Synthesis and Anticancer Activity of Newly Substituted 1,3,4-Thiadiazole Derivatives: A Novel Class of Anticancer Agents

Background: Cancer-associated inflammation can be initiated by mutations and can contribute to malignant tumors through the recruitment and activation of inflammatory cells. Tumor necrosis factor (TNF, also known as TNF-α) released from macrophages and T-lymphocytes was known in the late 1970s as having the capability to suppress neoplasm cell proliferation and induce tumor regression. Moreover, some of the sulfonamide derivatives are used as TNF-α inhibitors and in the treatment of inflammatory diseases. Methods: In sillico studies were conducted for the synthesis of a novel series of 1,3,4-thiadiazole derivatives comprising sulfonamide to act as anticancer agents. The structures of synthesized compounds were characterized by various spectroscopic methods, such as Infrared, 1H Nuclear magnetic resonance, and Mass spectroscopy. Subsequently, synthesized compounds were tested for in vitro cytotoxicity against MCF-7 human cancer cell lines using the MTT assay. Results: The docking study revealed that the newly synthesized molecules showed greater docking scores and similar interaction as reference molecules like Celecoxib and Sulfasalazine. Compounds 6a and 6c had more binding affinity onto the TNF-α dimer (PDB Id: 2az5) binding surface due to the extra stability of complex as a result of an extra (π-π) stacking and hydrogen-bond interaction with chain A amino acid TYR 59, TYR 151, TYR119, LEU120, GLY121 and chain B amino acid TYR 59, SER 60, GLN 61 than Celecoxib. Synthesized compounds were tested for in vitro cytotoxicity against MCF-7 human cancer cell lines using the MTT assay. In preliminary MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide), cytotoxicity studies of derivatives (6a and 6c) were found to be most effective with IC50 value of 0.052 and 0.047 μM. Conclusion: The synthesized compounds are potential anticancer agents and can be utilized to create novel anticancer drugs, according to the study.