Melanoma is one of the most serious types of skin cancer. It causes more than 80% of skin cancer deaths. In the majority of melanomas, the mitogen-activated protein kinase (MAPK; RAS-RAF-MEK-ERK) is over expressed. The discovery of BRAFV600E mutations in approximately 50% of melanoma cells, made BRAFV600E inhibitors one of the first choices for targeted therapy. In this study, a series of new chalcones and chalcones based heterocyclic compounds, containing a sulfonyl moiety were designed, synthesized and evaluated for their in-vitro anticancer activity against WM266.4 human melanoma cell line. compounds 4a, 7a, 8a and 9b showed the most potent cytotoxic effect (IC50 ranging from 0.3 to 0.52 μM). For further investigations, the most active compounds were evaluated as BRafV600E enzyme inhibitors. compounds 4a, 4b, 7a and 8a displayed the most potent activity (IC50= 12.65 – 50.23 nM), compared to the reference drug sorafenib, (IC50= 57.8 nM). Docking studies of the synthesized compounds into the active site of BRaf V600E enzyme were performed to predict their affinities toward this enzyme, and hence the proposed binding mode and the mode of action could be deduced.