Design, synthesis, in vitro determination and molecular docking studies of 4-(1-(tert-butyl)-3-phenyl-1H-pyrazol-4-yl) pyridine derivatives with terminal sulfonamide derivatives in LPS-induced RAW264.7 macrophage cells

In the present work, a new series of 4-(1-(tert-butyl)-3-phenyl-1H-pyrazol-4-yl) pyridine possessing terminal ethyl or propyl sulfonamides was designed and synthesized. The cytotoxic effect of the final compounds was measured by applying MTT assay in LPS-Induced RAW264.7 macrophage cells. The final target compounds were screened for their anti-inflammatory effect through their ability to inhibit NO and PGE(2) production and cytokines production (TNF-alpha, IL-6, IL-1 beta) in LPS-induced RAW264.7 macrophage at 10 mu M concentration. Compounds 8d, 9d, and 9k showed the highest inhibitory effect on NO production. Compounds 8d and 9k exhibited high PGE(2) inhibition with IC50 values of 3.47, 2.54 mu M, respectively. Compounds 8d and 9k exhibited high cytokines inhibition >= 60%. The most potent compounds 8d and 9k were tested to determine their effect on iNOS and COX-2 mRNA expression level. Compound 9k activity on iNOS and COX-2 proteins level, pro-inflammatory mediators and cytokines was determined and showed remarkable inhibition for both proteins level. Compounds 8d, 9k showed high binding affinity to COX-2 active site and exhibited similar binding interactions of the native ligand celecoxib.

Automated summary

In this study, a new series of compounds were designed and synthesized with potential cytotoxic and anti-inflammatory effects. Compounds 8d and 9k showed the highest inhibitory effect on NO production, PGE(2) inhibition, and cytokines inhibition. Additionally, compounds 8d and 9k exhibited high binding affinity to the COX-2 active site, similar to the native ligand celecoxib.