Synthesis and the hypoglycemic activity of pyrazolidene-3-carboxylic acids and their derivatives exo-functionalized with the hydrazinilidene-1,3-thiazolidine fragment

M. K. Bratenko, M. M. Barus, O. M. Denysenko, R. V. Rodik, M. V. Vovk, O. K. Yarosh


It has been shown that 4- formylpyrazole-3-carboxylic acids and their ethyl esters interact selectively with thiosemicarbazide and its N4-aryl-derivatives in boiling acetic acid with formation of the corresponding 4-pyrazolylthiosemicarbazones with the yields of 76-91%. It has been found that heating of 4-pyrazolylthiosemicarbazones with diethyl acetylenedicarboxylate in boiling ethanol for 3 hours leads to formation of 1,3-thiazolidine-containing polyfunctional pyrazole derivatives with yields of 73-95%. Formation of compounds of this type indicates that the process occurs according to the scheme of the primary attack of a highly electrophilic triple bond of acetylenedicarboxylate by the nucleophilic atom of sulfur of the thiosemicarbazone fragment with subsequent intramolecular condensation, which leads to formation of the 4-oxo-1,3-thiazolidine-5-ilidene cycle. The structure of the 1,3-thiazolidinilidenehydrazonepyrazoles synthesized has been proven by a complex of spectral methods; the most informative of them are 13C NMR spectra with signals of carbon atoms of the thiazolidine cycle: C4 (159-161 ppm), C2 (162-165 ppm), C5 (163-165 ppm), as well as of the exo-cyclic ethoxycarbonylethylidene fragment: HC= (114-118 ppm); and of C(O) O (165 ppm). It has been determined that the compounds synthesized cause the hypoglycemic dose-dependent effect in mice, which is much more potent than the same effect of the reference medicine – pioglitazone.


4-formylpyrazole-3-carboxylic acids; thiosemicarbazones; diethylacetylenedicarboxylate; 1,3-thiazolidine-4-ones; cyclocondensation; hypoglycemic activity


Eckel R. H., Grundy S. M., Zimmet P. Z. The Lancet, 2005, Vol. 365, pp.1415-1428.

Khan S. E. Diabetologia, 2003, Vol. 46, No.1, pp.3-19.

Yarosh O. K. Farmakologiya ta likarska toksykologiya, 2011, No.5(24), pp.390-392.

Yarosh O. K. Farmakologiya ta likarska toksykologiya, 2011, No.5(24), pp. 393-394.

Yarosh O. K., Denysenko O. M., Rodik R. V., Kаlchenko V. I. Materialy dopovidey naukovoho seminaru. Hurzuf, 2013, pp.15-20.

Shimabukuro M., Zhou Y. T., Lee Y., Unger R. U. Journal of Biological Chemistry, 1998, Vol. 273, pp.3547-3550.

Nissen S. E., Wolski K. New England Journal of Medicine, 2007, Vol. 356, pp.2457-2471.

Lincoff A. M., Wolski K., Nockols S. J., Nissen S. E. Journal of American Medicine, 2007, Vol. 298, pp.1180-1188.

Guzman-Perez A., Webster R. T., Allen M. C., Broun J. A., Buchholz A. R., Cook E. R., Day W. W., Hamanaka E. S., Kennedy S. P., Knight D. R., Kowalczuk P. J., Marala R. P., Mularski C. J., Novomisle W. A., Ruggeri R. B., Tracy W. R., Hill R. J. Bioorganic Medicinal Chemistry Letters, 2001, Vol. 11, No.6, pp.803-807.

Roelfan S. G., Arnold C., Wllnga K. Journal of Agriculture and Food Chemistry, 1979, Vol. 84, No.2, pp.406-409.

Vovk M. V., Bratenko V. O., Chornous V. O. 4-Funktsionalno zamishcheni pirazoly. Chernintsi, 2008, Prut, pp.203-220.

Perez-Fernandez R., Goya P., Elguero J. Arkivoc, 2014, pp.233-293.

Gregory R., Greg A., Beverly B., Christine B., Bork B., Bryan F. B., Michele E. G., Jiaping D. Journal of Medicinal Chemistry, 2001, Vol. 44, No.16, pp.2601-2616.

Hernandez-Varguez E., Agoayo-Ortis R., Ramirez-Espinoza J. J., Estrada-Soto S., Hernandes-Luis F. Europien Journal of Medicinal Chemistry, 2013, Vol. 69, No.1, pp.10-21.

Bhosle M. R., Mali J. R., Pal S., Srivastava A. K., Mane R. Bioorganic and Medicіnal Chemistry Letters, 2014, Vol. 24, No.12, pp.2651-2654.

Bratenko M. K., Barus M. M., Vovk M. V. Khimiya heterotsiklicheskikh soedinenii – Chemistry of heterocyclic compounds, 2009, No.12, pp.1817-1822.

Hassan A. A., Shawky A. M., Shehata H. S. Journal of Heterocyclic Chemistry, 2012, Vol. 49, No.1, pp.21-37.

Holla B. S., Malini K. V., Rao B. S., Sarojini B. K., Kumari N. S. Europien Journal of Medicinal Chemistry, 2003, Vol. 38, No.3, pp.3313-3318.

Hildegard J., Seifert K., Johne S., Bluka E. Pharmazie, 1978, Vol. 33, No.2, pp.259-265.

Cukovali A., Yilmaz I., Gur S., Kazaz C. Europien Journal of Medicinal Chemistry, 2006, Vol. 41, No.2, pp.201-207.

Neokhoritis C. G., Zagdanes-Tzitzikas T., Stefaniodu-Stefonotou J. Synthesis, 2014, No.5. pp.537-585.

Hassan A. A., Shehata H. S., Dopp D. Journal of Chemical Research, 2008, No.12, pp.725-730.

Benmohammed A., Khoumeri O., Diafri A., Terme T., Vanelle P. Molecules, 2014, Vol. 19, pp.3068-3083.

Montsevichute-Eringene E. V. Patologicheskaya phiziologiya, 1964, No.4, s. 71-78.

Doklinichni doslidzhennya likarskykh zasobiv. Metodychni rekomendatsii. Red. O. V.Stefanov. Kyiv, 2001, 527 s.

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