ANTI-INFLAMMATORY AND ANTIOXIDANT ACTIVITY OF 8-METHOXY-1,3-DIMETHYL-2,6-DIOXO-PURIN-7-YL DERIVATIVES WITH TERMINAL CARBOXYLIC, ESTER OR AMIDE MOIETIES IN ANIMAL MODELS.

The previous studies in a series of 8-methoxy-1,3-dimethyl-2,6-dioxo-purin-7-yl derivatives revealed their analgesic properties. We extended the study with these compounds in aim to assess their impact on inflammatory process. For this purpose we used: the zymosan-induced peritonitis and the carrageenan-induced edema model. Furthermore, the antioxidant activity of the investigated compounds by the FRAP assay was determined. For the most active derivatives from evaluated series their influence on plasma TNF-α level was also tested in vivo. All investigated purine-2,6-dione derivatives 1-11 decreased neutrophils count and inhibited intensity of early vascular permeability. Furthermore, all evaluated compounds reduced the volume of edema caused by subcutaneous injection of carrageenan. Derivatives 1 (with ester moiety), 3 and 4 (with carboxylic group) showed the highest activity in the zymosan-induced peritonitis. In addition, a significant inhibition of plasma TNF-α level in rats with endotoxemia was observed following intraperitoneal administration of these compounds. In turn, compounds 6 and 8-11 containing amide moiety showed the greatest anti-inflammatory (antiedematous) effect in the carrageenan-induced paw edema model. All compounds did not show significant antioxidant properties. The present studies revealed that the presented purine-2,6-dione derivatives exhibit a significant anti-inflammatory activity and this effect may result from their ability to lower TNF-α level.