Edinburgh Napier University

  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 IC 50 values over each of the 60 cell lines. The selected candidates exhibited promising activity with mean IC 50 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 IC 50 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 IC 50 76 nM, 32 nM, 35 nM, and 68 nM. The newly developed compounds represent a therapeutically promising approach for the treating various cancer types.