Synthesis and preliminary ex vivo evaluation of the spasmolytic activity of 1,3-thiazolium- and 1,3,4-thiadiazolium-5-methylthio- and 5-thioacetate derivatives

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Abstract

Seven new compounds have been synthetized in satisfactory yields (51-78 %) through the treatment of mesoionic 1,3-thiazolium-5-thiolate (4a-d) and 1,3,4-thiadiazolium- 5-thiolate (10a,b) with chloroacetic acid or methyl iodide: 1,3,4-thiadiazolium-5-methylthio- (11) and 5-thioacetate (12). The structure of the title compounds was elucidated by elemental analysis, IR, 1H and 13C NMR spectroscopy. The newly synthesized compounds 5a, 6a, 11 and 12 were evaluated for their ex vivo spasmolytic potential on four isolated smooth muscles (rat aorta and uterus, guinea pig ileum and trachea) and compared with scopolamine. Some of the compounds exhibited potent spasmolytic activity equal to or stronger than scopolamine

1. L. B. Kier and E. B. Roche, Medicinal chemistry of the mesoionic compounds, J. Pharm. Sci. 56 (1966) 149-168; DOI: 10.1002/jps.2600560202.

2. M. B. Oliveira, J. Miller, A. B. Pereira, S. E. Galembeck, G. L. C. Moura and A. M. Simas, Mesoionic 2-N-cycloalkylamino-5-alkyl-1,3-dithiolium-4-thiolates, Phosphorus, Sulfur, Silicon Relat. Elem. 108 (1996) 75-84; DOI: 10.1080/10426509608029640.

3. C. A. C. Bosco, G. S. Maciel, N. Rakov, C. B. Araújo, L. H. Acioli, A. M. Simas, P. F. Athayde- -Filho and J. Miller, Probing the nuclear susceptibility of mesoionic compounds using two-beam coupling with chirp-controlled pulses, Chem. Phys. Lett. 449 (2007) 101-106; DOI: 10.1016/ j.cplett.2007.10.037.

4. R. S. T. R. Nascimento, C. R. S. Morais, H. L. Lira, S. A. Morais, P. F. Athayde-Filho, L. F. L. Lucena, A. G. Souza and G. B. Campos, Synthesis and characterization of nanocomplexes of Eu(III) and Er(III) coordinate with 2(4-clorophenyl)-3-phenyl-1,3,4-thiadiazoleo-5-tiolate mesoionic, J. Alloys Comp. 495 (2010) 603-605; DOI: 10.1016/j.jallcom.2009.12.003.

5. S. A.Morais, C. R. S. Morais, P. F. Athayde-Filho, B. F. Lira and R. S. T. R. Nascimento, Akinetic study of the thermal decomposition of mesoionic compounds within scope of its application in nonlinear optical devices, J. Therm. Anal. Calorim. 97 (2009) 437-441; DOI: 10.1007/s10973-009-0082-8.

6. B. F. Lira, S. A. Morais, G. B. Rocha, J. Miller, G. L. C. Moura, A. M. Simas, C. Peppe and P. F. Athayde-Filho, 1,3-Thiazolium-5-thiolates mesoionic compounds: Semiempirical evaluation of their first static hyperpolarizabilities and synthesis of new examples, J. Braz. Chem. Soc. 21 (2010) 934-940; DOI: 101590/S0103-505320100000500024.

7. A. S.-Ribeiro, A. Echevarria, E. F. Silva, C. R. C. Franco, S. S. Veiga and M. B. M. Oliveira, Cytotoxic effect of a new 1,3,4-thiadiazolium mesoionic compound (MI-D) on cell lines of human melanoma, Br. J. Cancer 91 (2004) 297-304. DOI: 10.1038/sj.bjc.6601946.

8. R. F. Rodrigues, E. F. Silva, A. Echevarria, R. Fajardo-Bonin, V. F. Amaral, L. L. Leon and M. M. Canto-Cavalheiro, A comparative study of mesoionic compounds in Leishmania sp. and toxicity evaluation, Eur. J. Med. Chem. 42 (2007) 1039-1043; DOI: 10.1016/j.ejmech.2006.12.026.

