Anti-inflammatory activity of novel thiosemicarbazone compounds indole-based as COX inhibitors.

BACKGROUND: In this article, a series of 20 new thiosemicarbazone derivatives containing indole were synthesized and evaluated for their anti-inflammatory potential. METHODS: The compounds were obtained through a synthetic route of only two steps, with yields that varied between 33.6 and 90.4%, and characterized by spectroscopic and spectrometric techniques. RESULTS: An initial screening through the lymphoproliferation assay revealed that compounds LT76, LT81, and LT87 were able to inhibit lymphocyte proliferation, with CC50 of 0.56 ± 0.036, 0.9 ± 0.01 and 0.5 ± 0.07 µM, respectively, better results than indomethacin (CC50 > 12 µM). In addition, these compounds were able to suppress the in-vitro production of TNF-α and NO, in addition to stimulating the production of IL-4. Reinforcing in-vitro assays, the compounds were able to inhibit COX-2 similar to Celecoxib showing greater selectivity for this isoform (LT81 SI: 23.06 versus Celecoxib SI: 11.88). Animal studies showed that compounds LT76 (64.8% inhibition after 6 h), LT81 (89% inhibition after 6 h) and LT87 (100% inhibition after 4 h) were able to suppress edema in mice after inoculation carrageenan with greater potency than indomethacin, and immunohistochemistry revealed that the groups treated with LT76, LT81 and LT87 reduced the expression of COX-2, similar or better results when compared to indomethacin. Complementarily, in-silico studies have shown that these compounds have a good pharmacokinetic profile, for respecting the parameters of Lipinski and Veber, showing their good bioavailability. CONCLUSIONS: These results demonstrate the potency of thiosemicarbazone derivatives containing indole and confirm their importance as scaffolds of molecules with notorious anti-inflammatory activity.

Reduction of carrageenan-induced acute pulmonary inflammation in mice by novel thiazolidinedione derivative LPSF/RA-4.

A number of studies have demonstrated the biological activities of peroxisome proliferator-activated receptors. However, few studies have addressed the effects of the agonists of these receptors on lung diseases. The aim of the present study was to evaluate the anti-inflammatory action of a novel synthetic thiazolidine derivative (5Z)-3-benzyl-5-(1H-indol-3-ylmethylene)-thiazolidine-2,4-dione (LPSF/RA-4) on acute lung inflammation (pleurisy) induced by carrageenan. Forty mice were randomly allocated to the following groups: (I) saline control group (sham); (II) carrageenan (CAR) group; (III) CAR+LPSF/RA-4 group treated with LPSF/RA-4 (60 µmol/kg); and (IV) INDO group treated with indometacin (5mg/kg). Total cell counts and the measure of nitric oxide (NO) were performed in pleural exudates. Lung fragments were processed for light microscopy, transmission electron microscopy, immunohistochemistry and Western blotting. The influx of leucocytes and NO levels were significantly reduced following treatment with LPSF/RA-4 and INDO. Histopathological and ultrastructural analyses of the CAR group revealed evident tissue alterations, such as oedema, infiltrates of inflammatory cells and emphysema. These alterations were significantly reduced in the groups treated with LPSF/RA-4 or INDO. Immunohistochemistry revealed an increase in inflammatory markers (COX-2, iNOS, TNF-α and IL-1ß) in the lung tissue of the CAR group, whereas the groups treated with LPSF/RA-4 and INDO exhibited significant reductions in such immunomarkers. Western blot analysis revealed an increased expression of COX-2 and IL-1 in the CAR group, which was reduced by treatment with LPSF/RA-4. The present findings demonstrate the potent anti-inflammatory action of the novel derivative thiazolidinedione LPSF/RA-4 in acute lung injury induced by carrageenan.