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Synthesis and Anti-Inflammatory Activity of 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-Derived NRF2 Activators
Kit-Kay Mak1,2,3, Zhang Shiming3, Ola Epemolu4
1Pharmaceutical Chemistry Department, International Medical University, 126 Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.
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.
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ortho–para-Directing Activators: –CH3, –OH, –⁠NH2, –OCH3