9. R. F. Rodrigues, D. Castro-Pinto, A. Echevarria, C.M. Reis, C. N. Del Cistia, C. M. R. Sant’Anna, F. Teixeira, H. Castro, M. Canto-Cavalheiro, L. L. Leon and A. Tomás, Investigation of tripanothione redutase inhibitory activity by 1,3,4-thiadiazolium-2-aminide derivatives and molecular docking studies, Bioorg. Med. Chem. 20 (2012) 1760-1766; DOI: 10.1016/j.bmc.2012.01.009.

10. K. L. M. Cavalcante, N. A. Correia, K. L. G. Dias, D. F. Silva, J. C. Silva-Filho, I. G. A. Araújo, B. F. Lira, P. F. Athayde-Filho and I. A. Medeiros, Endothelium-derived nitric oxide contributes to the vasorelaxant response induced by mesoionic 2-(4-chlorophenyl)-3-methyl-4-(4-methoxyphenyl)-1,3-thiazolium-5-thyolate (CMMTT) in rats, J. Pharmacol. Sci. 110 (2009) 29-35; DOI: 10.1254/jphs.FP0071581.

11. K. Rehse, T. Ciborski and B. Müller, Platelet aggregation inhibiting and anticoagulant effects of oligoamines. XXVII. Inhibition of leucocyte adherence to endothelium by oligoamine RE 1492C and the NO-donor RE 2047, Arch. Pharm. (Weinheim) 328 (1995) 125-126; DOI: 10.1002/ardp. 19953280206.

12. L. B. Kier and E. B. Roche, Medicinal chemistry of the mesoionic compounds, J. Pharm. Sci. 56 (1967) 149-168; DOI: 10.1002/jps.2600560202.

13. C. S. Oliveira, V. S. Falcão-Silva, J. P. Siqueira-Júnior, D. P. Harding, B. F. Lira, J. G. F. Lorenzo, J. M. Barbosa-Filho and P. F. Athayde-Filho, Drug resistance modulation in Staphylococcus aureus, a new biological activity for mesoionic hydrochloride compounds, Molecules 16 (2011) 2023-2031; DOI: 10.3390/molecules16032023.

14. B. F. Lira, J. Miller, A. M. Simas, P. F. Athayde-Filho, A. F. Dias, R. O. Silva and V. C. Oliveira, Synthesis and complete assignments of 1H and 13C-NMR spectra of mesoionic 2-(p-trifluoromethylphenyl)-3-methyl-4-(p-tolyl)-1,3-thiazolium-5-thiolate and 2-(p-chlorophenyl)-3-methyl-4-(p-isopropylphenyl)-1,3-thiazolium-5-thiolate, Arkivoc vi (2004) 12-21.

15. P. F. Athayde-Filho, J. Miller, A. M. Simas, K. X. F. R. Sena and A. A. Chiappeta, Synthesis, characterization and evaluation of the activity of ten mesoionic compounds against microorganisms, Lat. Am. J. Pharm. 18 (1999) 17-22.

16. J. T. Lima J. R. G. S. Almeida, K. S. L.Mota, A. S. S. C. Lúcio, C. A. Câmara, J.M. B. Filho and B. A. Silva, Selective spasmolytic effect of a new furanoflavoquinone derivative from diplotropin on guinea-pig trachea, J. Chem. Pharm. Res. 3 (2011) 249-258.

17. E. E. Daniel, C. Y. Kwan and L. Janssen, Pharmacological techniques for the in vitro study of intestinal smooth muscles, J. Pharmacol. Toxicol. Meth. 45 (2001) 141-158.

18. B. M. Altura and B. T. Altura, Differential effects of substrate depletion on drug-induced contractions of rabbit aorta, Am. J. Physiol. 219 (1970) 1698-1705.

19. E. Tschirhart, N. Frossard, C. Bertrand and Y. Landry, Arachidonic acid metabolites and airway epithelium-dependent relaxant factor, J. Pharmacol. Exp. Ther. 243 (1987) 310-316.

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