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


Oezcelik A. B. , Ersan S., Ural A. U. , Oezkan S., Ertan M.

ARZNEIMITTEL-FORSCHUNG-DRUG RESEARCH, vol.57, no.8, pp.554-559, 2007 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 57 Issue: 8
  • Publication Date: 2007
  • Doi Number: 10.1055/s-0031-1296648
  • Title of Journal : ARZNEIMITTEL-FORSCHUNG-DRUG RESEARCH
  • Page Numbers: pp.554-559

Abstract

A series of 3-substituted-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5- thiadiazine-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-thiadia- zine-2-thione (la) was the most prominent one (104%) when compared to tranexamic acid. Besides, 3-ethyl-5-(4carboxycyclohexyl-methyl)-tetrahydro- 2H-1,3,5-thiadiazine-2-thione (Ib), 3-Isopropyl-5-(4-carboxycyclohexylmethyl)- tetrahydro-2H-1,3,5-thiadiazine-2-thione (Id) and 3-isobutyl-5-(4-carboxycyclohexyl-methyl)-tetrahydro-2H-1,3,5-thiadia- zine-2-thione (Ig) showed antiflbrinolytic activity similar to tranexamic acid. Antibacterial activities of these compounds against Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis), Gramnegative 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 la exhibited almost equally potent activity against B. subtilis (MIC and MBC: 6.25 mu g/mL). Compounds Ib-Id, If-Ig and In exhibited similar bactericidal activity against B. subtilis (MBC: 12.5 mu g/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-carboxycyclohexy(methyl)-tetrahydro-2H- 1,3,5-thiadiazine-2-thione (Ia) seems to be the most effective compound with antifibrinolytic and antimicrobial activity.