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-κB, many previously discovered agents suffered from cytotoxicity. In this study, new alkylthiourea quina...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-06-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/7/778 |
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| author | Sarah S. Darwish Po-Jen Chen Mostafa M. Hamed Reem A. Wagdy Shun-Hua Chen Ashraf H. Abadi Mohammad Abdel-Halim Tsong-Long Hwang Matthias Engel |
| author_facet | Sarah S. Darwish Po-Jen Chen Mostafa M. Hamed Reem A. Wagdy Shun-Hua Chen Ashraf H. Abadi Mohammad Abdel-Halim Tsong-Long Hwang Matthias Engel |
| author_sort | Sarah S. Darwish |
| collection | DOAJ |
| description | 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, <b>19</b>, strongly inhibited the production of IL-6 (IC<sub>50</sub> = 0.84 µM) and, less potently, of TNFα (IC<sub>50</sub> = 4.0 µM); in comparison, the reference compound, caffeic acid phenethyl ester (CAPE), showed IC<sub>50</sub>s of 1.1 and 11.4 µM, respectively. Interestingly, <b>19</b> was found to block the translocation of the NF-κB dimer to the nucleus, although its release from the IκB complex was unaffected. Furthermore, <b>19</b> suppressed the phosphorylation of NF-κB-p65 at Ser468 but not at Ser536; however, <b>19</b> 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. |
| first_indexed | 2024-03-09T06:04:15Z |
| format | Article |
| id | doaj.art-4f94eed140294a279c7ecbceba04a02c |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T06:04:15Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-4f94eed140294a279c7ecbceba04a02c2023-12-03T12:05:21ZengMDPI AGPharmaceuticals1424-82472022-06-0115777810.3390/ph15070778Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB InhibitorsSarah S. Darwish0Po-Jen Chen1Mostafa M. Hamed2Reem A. Wagdy3Shun-Hua Chen4Ashraf H. Abadi5Mohammad Abdel-Halim6Tsong-Long Hwang7Matthias Engel8Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, EgyptDepartment of Medical Research, E-Da Hospital, Kaohsiung 824005, TaiwanDrug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, GermanyDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, EgyptSchool of Nursing, Fooyin University, Kaohsiung 831, TaiwanDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, EgyptGraduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, TaiwanPharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, 66123 Saarbrücken, GermanyFor 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, <b>19</b>, strongly inhibited the production of IL-6 (IC<sub>50</sub> = 0.84 µM) and, less potently, of TNFα (IC<sub>50</sub> = 4.0 µM); in comparison, the reference compound, caffeic acid phenethyl ester (CAPE), showed IC<sub>50</sub>s of 1.1 and 11.4 µM, respectively. Interestingly, <b>19</b> was found to block the translocation of the NF-κB dimer to the nucleus, although its release from the IκB complex was unaffected. Furthermore, <b>19</b> suppressed the phosphorylation of NF-κB-p65 at Ser468 but not at Ser536; however, <b>19</b> 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.https://www.mdpi.com/1424-8247/15/7/7784-aminoquinazolinesNF-κB inhibitorinflammationmacrophage targetingTNFαIL-6 |
| spellingShingle | Sarah S. Darwish Po-Jen Chen Mostafa M. Hamed Reem A. Wagdy Shun-Hua Chen Ashraf H. Abadi Mohammad Abdel-Halim Tsong-Long Hwang Matthias Engel Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors Pharmaceuticals 4-aminoquinazolines NF-κB inhibitor inflammation macrophage targeting TNFα IL-6 |
| title | Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors |
| title_full | Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors |
| title_fullStr | Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors |
| title_full_unstemmed | Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors |
| title_short | Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors |
| title_sort | development of 4 phenylamino quinazoline alkylthiourea derivatives as novel nf κb inhibitors |
| topic | 4-aminoquinazolines NF-κB inhibitor inflammation macrophage targeting TNFα IL-6 |
| url | https://www.mdpi.com/1424-8247/15/7/778 |
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