Newly synthesized ethenyl pyridazines and ethenyl pyridazinones as anti-inflammatory agents with COVID-19 suppressing potential.

Pyridazine and pyridazinone derivatives were found to be effective anti-inflammatory agents that inhibit COX-2 while also suppressing TxA2, TNF-α, and IL-6, which are involved in severe inflammatory responses. As a result, Pyridazine and pyridazinone scaffolds may offer a useful treatment for intractable COVID-19, where cytokine storm worsens disease severity. In this study, novel pyridazine and pyridazinone compounds were synthesized and tested in vitro for their inhibitory effects on COX-1, COX-2, TxA2, TNF-α, and IL-6, using two reference standards, celecoxib and indomethacin. Derivatives 3d, 4g, 4j, 5a, 6a, 7b, and 8a inhibited COX-2 potently and selectively over COX-1. In addition, compounds 3d, 4b, 4e, 4g, 5a, 7b, and 8a,b showed considerable reduction of TxA2, TNF-α, and IL-6, indicating wide anti-inflammatory potential. Molecular docking investigations demonstrated substantial binding affinities for compound 3d to TxA2, TNF-α, and IL-6 active sites, and compound 4g to COX-2 enzyme, confirming experimental findings. Histopathological examination of paw tissues showed that both compounds significantly decreased inflammatory cell infiltration and preserved normal dermal structure, with benefits comparable to or greater than reference medicines. Importantly, 3d and 5a did not cause stomach lesions, making them as safe as celecoxib and better than indomethacin. Histological examinations of stomach mucosa confirmed these findings. To determine their anti-inflammatory mechanisms, iNOS and NF-κB levels were evaluated in inflamed tissues. Both compounds lowered iNOS and NF-κB expression similarly to reference medicines, demonstrating a dual mode of action including enzymatic (COX-2, iNOS) and transcriptional (NF-κB) pathways. Compound 3d inhibited NF-κB by 88.08 % and compound 5a by 94.58 %, relative to celecoxib (100 %), suggesting their potential as multi-target anti-inflammatory drugs. These results suggest compounds 3d and 5a as promising lead structures for next-generation anti-inflammatory agents that could treat severe COVID-19 and other cytokine-driven inflammatory disorders with efficacy, multi-target action, and improved safety. Both 10 mg/kg drugs significantly reduced paw edema more than the standards. Compound 3d inhibited 56.99 % after one hour, surpassing indomethacin (43.11 %) and nearing celecoxib (59.68 %), while compound 5a inhibited 58.60 %. Histopathological analysis of paw tissues showed that both drugs reduced inflammatory cell infiltration and preserved skin structure, outperforming reference treatments. No stomach lesions, which were confirmed by stomach mucosa histology, made 3d and 5a as safe as celecoxib and better than indomethacin. To confirm anti-inflammatory pathways, iNOS and NF-κB levels were measured in inflamed tissues.