Novel hybrid benzoisothiazole-1,2,3-triazole-4-carboxamides with sub-micromolar toxicity towards human breast carcinoma cells and high affinity to DNA

Abstract

A pharmacophore hybridization strategy to combine biologically active scaffolds was implemented for design and synthesis of benzoisothiazole-1,2,3-triazole-4-carboxamide conjugates via piperazine linker. In vitro screening led to identification of the compounds 5h and 5j, with para-chlorine- or fluorine- substitution on the phenyl ring, and isopropyl or cyclopropyl substituents in position 5 of 1,2,3-triazole cycle as potent anticancer agents. These compounds demonstrated toxicity towards human breast adenocarcinoma cells of the MCF-7 line in sub-micromolar concentrations with IC50 = 0.76 ± 0.04 μM and 0.90 ± 0.02 μM, respectively, while showing no toxicity in normal cells (IC50 > 100 μM). Colony formation and proliferation of carcinoma MCF-7 cells were effectively inhibited by the derivatives 5h and 5j. These derivatives caused DNA fragmentation of the MCF-7 cells. We suggest that the DNA-damaging action of the compounds 5h and 5j may be related to their high capability of intercalating into DNA molecule that is comparable to such ability of known anticancer agent – the doxorubicin. High affinity of the compounds 5h and 5j for the DNA was confirmed using computational molecular docking in silico.