Design, synthesis, and biological evaluation of novel imidazole derivatives possessing terminal sulphonamides as potential BRAFV600Einhibitors

Abstract

BRAF^V600E mutation has been detected in various malignant tumours. Developing of potent BRAF^V600E inhibitors is considered a leading step in the way to cure different cancer types. In the current work, a series of 38 4-(1H-imidazol-5-yl)pyridin-2-amine derivatives was designed and synthesized using Dabrafenib as a lead compound for structural-guided optimization. The target compounds were evaluated as potential anticancer agents against NCI 60 human cancer cell lines. In 5-dose testing mode, two compounds 14h and 16e were tested to determine their IC₅₀ values over each of the 60 cell lines. The selected candidates exhibited promising activity with mean IC₅₀ values of 2.4 µM and 3.6 µM, respectively. Melanoma cancer cell lines exhibited the highest sensitivity after the treatment with the tested compounds 14h and 16e. The mean IC₅₀ values of compounds 14h and 16e against Melanoma cancer cell lines are 1.8 µM and 1.88 µM, respectively. In addition, BRAF^V600E kinase inhibitory activity was determined for each derivative. Compounds 15i, 15j, 16a, and 16d were the most potent inhibitors against BRAF^V600E with IC₅₀ 76 nM, 32 nM, 35 nM, and 68 nM. The newly developed compounds represent a therapeutically promising approach for the treating various cancer types.

Keywords: Anticancer; BRAF(V600E) inhibitors; Imidazole; Protein kinase inhibitors; SAR.