Abstract

Background: Cancer is one of the leading causes of morbidity and mortality worldwide and extensive efforts have been devoted to the discovery of new anticancer agents. In the last few decades, the clinical efficacy of tiazofurin and its analogues, dasatinib and bleomycins has pointed out the importance of thiazole moiety in the field of cancer treatment.

Methods: In the present paper, some thiazolyl hydrazone derivatives were synthesized and evaluated for their cytotoxic effects on A549 human lung adenocarcinoma, C6 rat glioma and NIH/3T3 mouse embryonic fibroblast cell lines using MTT assay. The most effective compounds were also investigated for their effects on DNA synthesis, apoptosis and mitochondrial membrane potential. In order to investigate the relationship between anticancer activity and cholinesterases, all compounds were evaluated for their ability to inhibit AChE and BuChE using a modification of Ellman’s spectrophotometric method.

Results: Generally, the compounds showed more potent inhibitory effects on C6 cells than A549 cells. 2- [2-(4-(1H-1,2,4-Triazol-1-yl)benzylidene)hydrazinyl]-4-(4-nitrophenyl)thiazole (2) was the most promising agent due to its notable inhibitory effect on C6 cells with an IC50 value of 13.00±1.00 μg/mL when compared with cisplatin (IC50= 12.67±3.06 μg/mL) and low cytotoxicity against NIH/3T3 cell line (IC50= 733.33±256.58 μg/mL). DNA synthesis inhibition percent of compound 2 was 62.2%, whereas the inhibition percent of cisplatin was 53.95%. Compound 2 increased early and late apoptotic cell population (18.3%) more than cisplatin (16.3%). This compound also caused disturbance on mitochondrial membrane potential (40.2%) in C6 cells, which was similar to cisplatin (42.3%).

Conclusion: Compound 2, the most promising antitumor agent against C6 cells in this series, did not show any inhibitory activity against AChE and BuChE. This outcome pointed out that there is no relationship between the anticancer activity of compound 2 and cholinesterases.

Keywords: Thiazole, imidazole, triazole, cancer, DNA synthesis, apoptosis, mitochondrial membrane potential, acetylcholinesterase, butyrylcholinesterase.

Graphical Abstract