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- Title
Synthesis and Anti‐Inflammatory Activity of 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐Derived NRF2 Activators.
- Authors
Mak, Kit‐Kay; Shiming, Zhang; Epemolu, Ola; Dinkova‐Kostova, Albena T.; Wells, Geoffrey; Gazaryan, Irina G.; Sakirolla, Raghavendra; Mohd, Zulkefeli; Pichika, Mallikarjuna Rao
- 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 (LPSEc)‐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 (T1/2) and intrinsic clearance (Clint). The binding mode of the compounds and physicochemical properties were predicted via in silico studies.
- Subjects
NUCLEAR factor E2 related factor; ANTI-inflammatory agents; INFLAMMATORY mediators; LIVER microsomes; GENE expression
- Publication
ChemistryOpen, 2022, Vol 11, Issue 10, p1
- ISSN
2191-1363
- Publication type
Article
- DOI
10.1002/open.202200181