Dichloroacetate (DCA) as a small, cheap and available anticancer agent, is a pyruvate mimetic compound that stimulates the activity of pyruvate dehydrogenase (PDH) enzyme through inhibition of pyruvate dehydrogenase kinases (PDHK1-4). DCA turns on programed cell death (apoptosis) which suppressed in tumor cells and therefore inhibits tumor growth. DCA also interferes with the glucose uses of cancer cell, ravenous the cell of energy, but it does not starve normal cells of glucose. In the present study, using a novel synthetic method, we synthesized a series of N-phenyl-2,2-dichloroacetamide derivatives and evaluated their cytotoxic activities against various human cancer cell lines including NCI-H460 (lung cancer), HCA-7 (colon cancer) and MCF-7 (breast cancer). Toxicity risk factors of each compound were calculated. Docking studies were also done to find their binding site to PDHK receptor. The result showed that all synthesized compounds had an acceptable anti-cancer activity. Among them, the best compound was 2,2-dichloro-N-(3-((trifluoromethyl)sulfonyl) phenyl) acetamide (25) which had an IC50 of 6.5 μM against NCI-H460 cells, 10.5 μM against HCA-7 cells and 9.4 μM against MCF-7 cells. Toxicity risk factors studies have also implied that this compound is the best one in this series. Therefore, compound 25 might have a potential value for further study in drug development.