In Vitro and In Silico Study to Assess Toxic Mechanisms of Hybrid Molecules of Quinone-Benzocaine as Plastoquinone Analogues in Breast Cancer Cells

[Image: see text] We managed to obtain three different series of 2,3-dimethyl-1,4-benzoquinones, named nonhalogenated and halogenated (brominated and chlorinated) PQ analogues, via the molecular hybridization strategy. Sixteen of eighteen hybrid molecules were selected by the National Cancer Institute (NCI) of Bethesda for their in vitro antiproliferative potential against the full NCI 60 cell line panel. The hybrid molecules (BrPQ5, CIPQ1, and CIPQ3) showed good growth inhibition at 10 μM concentration, particularly against breast cancer cell lines. As per the results obtained from in vitro antiproliferative evaluation, cytotoxic activities of the hybrid molecules (BrPQ5, CIPQ1, and CIPQ3) were evaluated with an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in T47D and MCF7 breast cancer and human umbilical vein endothelial (HUVEC) cells. Molecules exhibited cytotoxic activity, and especially, CIPQ1 showed remarkable cytotoxic activity and good selectivity on T47D and MCF7 cells. Furthermore, CIPQ1 could inhibit cell proliferation, cause apoptotic cell death and disturb the cell cycle in T47D and MCF7 cells. Additionally, CIPQ1 caused oxidative stress induction in both cells, more so in T47D. In vitro study results indicated that the anticancer activity of CIPQ1 was more prominent in T47D cells than in MCF7 cells. The compound CIPQ1 showed a prominent binding with JNK3 in silico. Thus, the obtained hybrid molecules via the molecular hybridization strategy of two important pharmacophores could be useful in the discovery of novel antiproliferative agents, and CIPQ1 could be considered a promising drug candidate.