Design, synthesis, docking study, and anticancer evaluation of novel bis-thiazole derivatives linked to benzofuran or benzothiazole moieties as PI3k inhibitors and apoptosis inducers

Abstract

A molecular hybridization approach was used to construct and develop a variety of new bis-thiazoles coupled to benzofuran or benzothiazole moieties as anticancer drugs. The target compounds 6a-f and 7a-f were synthesized by reacting the respective bis-thiosemicarbazones 5a–f with bromoacetylbenzofuran or bromoacetybenzothiazole. Several analytical and spectroscopic techniques were used to characterize all of the products. Using the MTT assay, compounds 6a-f and 7a-f were tested for cytotoxicity against three human tumor cell lines: hepatocellular carcinoma (HEPG-2), colorectal carcinoma colon cancer (HCT-116), and human breast cancer (MCF7). The results showed that 6c and 7e had strong antitumor activity against HePG2, MCF7, and HCT-116, with IC50 values of 6.89, 9.94, and 12.67 µM for 6c and 8.37, 7.31, and 24.86 µM for 7e, respectively, when compared to the standard reference drug, doxorubicin (IC50 =5.50, 5.23 and 8.87 µM, respectively). The most active drugs' enzyme inhibition and cell cycle apoptosis properties were investigated further. Compound 6c's apoptotic and necrotic properties were promising. P53 and cyclinB1 gene expressions were also examined using Western Blot to investigate changes in apoptosis and cell cycle-related protein expression. The results showed up-regulation of P53 and down-regulation of cyclinB1 and were found to be inconsistent with those obtained by chemotherapeutics sorafenib, fluorouracil, and methotrexate. Interestingly, the molecular docking study indicated that chemicals 6c, 6d, and 7e could all be lodged in the active pocket of the 4JPS enzyme via various interactions.