Design and biological evaluation of 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors
The dual c-Met/vascular endothelial growth factor receptor 2 (VEGFR-2) TK inhibition is a good strategy to overcome therapeutic resistance to small molecules VEGFR-2 inhibitors. In this study, we designed 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2 TK inhibitors. We...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2023.2189578 |
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| author | Abdelfattah Hassan Fawzy A. F. Mubarak Ihsan A. Shehadi Ahmed M. Mosallam Hussain Temairk Mohamed Badr Aboubakr H. Abdelmonsef |
| author_facet | Abdelfattah Hassan Fawzy A. F. Mubarak Ihsan A. Shehadi Ahmed M. Mosallam Hussain Temairk Mohamed Badr Aboubakr H. Abdelmonsef |
| author_sort | Abdelfattah Hassan |
| collection | DOAJ |
| description | The dual c-Met/vascular endothelial growth factor receptor 2 (VEGFR-2) TK inhibition is a good strategy to overcome therapeutic resistance to small molecules VEGFR-2 inhibitors. In this study, we designed 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2 TK inhibitors. We introduced new synthetic methods for reported derivatives of 3-substituted quinazoline-2,4(1H,3H)-dione 2a–g, in addition to the preparation of some new derivatives namely, 3 and 4a–j. Three compounds namely, 2c, 4b, and 4e showed substantial amount of inhibition for both c-Met and VEGFR-2 TK (IC50 range 0.052–0.084 µM). Both compounds 4b, 4e showed HB with highly conserved residue Asp1222 in the HB region of c-Met TK. For VEGFR-2 TK, compound 4b showed HB with a highly conserved residue Asp1046 in the HB region. Compound 4e showed HB with Glu885 and Asp1046. Moreover, in silico prediction of pharmacokinetic and physicochemical parameters of target compounds was carried out using SwissADME website. The quinazoline-2,4(1H,3H)-dione derivatives are promising antiproliferative candidates that require further optimisation. |
| first_indexed | 2024-03-09T02:02:37Z |
| format | Article |
| id | doaj.art-3768d35228f6460582feda1e7e03f2fd |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2025-03-20T14:23:09Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-3768d35228f6460582feda1e7e03f2fd2024-09-09T17:23:19ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742023-12-0138110.1080/14756366.2023.2189578Design and biological evaluation of 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2-TK inhibitorsAbdelfattah Hassan0Fawzy A. F. Mubarak1Ihsan A. Shehadi2Ahmed M. Mosallam3Hussain Temairk4Mohamed Badr5Aboubakr H. Abdelmonsef6Department of Medicinal Chemistry, Faculty of Pharmacy, South Valley University, Qena, EgyptDepartment of Chemistry, Faculty of Science, South Valley University, Qena, EgyptDepartment of Chemistry, College of Sciences, Pure and Applied Chemistry Research Group, University of Sharjah, Sharjah, United Arab EmiratesDepartment of Chemistry, Faculty of Science, South Valley University, Qena, EgyptDepartment of Chemistry, Faculty of Science, South Valley University, Qena, EgyptDepartment of Biochemistry, Faculty of Pharmacy, Menoufia University, Menoufia, EgyptDepartment of Chemistry, Faculty of Science, South Valley University, Qena, EgyptThe dual c-Met/vascular endothelial growth factor receptor 2 (VEGFR-2) TK inhibition is a good strategy to overcome therapeutic resistance to small molecules VEGFR-2 inhibitors. In this study, we designed 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2 TK inhibitors. We introduced new synthetic methods for reported derivatives of 3-substituted quinazoline-2,4(1H,3H)-dione 2a–g, in addition to the preparation of some new derivatives namely, 3 and 4a–j. Three compounds namely, 2c, 4b, and 4e showed substantial amount of inhibition for both c-Met and VEGFR-2 TK (IC50 range 0.052–0.084 µM). Both compounds 4b, 4e showed HB with highly conserved residue Asp1222 in the HB region of c-Met TK. For VEGFR-2 TK, compound 4b showed HB with a highly conserved residue Asp1046 in the HB region. Compound 4e showed HB with Glu885 and Asp1046. Moreover, in silico prediction of pharmacokinetic and physicochemical parameters of target compounds was carried out using SwissADME website. The quinazoline-2,4(1H,3H)-dione derivatives are promising antiproliferative candidates that require further optimisation.https://www.tandfonline.com/doi/10.1080/14756366.2023.2189578c-MetVEGFR-2colorectal cancerquinazoline-24(1H3H)-dioneN-acylhydrazone |
| spellingShingle | Abdelfattah Hassan Fawzy A. F. Mubarak Ihsan A. Shehadi Ahmed M. Mosallam Hussain Temairk Mohamed Badr Aboubakr H. Abdelmonsef Design and biological evaluation of 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors Journal of Enzyme Inhibition and Medicinal Chemistry c-Met VEGFR-2 colorectal cancer quinazoline-24(1H3H)-dione N-acylhydrazone |
| title | Design and biological evaluation of 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors |
| title_full | Design and biological evaluation of 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors |
| title_fullStr | Design and biological evaluation of 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors |
| title_full_unstemmed | Design and biological evaluation of 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors |
| title_short | Design and biological evaluation of 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors |
| title_sort | design and biological evaluation of 3 substituted quinazoline 2 4 1h 3h dione derivatives as dual c met vegfr 2 tk inhibitors |
| topic | c-Met VEGFR-2 colorectal cancer quinazoline-24(1H3H)-dione N-acylhydrazone |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2023.2189578 |
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