SYNTHESIS AND ANTIEXUDATIVE ACTIVITY EVALUATION OF ANTIPIRYLAMIDES OF 5-ARYLMETHYLIDENE-2-THIOXO-4-THIAZOLIDINONE-3-ALKANECARBOXYLIC ACIDS

Анотація

SYNTHESIS AND ANTIEXUDATIVE ACTIVITY EVALUATION OF ANTIPIRYLAMIDES OF 5-arylmethylidene-2-thioxo-4-thiazolidINONE-3-alkanecarboxylic acidS

I.L. Demchyk

DanyloHalytskyLvivNationalMedicalUniversity

Introduction.Thiazolidinone derivatives are well known class of biological active substances that became basic for the whole number of innovative medicinal agents, such as hypoglycemic thiazolidinediones, aldose reductase inhibitors, dual inhibitors of COX-2/5-LOX, modern diuretics, Mur family inhibitors (UDP-MurNAc/L-Ala ligases) etc. In addition, 4-thiazolidinone derivatives have been demonstrated to possess antibacterial, antifungal, anticonvulsant, anticancer and antituberculosis activities.

The aim of this work was to study the antiexudative activity of novel antipirilamides 5-arylmethylidene-2-thioxo-4-thiazolidinone-3-alkancarboxylic acids on the formalin model oedema in rats.

Investigation methods. For antiexudative tests adult male and female rats weighing 140-150 g were used. The formalin-induced hind paw oedema in rats was produced by the method of Hole et al. Diclofenac sodium, ibuprofen, phenylbutazone and acetylsalicylic acid were used as reference compounds. The synthesized compounds were intraperitoneally injected (4 h after formalin) in a dose 100 mg/kg. Control rats received only solution of 0.5% carboxymethylcellulose with one drop of Twin-80. The hind paw volume was measured with an electronic onkograph immediately before and 4h after formalininjection. The effect of test compounds on decrease of paw oedema was compared with that control in rats. The antiexudative activity was expressed as a decrease of rats paw oedema and is given in percentage.

Results and discussion. Novel antipyrilamides of 5-arylmethylidene-2-thioxo-4-thiazolidinone-3-alkancarboxylic acids were synthesized via acylation reaction of 4-aminoantypirine with corresponding acid chlorides. Among tested compounds 2.5, 2.6 were found to be the most active of all the tested one. These compounds decreased carrageenan-induced edema on 59% and 69 %, respectively. These data are comparable with effect of reference compounds. For other derivatives 2.1-2.4 moderate antiexudative activity was observed.

Conclusions.The preliminary results of antiexudative activity on the formalin foot oedema model in rats allowed to identify the active compound 2.5 and 2.6 with effect level comparable to that of diclofenac sodium, ibuprofen, phenylbutazone and acetylsalicylic acid.

References

1. Zimenkovsky B.S. 4-Thiazolidones. Chemistry, physiological performance and prospects / B.S. Zimenkovsky, R.B. Lesyk. -Vinnytsya: Nova Knyga, 2004 -106 p.
2. Lesyk R.B., ZimenkovskyB.S. 4-Thiazolidones: Centenarian history, current status and perspectives for modern organic and medicinal chemistry// Curr. Org. Chem. – 2004. – Vol. 8. – P. 1547-1577.
3. R. Dayam, T. Sanchez, O. Clementetal. Beta-diketoacid pharmacophore hypothesis. Discovery of a novel class of HIV-1 integrase inhibitors // J. Med. Chem. – 2005. – Vol. 48, № 1. – P. 111-120.
4. W. T. Sing, C. L. Lee, S. L. Yeo et al.  Arylalkylidenerhodanine with bulky and hydrophobic functional group as selective HCV NS3 protease inhibitor // Bioorg. Med. Chem. Lett. – 2001. – Vol. 11, №2. – P. 91-94.
5. A. Degterev, A. Lugovskoy, M. Cardoneetal. Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xl // Nature Cell Biology. – 2001. – № 3. – P. 173-182.
6. Mazieres J. Perspectives on farnesyltransferase inhibitors in cancer therapy / J. Mazieres, A. Pradines, G. Favre // Cancer Lett. – 2004. – Vol. 206, № 2. – P. 159-167.
7. Trocko N. Synthesis of amide 5-arylidene-2.4-dioxo-thiazolidine-3-acetic acids with 1,2,4-triazole system / N. Trocko, M. Dobosz, V. Lukianchuk // Acta Poloniae Pharmaceutica. – 2006. – Vol. 63, №1. – P. 47-52.
8. Popov K. Condensation of  2,4-tetrahydro-1,3-tyazole with aromatic aldehyde / K. Perhal-Popov, J. Chekovych, M. Perhal // Zhurnal orhanycheskoy khimii. - 1994. - Vol. 61, № 9. - P. 2112-2116..
9. Trynus F.P, Nesteroydnye protyvovospalytelnye sredstva / F.P. Trynus, N.A. Mohort, B.M. Klebanov. -Kyiv: Zdorovya, 1975. - 239s.