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

Abstract

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-κB, many previously discovered agents suffered from cytotoxicity. In this study, new alkylthiourea quinazoline derivatives were developed that selectively inhibit the activation of NF-κB 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 µM) and, less potently, of TNFα (IC50 = 4.0 µM); in comparison, the reference compound, caffeic acid phenethyl ester (CAPE), showed IC50s of 1.1 and 11.4 µM, respectively. Interestingly, 19 was found to block the translocation of the NF-κB dimer to the nucleus, although its release from the IκB complex was unaffected. Furthermore, 19 suppressed the phosphorylation of NF-κB-p65 at Ser468 but not at Ser536; however, 19 did not inhibit any kinase involved in NF-κB 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.

The Mystery of EVP4593: Perspectives of the Quinazoline-Derived Compound in the Treatment of Huntington’s Disease and Other Human Pathologies

“…Nevertheless, the mechanisms of pharmacological activities of many quinazoline derivatives remain poorly understood. Among the key targets of quinazoline derivatives are kinases, transcription factors, receptors and ion channels [ 3 , 4 , 5 , 6 , 7 ]. Here, we focused on one quinazoline derivative (4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine)—EVP4593 (also marked as QNZ in papers).…”

Transition metal(ii) complexes of halogenated derivatives of (E)-4-(2-(pyridin-2-ylmethylene)hydrazinyl)quinazoline: structure, antioxidant activity, DNA-binding DNA photocleavage, interaction with albumin andin silicostudies

“…3,4 Quinazolines constitute a class of heterocycles that contain two fused aromatic benzene and pyrimidine rings and exhibit a plethora of biological activities. [5][6][7][8][9][10] Hydrazones contain a characteristic R 1 R 2 CvN-NHR 3 functional group which due to its isomerization and nucleophilic, electrophilic and acidic sites gives rise to versatile uses of their carrier compounds. [10][11][12][13] In conjunction with well-situated electron donors, hydrazones are capable of forming metal complexes which were found to exhibit catalytic [14][15][16][17] and biological activities.…”