Rania Farag A. El-Telbany

Mohammed S. Abdel-Maksoud

Karim I. Mersal

Seyed-Omar Zaraei

Mohammed I. El-Gamal

Se-In Choi

Kyung-Tae Lee

Hee-Kwon Kim

Kwan Hyi Lee

Chang-Hyun Oh



Abstract

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.

Journal Article Type Article
Acceptance Date Feb 1, 2021
Online Publication Date Feb 7, 2021
Publication Date 2021-04
Deposit Date Dec 11, 2022
Journal European Journal of Medicinal Chemistry
Print ISSN 0223-5234
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 215
Article Number 113277
DOI https://doi.org/10.1016/j.ejmech.2021.113277
Keywords BRAFV600E, Imidazol-5-ylpyrimidine, MAPK14, Melanoma, Molecular docking, TNF-α
Public URL http://researchrepository.napier.ac.uk/Output/2973719