Design, synthesis and anti-inflammatory activity of imidazol-5-yl pyridine derivatives as p38α/MAPK14 inhibitor

P38 alpha VMAPK14 is intracellular signalling regulator involved in biosynthesis of inflammatory mediator cytokines (TNF-alpha, IL-1, IL-6, and IL-1b), which induce the production of inflammatory proteins (iNOS, NF-kappa B, and COX-2). In this study, drug repurposing strategies were followed to repositioning of a series of B-RAF(V600E) imidazol-5-yl pyridine inhibitors to inhibit P38a kinase. A group 25 reported P38a kinase inhibitors were used to build a pharmacophore model for mapping the target compounds and proving their affinity for binding in P38a active site. Target compounds were evaluated for their potency against P38a kinase, compounds 1 la and 11d were the most potent inhibitors (IC50 = 47 nM and 45 nM, respectively). In addition, compound 11d effectively inhibited the production of pminflammatory cytokines TNF-alpha, 1L-6, and 1L-1 beta in LPS-induced RAW 264.7 macrophages with IC50 values of 78.03 mu M, 17.6 nM and 82.15 nM, respectively. The target compounds were tested for their anti-inflammatory activity by detecting the reduction of Nitric oxide (NO) and prostaglandin (PGE2) production in LPS-stimulated RAW 264.7 macrophages. Compound 11d exhibited satisfied inhibitory activity of the production of PGE2 and NO with IC(50 )values of 0.29 mu M and 0.61 mu M, respectively. Molecular dynamics simulations of the most potent inhibitor 11d were carried out to illustrate its conformational stability in the binding site of P38a kinase.

Automated summary

In this study, drug repurposing strategies were used to reposition a series of inhibitors to target P38α kinase, leading to the identification of compounds with anti-inflammatory activity by effectively inhibiting the production of inflammatory cytokines. The most potent inhibitor, compound 11d, exhibited satisfactory inhibitory activity against the production of PGE2 and NO in LPS-stimulated macrophages.