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

Ali, Eslam M.H.; Abdel-Maksoud, Mohammed S.; Hassan, Rasha Mohamed; Mersal, Karim I.; Ammar, Usama M.; Se-In, Choi; He-Soo, Han; Kim, Hee-Kwon; Lee, Anna; Lee, Kyung-Tae; Oh, Chang-Hyun

Authors

Eslam M.H. Ali

Mohammed S. Abdel-Maksoud

Rasha Mohamed Hassan

Karim I. Mersal

Choi Se-In

Han He-Soo

Hee-Kwon Kim

Anna Lee

Kyung-Tae Lee

Chang-Hyun Oh



Abstract

P38α/MAPK14 is intracellular signalling regulator involved in biosynthesis of inflammatory mediator cytokines (TNF-α, IL-1, IL-6, and IL-1b), which induce the production of inflammatory proteins (iNOS, NF-kB, 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 P38α kinase. A group 25 reported P38α kinase inhibitors were used to build a pharmacophore model for mapping the target compounds and proving their affinity for binding in P38α active site. Target compounds were evaluated for their potency against P38α kinase, compounds 11a and 11d were the most potent inhibitors (IC 50 = 47 nM and 45 nM, respectively). In addition, compound 11d effectively inhibited the production of proinflammatory cytokines TNF-α, 1L-6, and 1L-1β in LPS-induced RAW 264.7 macrophages with IC 50 values of 78.03 nM, 17.6 µM 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 µM and 0.61 µM, respectively. Molecular dynamics simulations of the most potent inhibitor 11d were carried out to illustrate its conformational stability in the binding site of P38α kinase.

Journal Article Type Article
Acceptance Date Dec 21, 2020
Online Publication Date Dec 28, 2020
Publication Date 2021-02
Deposit Date Dec 11, 2022
Journal Bioorganic & Medicinal Chemistry
Print ISSN 0968-0896
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 31
Article Number 115969
DOI https://doi.org/10.1016/j.bmc.2020.115969
Keywords P38α, Anti- inflammatory, Pharmacophore, TNF-α, 1L-6, 1L-1β, Nitric Oxide, PGE2
Public URL http://researchrepository.napier.ac.uk/Output/2973750