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

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-1 beta, IL-6, TNF-alpha, and IFN-gamma) and inflammatory mediators (PGE2, COX-2, and NF-kappa B). 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.

Automated summary

This study investigated the NRF2 activity of compounds containing tetrahydrobenzo[b]thiophene, a new scaffold. The compounds disrupted the interaction between KEAP1 and NRF2, leading to anti-inflammatory effects and reversal of elevated pro-inflammatory cytokines and mediators.