Design and Synthesis of Novel 1-Hydroxy-2,4,5-triaryl Imidazole Derivatives as Anti-Cytokine Agent

Document Type : Research article

Authors

1 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

2 Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.

Abstract

Among Recent advances in the identification of anti-inflammation agents, anti-cytokines (like Interleukin-1), related to p38 MAPK families play an important role; Here in we designed new effective and low toxic anti-cytokine agents based on 1-Hydroxy-2,4,5-triaryl imidazole derivatives. The reaction of oximoinoketone intermediate with ten different aromatic aldehyde and ammonium acetate in refluxing acetic acid condition give imidazole derived product, the IL-1β inhibitory assay were performed on Human PBMCs (peripheral blood mononuclear cells) using an enzyme-linked immunosorbent assay (ELISA) kit and then in computational part the binding mode of the best compound was accomplished  by docking in Crystal structure of p38 MAP kinase (PDB ID: 1A9U) compared with SB202190 as standard drug. All compounds were synthesized and evaluated in biological assay showing the inhibitory activity from 28% to 82% compared to SB202190 and binding mode analysis revealed that the hydrogen-bond interactions with residues (Met109, Val30) were key point in inhibitor binding. Compound 5g clearly proved the best inhibitory action and could be further utilized for designing newer anti-cytokine agents and p38α MAP kinase potentially inhibitory action.

Graphical Abstract

Design and Synthesis of Novel 1-Hydroxy-2,4,5-triaryl Imidazole Derivatives as Anti-Cytokine Agent

