Several trifluoromethylquinoline derivatives containing a biologically active benzenesulfonamide moiety 2-14, 16, urea derivatives 15, 17, 4-isothiocyanate 18 and the corresponding carbamimidothioic acid derivatives 19-30, were synthesized from the strategic starting material 4-chloro-7-trifluoromethylquinoline 1. The structures of the newly synthesized compounds were elucidated on the basis of elemental and spectral analyses. All the prepared compounds were evaluated for their in vitro anticancer activity against various cancer cell lines. Most of the synthesized compounds showed good activity, especially compound 15 which exhibited higher activity than the reference drug doxorubicin. In order to suggest the mechanism of action for their cytotoxic activity, molecular docking for all synthesized compounds was done on the active site of PI3K and good results were obtained.