Generally, highly selective COX-2 inhibitors cause cardiovascular side effects. Celecoxib is the highly marketed coxib, so there is still a need for the synthesis of COX-2 inhibitors with less adverse effects. Moreover, low-dose radiotherapy (LD-RT) is clinically used for the treatment of inflammatory diseases. The present study aimed to investigate the analgesic and anti-inflammatory activity of a novel series of 1,3,4-thiadiazole derivatives alone or combined with LD-RT with a single dose of 0.5 Gy. Initially, in vitro COX-1/COX-2 inhibition assays were performed, identifying the sulfonamide-containing compounds 5-10 as the most potent candidates, with IC50 values in the range of 0.32-0.37 µM and the highest selectivity indices. These compounds and celecoxib were subjected to in vivo examination after their safety was assessed through the acute toxicity test. Treatment with compounds 5-10 inhibited carrageenan-induced edema by nearly 47-56%, which was nearly equivalent to celecoxib. Compounds 7 and 8 and celecoxib showed an analgesic activity of 64.15%, 49.05%, and 84.90%, respectively, whereas compounds 5, 6, 9, and 10 did not show any analgesic activity unless combined with LD-RT. Ulcerogenic activity, histological paw examination, and docking studies were performed. Compounds 5-10 were nearly similar to celecoxib, showing normal histological features with no ulcerogenic activity.
Keywords: COX-2 inhibitors; LD-RT; analgesic; anti-inflammatory; thiadiazoles; ulcerogenicity.
© 2020 Deutsche Pharmazeutische Gesellschaft.