Keywords

Main Subjects



(1) Wrobleski ST, Lin S, Hynes J, Wu H, Pitt S, Shen DR,Zhang R, Gillooly KM, Shuster DJ and McIntyreKW. Synthesis and SAR of new pyrrolo [2, 1-f][1,2, 4] triazines as potent p38α MAP kinase inhibitors.Bioorg. Med. Chem. Lett. (2008) 18: 2739-44.
(2) Khorasanizadeh M, Eskian M, Gelfand EW andRezaei N. Mitogen-activated protein kinases astherapeutic targets for asthma. Pharmacol. Ther.(2017) 174: 112-26.
(3) Natarajan SR, Wisnoski DD, Singh SB, StelmachJE, O’Neill EA, Schwartz CD, Thompson CM,Fitzgerald CE, O’Keefe SJ and Kumar S. p38MAP kinase inhibitors. Part 1: design and development of a new class of potent and highly selective inhibitors based on 3, 4-dihydropyrido [3, 2-d] pyrimidone scaffold. Bioorg. Med. Chem. Lett. (2003) 13: 273-6.
(4) Cumming JG, McKenzie CL, Bowden SG, Campbell D, Masters DJ, Breed J and Jewsbury PJ. Novel, potent and selective anilinoquinazoline and anilinopyrimidine inhibitors of p38 MAP kinase. Bioorg. Med. Chem. Lett. (2004) 14: 5389-94.
(5) Fleischmann RM, Tesser J, Schiff MH, Schechtman J, Burmester GR, Bennett R, Modafferi D, Zhou L, Bell D and Appleton B. Safety of extended treatment with anakinra in patients with rheumatoid arthritis.Ann. Paediatr. Rheumatol. (2006) 65: 1006-12.
(6) Abeywardane A, Andersen D, Morwick TM, Snow RJ and Ward YD. Anti-cytokine heterocyclic compounds. Google Patents EP1756065A1 (2011).
(7) Seerden JPG, Leusink-Ionescu G, Leguijt R, Saccavini C, Gelens E, Dros B, WoudenbergVrenken T, Molema G, Kamps JA and Kellogg RM. Syntheses and structure–activity relationships for some triazolyl p38α MAPK inhibitors. Bioorg. Med. Chem. Lett. (2014) 24: 1352-7.
(8) Schnöder L, Hao W, Qin Y, Liu S, Tomic I, Liu X, Fassbender K and Liu Y. Deficiency of neuronal p38α MAPK attenuates amyloid pathology in
Alzheimer disease mouse and cell models through facilitating lysosomal degradation of BACE1. J. Biol. Chem. (2016) 291: 2067-79.
(9) Boehm JC, Bower MJ, Gallagher TF, Kassis S, Johnson SR and Adams JL. Phenoxypyrimidine inhibitors of p38α kinase: synthesis and statisticalevaluation of the p38 inhibitory potencies of a series of 1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-(2- phenoxypyrimidin-4-yl) imidazoles. Bioorg. Med.
Chem. Lett. (2001) 11: 1123-6.
(10) Adams JL, Boehm JC, Gallagher TF, Kassis S, Webb EF, Hall R, Sorenson M, Garigipati R, Griswold DE and Lee JC. Pyrimidinylimidazole inhibitors of p38: cyclic N-1 imidazole substituents enhance  191 Novel Imidazole Derivatives as Anti-cytokine Agent p38 kinase inhibition and oral activity. Bioorg. Med. Chem. Lett. (2001) 11: 2867-70.
(11) Johnson JC, Martinez O, Honko AN, Hensley LE, Olinger GG and Basler CF. Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells. Antiviral Res. (2014) 107: 102-9.
(12) Revesz L, Blum E, Di Padova FE, Buhl T, Feifel R, Gram H, Hiestand P, Manning U, Neumann U andRucklin G. Pyrazoloheteroaryls: Novel p38α MAP kinase inhibiting scaffolds with oral activity. Bioorg. Med. Chem. Lett. (2006) 16: 262-6.
(13) Amir M, Somakala K, Ali S. p38 MAP kinase inhibitors as anti inflammatory agents. Mini. Rev. Med. Chem. (2013) 13: 2082-96.
(14) Bellei B, Pitisci A, Migliano E, Cardinali G and Picardo M. Pyridinyl imidazole compounds interfere with melanosomes sorting through the inhibition of
Cyclin G-associated Kinase, a regulator of cathepsins maturation. Cell. Signal. (2014) 26: 716-23.
(15) Anastassiadis T, Deacon SW, Devarajan K, Ma H and Peterson JR. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol. (2011) 29: 1039-45.
(16) Janssens S and Beyaert R. Functional diversity and regulation of different interleukin-1 receptorassociated kinase (IRAK) family members. Mol. Cell (2003) 11: 293-302.
(17) Johnson GL and Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science (2002) 298: 1911-2.
(18) Subramaniam S, Stansberg C, and Cunningham C. The interleukin 1 receptor family. Dev. Comp. Immunol. (2004) 28: 415-28.
(19) Ravingerová T, Barančík M and Strnisková M. Mitogen-activated protein kinases: a new therapeutic target in cardiac pathology. Mol. Cell. Biochem. (2003) 247: 127-38.
(20) Cuenda A and Rousseau S. p38 MAP-kinases pathway regulation, function and role in humandiseases. Biochim. Biophys. Acta (2007) 1773: 1358-75.
(21) Schieven GL. The p38α kinase plays a central rolein inflammation. Curr. Top. Med. Chem. (2009) 9:1038-48.
(22) Lee JCL, Adams JL, Gallagher TF, Green DW,Heys JR, McDonnell PC, McNulty DE, Strickler JEand Young PR. Screening methods using cytokinesuppressive anti-inflammatory drug (CSAID)binding proteins. Google Patents EP0724588B1(1999).
(23) Ishii M, Suzuki Y, Takeshita K, Miyao N, KudoH, Hiraoka R, Nishio K, Sato N, Naoki K and AokiT. Inhibition of c-Jun NH2-terminal kinase activityimproves ischemia/reperfusion injury in rat lungs. J. Immunol. (2004) 172: 2569-77.
(24) Campbell J, Ciesielski CJ, Hunt AE, HorwoodNJ, Beech JT, Hayes LA, Denys A, Feldmann M,Brennan FM and Foxwell BMA. A novel mechanismfor TNF-α regulation by p38 MAPK: involvement ofNF-κB with implications for therapy in rheumatoidarthritis. J. Immunol. (2004) 173: 6928-37.
(25) Kane D and FitzGerald O. Tumor necrosis factor-αin psoriasis and psoriatic arthritis: A clinical, genetic,and histopathologic perspective. Curr. Rheumatol.Rep. (2004) 6: 292-8.
(26) Khoshneviszadeh M, Shahraki O, KhoshneviszadehM, Foroumadi A, Firuzi O, Edraki N, Nadri H,Moradi A, Shafiee A and Miri R. Structure-baseddesign, synthesis, molecular docking study andbiological evaluation of 1, 2, 4-triazine derivativesacting as COX/15-LOX inhibitors with anti-oxidantactivities. J. Enzyme Inhib. Med. Chem. (2016) 31:1602-11.
(27) Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G, Lee PW and Tang Y. admetSAR: a comprehensive source
and free tool for assessment of chemical ADMETproperties. J. Chem. Inf. Model. (2012) 52: 3099-105.