Synthesis and Anti-Inflammatory Activity of 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-Derived NRF2 Activators

Kit-Kay Mak, Zhang Shiming, Ola Epemolu, Albena T. Dinkova-Kostova, Geoffrey Wells, Irina G. Gazaryan, Raghavendra Sakirolla, Zulkefeli Mohd, Mallikarjuna Rao Pichika (Lead / Corresponding author)

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Abstract

This is the first study investigating the nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity of compounds containing a new scaffold, tetrahydrobenzo[b]thiophene. Eighteen compounds were synthesised and confirmed their NRF2 activation through NQO1 enzymatic activity and mRNA expression of NQO1 and HO-1 in Hepa-1c1c7 cells. The compounds disrupted the interaction between Kelch-like ECH-associated protein 1 (KEAP1) and NRF2 via interfering with the KEAP1's Kelch domain. The compounds exhibited anti-inflammatory activity in Escherichia coli Lipopolysaccharide (LPS Ec )-stimulated RAW 264.7 cells. The anti-inflammatory activity of the compounds was associated with their ability to activate NRF2. The compounds reversed the elevated levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and IFN-γ) and inflammatory mediators (PGE2, COX-2, and NF-κB). The compounds were metabolically stable in human, rat, and mouse liver microsomes and showed optimum half-life (T 1/2 ) and intrinsic clearance (Cl int ). The binding mode of the compounds and physicochemical properties were predicted via in silico studies.

Original languageEnglish
Article numbere202200181
Number of pages11
JournalChemistryOpen
Volume11
Issue number10
Early online date25 Oct 2022
DOIs
Publication statusPublished - Oct 2022

Keywords

  • Mice
  • Rats
  • Humans
  • Animals
  • Kelch-Like ECH-Associated Protein 1/genetics
  • NF-E2-Related Factor 2/genetics
  • NF-kappa B/genetics
  • Lipopolysaccharides/pharmacology
  • Cyclooxygenase 2/genetics
  • Tumor Necrosis Factor-alpha/metabolism
  • Thiophenes/pharmacology
  • Dinoprostone
  • Interleukin-6/metabolism
  • Anti-Inflammatory Agents/pharmacology
  • Cytokines/metabolism
  • Inflammation Mediators
  • RNA, Messenger
  • thiophenes
  • NRF2 activators
  • tetrahydrobenzothiophene
  • anti-inflammatory

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