Evaluation of 3-(3-chloro-phenyl)-5-(4-pyridyl)-4,5-dihydroisoxazole As a Novel Anti-inflammatory Drug Candidate

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 Jun 23

PMID 22723938

Citations 2

Authors

Amanda Roberta Revoredo Vicentino

Vitor Coutinho Carneiro

Anderson de Mendonca Amarante

Claudia Farias Benjamim

Alcino Palermo de Aguiar

Marcelo Rosado Fantappie

Affiliations

Soon will be listed here.

Abstract

Background: 3-(3-chloro-phenyl)-5-(4-pyridyl)-4,5-dihydroisoxazole (DIC) is a five-membered heterocyclic compound containing a N-O bond. The anti-inflammatory effects of this compound were studied both in vitro and in vivo.

Principal Findings: DIC effectively decreased TNF-α and IL-6 release from LPS-stimulated macrophages in a dose dependent manner. DIC diminished the levels of COX-2 with subsequent inhibition of PGE(2) production. DIC also compromised HMGB1 translocation from the nucleus to the cytoplasm. Moreover, DIC prevented the nuclear translocation of NF-κB and inhibited the MAPK pathway. In vivo, DIC inhibited migration of neutrophils to the peritoneal cavity of mice.

Conclusions: This study presents the potential utilization of a synthetic compound, as a lead for the development of novel anti-inflammatory drugs.

Citing Articles

Emerging Role of HMGB1 in the Pathogenesis of Schistosomiasis Liver Fibrosis.

Vicentino A, Carneiro V, Allonso D, Guilherme R, Benjamim C, Dos Santos H Front Immunol. 2018; 9:1979.

PMID: 30258438 PMC: 6143665. DOI: 10.3389/fimmu.2018.01979.

HMGB1 in health and disease.

Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L Mol Aspects Med. 2014; 40:1-116.

PMID: 25010388 PMC: 4254084. DOI: 10.1016/j.mam.2014.05.001.

References

Andersson U, Tracey K . HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 2011; 29:139-62. PMC: 4536551. DOI: 10.1146/annurev-immunol-030409-101323. View

Takeda K, Kaisho T, Akira S . Toll-like receptors. Annu Rev Immunol. 2003; 21:335-76. DOI: 10.1146/annurev.immunol.21.120601.141126. View

Holden N, Tacon C . Principles and problems of the electrophoretic mobility shift assay. J Pharmacol Toxicol Methods. 2010; 63(1):7-14. DOI: 10.1016/j.vascn.2010.03.002. View

Janeway Jr C, Medzhitov R . Innate immune recognition. Annu Rev Immunol. 2002; 20:197-216. DOI: 10.1146/annurev.immunol.20.083001.084359. View

Cirillo P, Pargellis C, Regan J . The non-diaryl heterocycle classes of p38 MAP kinase inhibitors. Curr Top Med Chem. 2002; 2(9):1021-35. DOI: 10.2174/1568026023393390. View

Penzo M, Molteni R, Suda T, Samaniego S, Raucci A, Habiel D . Inhibitor of NF-kappa B kinases alpha and beta are both essential for high mobility group box 1-mediated chemotaxis [corrected]. J Immunol. 2010; 184(8):4497-509. PMC: 2915896. DOI: 10.4049/jimmunol.0903131. View

Xu W, Huang X, Tang E . Solid-phase synthesis of 1,2-diheterocyclic-substituted (E)-olefins from a supported selenium resin. J Comb Chem. 2005; 7(5):726-33. DOI: 10.1021/cc050044+. View

Kim J, Shin J, Ryu J, Kim S, Cho Y, Choi J . Anti-inflammatory effect of anemarsaponin B isolated from the rhizomes of Anemarrhena asphodeloides in LPS-induced RAW 264.7 macrophages is mediated by negative regulation of the nuclear factor-kappaB and p38 pathways. Food Chem Toxicol. 2009; 47(7):1610-7. DOI: 10.1016/j.fct.2009.04.009. View

Habeeb A, Praveen Rao P, Knaus E . Design and synthesis of 4,5-diphenyl-4-isoxazolines: novel inhibitors of cyclooxygenase-2 with analgesic and antiinflammatory activity. J Med Chem. 2001; 44(18):2921-7. DOI: 10.1021/jm0101287. View

10.

Wan H, Coppens J, van Helden-Meeuwsen C, Leenen P, van Rooijen N, Khan N . Chorionic gonadotropin alleviates thioglycollate-induced peritonitis by affecting macrophage function. J Leukoc Biol. 2009; 86(2):361-70. DOI: 10.1189/jlb.0208126. View

11.

Rakesh , Sun D, Lee R, Tangallapally R, Lee R . Synthesis, optimization and structure-activity relationships of 3,5-disubstituted isoxazolines as new anti-tuberculosis agents. Eur J Med Chem. 2008; 44(2):460-72. PMC: 2674295. DOI: 10.1016/j.ejmech.2008.04.007. View

12.

Vermeulen L, De Wilde G, Van Damme P, Vanden Berghe W, Haegeman G . Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J. 2003; 22(6):1313-24. PMC: 151081. DOI: 10.1093/emboj/cdg139. View

13.

Laufer S, Margutti S, Fritz M . Substituted isoxazoles as potent inhibitors of p38 MAP kinase. ChemMedChem. 2006; 1(2):197-207. DOI: 10.1002/cmdc.200500025. View

14.

Wagner G, Laufer S . Small molecular anti-cytokine agents. Med Res Rev. 2005; 26(1):1-62. DOI: 10.1002/med.20042. View

15.

Stojanovic I, Cuzzocrea S, Mangano K, Mazzon E, Miljkovic D, Wang M . In vitro, ex vivo and in vivo immunopharmacological activities of the isoxazoline compound VGX-1027: modulation of cytokine synthesis and prevention of both organ-specific and systemic autoimmune diseases in murine models. Clin Immunol. 2007; 123(3):311-23. DOI: 10.1016/j.clim.2007.03.004. View

16.

Savill J, Wyllie A, Henson J, Walport M, Henson P, Haslett C . Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages. J Clin Invest. 1989; 83(3):865-75. PMC: 303760. DOI: 10.1172/JCI113970. View

17.

Choy E, Panayi G . Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001; 344(12):907-16. DOI: 10.1056/NEJM200103223441207. View

18.

Ozoe Y, Asahi M, Ozoe F, Nakahira K, Mita T . The antiparasitic isoxazoline A1443 is a potent blocker of insect ligand-gated chloride channels. Biochem Biophys Res Commun. 2009; 391(1):744-9. DOI: 10.1016/j.bbrc.2009.11.131. View

19.

El Gazzar M . HMGB1 modulates inflammatory responses in LPS-activated macrophages. Inflamm Res. 2007; 56(4):162-7. DOI: 10.1007/s00011-006-6112-0. View

20.

Gallagher T, Seibel G, Kassis S, Laydon J, BLUMENTHAL M, Lee J . Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. Bioorg Med Chem. 1997; 5(1):49-64. DOI: 10.1016/s0968-0896(96)00212-x. View