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

Affiliation

Ali EMH(1), Abdel-Maksoud MS(2), Hassan RM(2), Mersal KI(3), Ammar UM(4), Se-In C(5), He-Soo H(5), Kim HK(6), Lee A(7), Lee KT(8), Oh CH(9).
Author information:
(1)Center for Biomaterials, Korea Institute of Science & Technology
(KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; University of Science & Technology
(UST), Daejeon, Yuseong-gu, 34113, Republic of Korea; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information
(MTI), Cairo 12055, Egypt.
(2)Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre
(NRC),
(ID: 60014618), P.O. 12622, Dokki, Giza, Egypt.
(3)Center for Biomaterials, Korea Institute of Science & Technology
(KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; University of Science & Technology
(UST), Daejeon, Yuseong-gu, 34113, Republic of Korea.
(4)Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
(5)Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
(6)Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Jeonbuk National University Medical School and Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju 54907, Republic of Korea; Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju 54907, Republic of Korea.
(7)Department of Chemistry, Hanseo University, Seosan 31962, Republic of Korea.
(8)Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea. Electronic address: [Email]
(9)Center for Biomaterials, Korea Institute of Science & Technology
(KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; University of Science & Technology
(UST), Daejeon, Yuseong-gu, 34113, Republic of Korea. Electronic address: [Email]

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 (IC50 = 47 nM and 45 nM, respectively). In addition, compound 11d effectively inhibited the production of proinflammatory cytokinesTNF-α, 1L-6, and 1L-1β in LPS-induced RAW 264.7 macrophages with IC50 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 IC50 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.