Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors

For many inflammatory diseases, new effective drugs with fewer side effects are needed. While it appears promising to target the activation of the central pro-inflammatory transcription factor NF-kappa B, many previously discovered agents suffered from cytotoxicity. In this study, new alkylthiourea quinazoline derivatives were developed that selectively inhibit the activation of NF-kappa B in macrophage-like THP-1 cells while showing low general cytotoxicity. One of the best compounds, 19, strongly inhibited the production of IL-6 (IC50 = 0.84 mu M) and, less potently, of TNF alpha (IC50 = 4.0 mu M); in comparison, the reference compound, caffeic acid phenethyl ester (CAPE), showed IC(50)s of 1.1 and 11.4 mu M, respectively. Interestingly, 19 was found to block the translocation of the NF-kappa B dimer to the nucleus, although its release from the I kappa B complex was unaffected. Furthermore, 19 suppressed the phosphorylation of NF-kappa B-p65 at Ser468 but not at Ser536; however, 19 did not inhibit any kinase involved in NF-kappa B activation. The only partial suppression of p65 phosphorylation might be associated with fewer side effects. Since several compounds selectively induced cell death in activated macrophage-like THP-1 cells, they might be particularly effective in various inflammatory diseases that are exacerbated by excess activated macrophages, such as arteriosclerosis and autoimmune diseases.

Automated summary

This study developed new drugs that selectively inhibit the activation of NF-kappa B in macrophages, which may help treat inflammatory diseases with fewer side effects.