Novel Thiazole-Hydrazide Derivatives and Their Anticancer Properties

Objective: Cancer is described as uncontrolled cell division, and it is a major problem in Türkiye, as well as around the world. Current treatment options are insufficient in some cases, particularly the treatment rate for lung cancer cases, which is very low. Meanwhile, current pharmaceuticals have several side effects, such as drug-drug interactions, and cognitive disorders. Additionally, developing drug resistance is a major problem for current and future management of the disease. Accordingly, the search for new molecules or alternative treatment options is actively achieved. Methods: In this study, eight novel thiazole-hydrazide analogs were designed and synthesized, and their structural elucidation was performed via HRMS, 1H-NMR, and 13C-NMR. Their biological activity profile was investigated on A549 lung carcinoma and MCF7 breast adenocarcinoma cells. To determine the selective cytotoxicity on cancer cells, they were also tested against NIH/3T3 healthy cell line. Besides that, an in silico study was performed to understand the binding modes of the compounds. Results: The results showed that in the serial 4f and 4g, the most bulky analogues, showed no inhibition against any cell type, even at the highest concentration tested. On the other hand, 4a, 4b, 4d, 4e, and 4h showed less cytotoxicity on healthy cells than A549 cells, so they exhibited significant cytotoxicity and a selective profile against A549 cancer cells. While they also inhibited MCF7 cells. The major point is that para-chlorophenyl analogs at the fourth position on thiazole (4a and 4d) displayed a better anticancer profile than ortho-chlorophenyl analogs. These two compounds were also investigated for their apoptotic effects using in silico studies. Both experimental and in silicon studies revealed that the combination of thiazole and hydrazinoacetyl has a significant impact against cancer cells, and in silico study also suggested that tri-substitute thiazole ring has anticancer potential that induced cancer cell death via apoptosis. Conclusion: Results of this study was presented that compound 4a was the most potent compound against lung cancer cells (A549) and 4d was the most potent compound against breast cancer cells (MCF-7). Furthermore, analyzing the molecular docking study for promising compounds (4a and 4d) suggested that interactions with the loop region residues have a pivotal role in inducing caspase-3 enzyme activity. It was concluded that hybridization of thiazole and hydrazinoacetyl moieties is responsible for the anticancer activity.