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

BRAFV600E mutation has been detected in various malignant tumours. Developing of potent BRAFV600E 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, BRAFV600E kinase inhibitory activity was determined for each derivative. Compounds 15i, 15j, 16a, and 16d were the most potent inhibitors against BRAFV600E 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.

Structural optimization of imidazothiazole derivatives affords a new promising series as B-Raf V600E inhibitors; synthesis, in vitro assay and in silico screening.

BRAF mutation is commonly known in a number of human cancer types. It is counted as a potential component in treating cancer. In this study, based on structural optimization of previously reported inhibitors (3-fluro substituted derivatives of imidazo[2,1-b]thiazole-based scaffold), we designed and synthesized sixteen new imidazo[2,1-b]thiazole derivatives with m-nitrophenyl group at position 6. The electron withdrawing properties was reserved while the polarity was modified compared to previously synthesized compounds (-F). Furthermore, the new substituted group (-NO2) provided an additional H-bond acceptor(s) which may bind with the target enzyme through additional interaction(s). In vitro cytotoxicity evaluation was performed against human cancer cell line (A375). In addition, in vitro enzyme assay was performed against mutated B-Raf (B-Raf V600E). Compounds 13a, 13g and 13f showed highest activity on mutated B-Raf with IC50 0.021, 0.035 and 0.020 µM. All target compounds were tested for in vitro cytotoxicity against NCI 60 cell lines. Compounds 13a and 13g were selected for 5 doses test mode. Moreover, in silico molecular simulation was explored in order to explore the possible interactions between the designed compounds and the B-Raf V600E active site.