A Structure‐Based Design Strategy with Pyrazole‐Pyridine Derivatives Targeting TNFα as Anti‐Inflammatory Agents: E‐Pharmacophore, Dynamic Simulation, Synthesis and In Vitro Evaluation

Abstract

Any pathogenic attack, infection, or disease can initiate inflammation. It results in significant adverse consequences like inflammatory bowel disease, rheumatoid arthritis, etc. TNFα is one of the major pro‐inflammatory cytokines for the progression of inflammation—the present study designed a series of hybrid compounds consisting of the pyrazole‐pyridine moiety. Virtual screening was performed utilizing the e‐pharmacophore hypothesis with the co‐ligand of TNFα, screening, docking, and ADMET study. Induced fit docking, DFT analysis, and molecular dynamic simulation showed that the four best molecules ‐ Dh1‐ Dh4 – showed crucial interaction with Tyrosine, higher dock scores, and better stability than Diclofenac. Following the synthesis of hit molecules, an in vitro albumin denaturation IC50 of Dh1 was found to be 118.01μM. Further in‐depth in vitro and in vivo analyses of these pyrazole‐pyridine small compounds may serve as potential space for creating new anti‐inflammatory leads.