Novel 2-oxo-tetrahydropyrimidine derivatives as BRAFV600E inhibitors targeting melanoma: Design, synthesis and anticancer activity

Document Type : Original research articles

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Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11884, Egypt

Abstract

Pyrimidine-based scaffolds have been shown to have anticancer effect and to suppress BRAFV600E kinase activity. Therefore, in this research, a new series of 2-oxo-tetrahydropyrimidine 2a-f was synthesized. The structures of the newly synthesized compounds were validated using Fourier transform infrared (FT-IR), Proton nuclear magnetic resonance (1HNMR), Carbon-13 nuclear magnetic resonance (13CNMR), mass spectroscopy and elemental analysis. In vitro testing was performed on all derivatives against BRAFV600E enzyme, in comparison with Vemurafenib to determine their enzyme inhibitory activity. The results revealed that all derivatives inhibited BRAFV600E enzyme with variable values (IC50= 0.53±0.023 - 5.717±0.242 μM). Compound 2e was the most potent among the series showing moderate activity (IC50= 0.53±0.023 μM) relative to the reference drug (IC50= 0.052±0.003 μM). Furthermore, compound 2e was subjected to in vitro cytotoxicity study against melanoma cell WM266.4. The cytotoxic study indicated that compound 2e has a reasonable anticancer activity (IC50= 19.58±0.7 μM), relative to Vemurafenib (IC50= 7.681±.0.3μM). Molecular docking analysis against BRAFV600E kinase proved excellent fitting inside the binding site. Compound 2e could be identified as a promising candidate for further research.

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