Synthesis, anticancer properties evaluation and in silico studies of 2-chloro- and 2,2-dichloroacetamides bearing thiazole scaffolds

Abstract

Aim. The study aimed to synthesize and evaluate the anticancer activity of a series of 2-chloro- and 2,2-dichloroacetamides bearing thiazole scaffolds. Particular attention was paid to their cytotoxic effects, chemical properties, and action mechanisms, with a focus on glutathione S-transferase (GST) inhibition as a potential pathway for anticancer activity. Materials and methods. The compounds were synthesized using acylation reactions and characterized via 1H and 13C NMR spectroscopy as well as LC-MS. Their cytotoxicity was assessed using the MTT assay across cancer and pseudo-normal cell lines. Quantum-chemical calculations were performed using DFT, while molecular docking studies analyzed interactions with GST to explore their mechanistic roles. Results. Among the synthesized derivatives, 2-chloroacetamides exhibited significant cytotoxic activity against human acute T cell leukemia (Jurkat) and triple-negative breast cancer (MDA-MB-231) cell lines, as well as Ba/F3 cells with calreticulin mutations. In contrast, 2,2-dichloroacetamides showed negligible activity across all tested cell lines. Quantum-chemical analysis indicated that structural and electronic differences between these two compound classes likely influence their bioactivity. Molecular docking studies revealed higher binding affinities of glutathione-2-chloroacetamide conjugates to GST, compared to the reference glutathione-etacrynic acid complex, suggesting GST inhibition as a potential mechanism underlying their anticancer effects. Conclusions. The synthesized 2-chloroacetamides demonstrate promising potential as anticancer agents, likely due to their ability to form inhibitory conjugates with glutathione, thereby affecting GST activity. These findings underline the importance of further studies to optimize these compounds for therapeutic use.