Discovery, synthesis and molecular substantiation of N-(benzo[d]thiazol-2-yl)-2-hydroxyquinoline-4-carboxamides as anticancer agents

Abstract

The effort was taken to develop a series of benzothiazole and quinoline fused bioactive compounds obtained through a four-step synthetic route using a range of substituted acetoacetanilides. Achieved N-(benzo[d]thiazol-2-yl)-2-hydroxyquinoline-4-carboxamides (6a-l) were produced up to 96% of yield while the eco-friendly p-TSA used as a catalyst. Further, the anticancer activity of these compounds was determined using a range of cancer cell lines starting from MCF-7 (Breast cancer), HCT-116 (Colon cancer), PC-3 & LNCaP (Prostate) and SK-HEP-1 (Liver cancer). Present study compounds were also testified for antioxidant properties prior to anticancer studies since the Reactive Oxygen Species (ROS) being vital in cancer development. To determine the cell membrane stability effects of the compounds, human red blood cells (HRBC) based membrane protection assay was determined. In the results, compounds 6a-l were able to produce a dominated result values over PC3 cell lines (Prostate cancer) than the other cell lines used in this study. Since the connectivity of human germ cell alkaline phosphatase (hGC-ALP) in the development of prostate cancer is known, the most active compounds were evaluated for the hGC-ALP inhibition in order to ensure a mechanism of anticancer action of these compounds. The mode of interaction and binding affinity of these compounds was also investigated by a molecular docking study. In the results, 6d, 6i, 6k, and 6l were found with least IC50 values <0.075 µM and highest relative activity of 92%, 90%, and 96% respectively. The need for further animal model evaluation and pre-clinical studies recognized.