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 PGE₂ production and cytokines production (TNF-α, IL-6, IL-1β) in LPS-induced RAW264.7 macrophage at 10 μM concentration. Compounds 8d, 9d, and 9k showed the highest inhibitory effect on NO production. Compounds 8d and 9k exhibited high PGE₂ inhibition with IC₅₀ values of 3.47, 2.54 μM, 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. [ABSTRACT FROM AUTHOR]