Discovery and evaluation of novel synthetic 5-alkyl-4-oxo-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoxaline-1-carbox-amide derivatives as anti-inflammatory agents.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read Online Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Taylor & Francis Country of Publication: England NLM ID: 101150203 Publication Model: Print Cited Medium: Internet ISSN: 1475-6374 (Electronic) Linking ISSN: 14756366 NLM ISO Abbreviation: J Enzyme Inhib Med Chem Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basingstoke, UK : Taylor & Francis, c2002-
    • Subject Terms:
      Drug Discovery*; Amides/*pharmacology ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Anti-Ulcer Agents/*pharmacology ; Quinoxalines/*pharmacology ; Stomach Ulcer/*drug therapy; Amides/chemical synthesis ; Amides/chemistry ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis ; Anti-Inflammatory Agents, Non-Steroidal/chemistry ; Anti-Ulcer Agents/chemical synthesis ; Anti-Ulcer Agents/chemistry ; Cell Survival/drug effects ; Cells, Cultured ; Cytokines/antagonists & inhibitors ; Cytokines/biosynthesis ; Dose-Response Relationship, Drug ; Inflammation/drug therapy ; Inflammation/metabolism ; Lipopolysaccharides/antagonists & inhibitors ; Lipopolysaccharides/pharmacology ; Male ; Mice ; Molecular Structure ; Nitric Oxide/antagonists & inhibitors ; Nitric Oxide/metabolism ; Quinoxalines/chemical synthesis ; Quinoxalines/chemistry ; RAW 264.7 Cells ; Rats ; Stomach Ulcer/metabolism ; Structure-Activity Relationship
    • Abstract:
      To develop novel anti-inflammatory agents, a series of 5-alkyl-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide derivatives were designed, synthesised, and evaluated for anti-inflammatory effects using RAW264.7 cells. Structures of the synthesised compounds were determined using 1 H NMR, 13  C NMR, and HRMS. All the compounds were screened for anti-inflammatory activity based on their inhibitory effects against LPS-induced NO release. Among them, 5-(3,4,5-trimethoxybenzyl)-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide ( 6p ) showed the highest anti-inflammatory activity and inhibited NO release more potently than the lead compound D1 . Further studies revealed that compound 6p reduced the levels of NO, TNF-α, and IL-6, and that its anti-inflammatory activity involves the inhibition of COX-2 and iNOS and downregulation of the mitogen-activated protein kinases (MAPK) signal pathway. Notably, compound 6p displayed more prominent anti-inflammatory activity than D1 and the positive control ibuprofen in the in vivo acute inflammatory model. Overall, these findings indicate that compound 6p is a therapeutic candidate for the treatment of inflammation.
    • References:
      Bioorg Med Chem Lett. 2016 Mar 15;26(6):1576-1579. (PMID: 26876930)
      Arch Pharm (Weinheim). 2008 May;341(5):288-93. (PMID: 18389515)
      Bioorg Chem. 2019 May;86:583-597. (PMID: 30782576)
      Eur J Med Chem. 2018 May 25;152:417-423. (PMID: 29751235)
      Life Sci. 2004 Jun 25;75(6):639-53. (PMID: 15172174)
      Biochem Pharmacol. 2015 Jun 1;95(3):156-69. (PMID: 25850000)
      Clin Exp Immunol. 2007 Feb;147(2):227-35. (PMID: 17223962)
      Acta Pharm Sin B. 2017 Mar;7(2):230-240. (PMID: 28303231)
      Bioorg Chem. 2018 Aug;78:358-371. (PMID: 29627656)
      Bioorg Med Chem. 2019 Feb 1;27(3):516-524. (PMID: 30617018)
      Front Immunol. 2014 Oct 07;5:491. (PMID: 25339958)
      Biofactors. 2015 Jan-Feb;41(1):58-65. (PMID: 25728636)
      Endocr Rev. 2001 Apr;22(2):153-83. (PMID: 11294822)
      Eur J Med Chem. 2010 Nov;45(11):4807-12. (PMID: 20813431)
      Eur J Med Chem. 2019 Jan 15;162:70-79. (PMID: 30419492)
      J Ethnopharmacol. 2015 Dec 24;176:394-401. (PMID: 26560439)
      Eur J Med Chem. 2017 Sep 29;138:170-181. (PMID: 28667873)
      J Sci Food Agric. 2019 Mar 30;99(5):2329-2339. (PMID: 30338529)
      Eur J Med Chem. 2016 May 4;113:63-74. (PMID: 26922229)
      Neurochem Res. 2016 Jul;41(7):1570-7. (PMID: 26961887)
      Cell. 2010 Mar 19;140(6):883-99. (PMID: 20303878)
      J Med Chem. 1997 Aug 15;40(17):2762-9. (PMID: 9276022)
      Medchemcomm. 2017 Jun 2;8(7):1498-1504. (PMID: 30108861)
      J Pharm Pharmacol. 2002 Apr;54(4):453-72. (PMID: 11999122)
    • Contributed Indexing:
      Keywords: MAPKs; NO; Synthesis; anti-inflammatory activity
    • Accession Number:
      0 (Amides)
      0 (Anti-Inflammatory Agents, Non-Steroidal)
      0 (Anti-Ulcer Agents)
      0 (Cytokines)
      0 (Lipopolysaccharides)
      0 (Quinoxalines)
      31C4KY9ESH (Nitric Oxide)
    • Publication Date:
      Date Created: 20191112 Date Completed: 20200113 Latest Revision: 20210507
    • Publication Date:
      20240105
    • Accession Number:
      PMC6853232
    • Accession Number:
      10.1080/14756366.2019.1680658
    • Accession Number:
      31707866