Novel series of substituted furan (7b-d, 8b-d), furo[2,3-d]pyrimidine (14a-d), and furo[3,2-e][1,2,4] triazolo[1,5-c]pyrimidine (15a-d) were synthesized and evaluated for their in vitro anticancer activity in the full NCI 60 cell lines panel assay. Six compounds showed promising growth inhibitory activity (55.73-174.62%). Compound 8d displayed the highest growth inhibitory activity toward numerous cell lines with a superior growth inhibitory activity (174.62%) against LOXIMVI melanoma cell line in which BRAF kinase is highly expressed. Moreover, compound 8d was further screened for BRAF kinase inhibitory activity and revealed IC50=47.61 ng/ml compared to vemurafenib (IC50= 18.41ng/ml). Interestingly, in vitro cytotoxicity of 8d against LOXIMVI cells showed comparable IC50=10.19 ug/ml with vemurafenib (IC50= 5.44 ug/ml). Furthermore, the cell cycle analysis of 8d at LOXIMVI cells revealed cell cycle arrest at pre-G1 and S phases. The flow cytometry analysis showed that 8d induced apoptosis and necrosis on LOXIMVI cells with significant higher percentage than the control.