Evaluation of genotoxic effects of 3-methyl-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione on human peripheral lymphocytes.

CONTEXT: Tranexamic acid is commonly used for curing abnormal bleeding in a variety of diseases. In a previous study, 12 different tetrahydro-2H-1,3,5-thiadiazine derivatives were synthesized from the amine group of tranexamic acid. Their antifibrinolytic and antimicrobial activities were compared with tranexamic acid. 3-Methyl-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (3-MTTT) was the most remarkable one, which may be used as a drug. OBJECTIVES: In vitro genotoxicity of 3-MTTT was investigated using chromosome aberrations (CAs), sister chromatid exchanges (SCEs), micronucleus (MN) and comet assays. MATERIALS AND METHODS: Various concentrations 0.78, 1.56, 3.13, 6.25, 12.50 and 25.00 µg/mL of 3-MTTT were applied to lymphocytes obtained from two donors for periods of 24 and 48 h. A negative (distilled water), a solvent (2:1 PBS:10% NaOH for cultured lymphocyte, and PBS for isolated lymphocytes) and a positive control (MMC for cultured lymphocytes and H2O2 for isolated lymphocytes) were also maintained. RESULTS: While this compound did not increase the frequency of abnormal cells and CA/cell ratio compared to negative control (except 48 h, 25 µg/mL), it significantly increased the frequency of SCEs at the four highest concentrations at both treatment periods (except 6.25 µg/mL, 48 h). It significantly decreased the MI in all the concentrations at 24 h (except 0.78 µg/mL) and in the highest three concentrations at 48 h. This compound did not significantly increase the frequency of MN and DNA damage compared to negative control. This compound did not affect the replication and nuclear division index. DISCUSSION AND CONCLUSION: Our results demonstrated that this compound does not represent a significant risk at the genetic level in in vitro human lymphocytes.

Synthesis of 3-substituted-5-(4-carb oxycyclohexylmethyl) - tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives as antifibrinolytic and antimicrobial agents.

A series of 3-substituted-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5thiadiazine-2-thione derivatives was prepared and examined for antifibrinolytic and antimicrobial activities. Their structures were elucidated by spectral methods. Antifibrinolytic activities of these compounds, were investigated in vitro and compared to tranexamic acid (CAS 1197-18-8). Among the synthesized compounds, 3-methyl-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Ia) was the most prominent one (104%) when compared to tranexamic acid. Besides, 3-ethyl-5-(4-carboxycyclohexyl-methyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Ib), 3-iso-propyl-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Id) and 3-isobutyl-5-(4-carboxycyclohexyl-methyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Ig) showed antifibrinolytic activity similar to tranexamic acid. Antibacterial activities of these compounds against Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis), Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and yeast-like fungi (Candida albicans, Candida tropicalis) were investigated by the micro-dilution method and compared with the activity of tranexamic acid, ofloxacin and fluconazole. By this way their minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC) and minimal fungicidal concentration (MFC) values were determined. Compound Ia exhibited almost equally potent activity against B. subtilis (MIC and MBC: 6.25 microg/mL). Compounds Ib-Id, If-Ig and In exhibited similar bactericidal activity against B. subtilis (MBC: 12.5 microg/mL). Compounds Ik and Im showed bacteriostatic activity against S. aureus. None of the compounds exhibited activity against Gram-negative bacteria. On the other hand, all compounds had potent antifungal activities against the yeast utilized. Among the synthesized compounds, 3-methyl-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Ia) seems to be the most effective compound with antifibrinolytic and antimicrobial activity.