Design, synthesis, and antiproliferative activity of new 5-ethylsulfonyl-indazole-3-carbohydrazides as dual EGFR/VEGFR-2 kinases inhibitors
A novel series of 5-ethylsulfonyl-indazole-3-carbohydrazides 7a–o, serving as dual inhibitors of EGFR and VEGFR-2 was developed. The antiproliferative effects of compounds 7a–o were assessed against four cancer cell lines via the MTT assay. Compounds 7g, 7i–7l, and 7o emerged as the most efficient s...
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| Format: | Article |
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Taylor & Francis Group
2025-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2025.2516075 |
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| author | Lamya H. Al-Wahaibi Hesham A. Abou-Zied Mohamed A. Mahmoud Bahaa G. M. Youssif Stefan Bräse Safwat M. Rabea |
| author_facet | Lamya H. Al-Wahaibi Hesham A. Abou-Zied Mohamed A. Mahmoud Bahaa G. M. Youssif Stefan Bräse Safwat M. Rabea |
| author_sort | Lamya H. Al-Wahaibi |
| collection | DOAJ |
| description | A novel series of 5-ethylsulfonyl-indazole-3-carbohydrazides 7a–o, serving as dual inhibitors of EGFR and VEGFR-2 was developed. The antiproliferative effects of compounds 7a–o were assessed against four cancer cell lines via the MTT assay. Compounds 7g, 7i–7l, and 7o emerged as the most efficient six derivatives, with GI50 values ranging from 25 nM to 42 nM. Compounds 7j, 7k, and 7o (GI50 values of 27, 25, and 30, respectively) demonstrated greater potency than erlotinib (GI50 value of 33 nM), particularly against breast (MCF-7) cancer cell lines, and were identified as the most potent dual EGFR/VEGFR-2 inhibitors. Apoptotic markers assay results showed that increased levels of p53 and Bax proteins, along with lower levels of antiapoptotic Bcl-2, govern the apoptosis process in these new compounds. Computational analyses, encompassing molecular docking, molecular dynamics (MD) simulations, and density functional theory (DFT) computations, elucidated the binding interactions of these drugs with EGFR and VEGFR-2. |
| format | Article |
| id | doaj-art-bc5407d5aa7045578a2ddd61f2374afa |
| institution | DOAJ |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-bc5407d5aa7045578a2ddd61f2374afa2025-08-20T03:24:01ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742025-12-0140110.1080/14756366.2025.2516075Design, synthesis, and antiproliferative activity of new 5-ethylsulfonyl-indazole-3-carbohydrazides as dual EGFR/VEGFR-2 kinases inhibitorsLamya H. Al-Wahaibi0Hesham A. Abou-Zied1Mohamed A. Mahmoud2Bahaa G. M. Youssif3Stefan Bräse4Safwat M. Rabea5Department of Chemistry, College of Sciences, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi ArabiaMedicinal Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, EgyptPharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, EgyptPharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, EgyptInstitute of Biological and Chemical Systems, IBCS-FMS, Karlsruhe Institute of Technology, Karlsruhe, GermanyMedicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia, EgyptA novel series of 5-ethylsulfonyl-indazole-3-carbohydrazides 7a–o, serving as dual inhibitors of EGFR and VEGFR-2 was developed. The antiproliferative effects of compounds 7a–o were assessed against four cancer cell lines via the MTT assay. Compounds 7g, 7i–7l, and 7o emerged as the most efficient six derivatives, with GI50 values ranging from 25 nM to 42 nM. Compounds 7j, 7k, and 7o (GI50 values of 27, 25, and 30, respectively) demonstrated greater potency than erlotinib (GI50 value of 33 nM), particularly against breast (MCF-7) cancer cell lines, and were identified as the most potent dual EGFR/VEGFR-2 inhibitors. Apoptotic markers assay results showed that increased levels of p53 and Bax proteins, along with lower levels of antiapoptotic Bcl-2, govern the apoptosis process in these new compounds. Computational analyses, encompassing molecular docking, molecular dynamics (MD) simulations, and density functional theory (DFT) computations, elucidated the binding interactions of these drugs with EGFR and VEGFR-2.https://www.tandfonline.com/doi/10.1080/14756366.2025.2516075ApoptosisDFTcancerEGFRVEGFR-2 |
| spellingShingle | Lamya H. Al-Wahaibi Hesham A. Abou-Zied Mohamed A. Mahmoud Bahaa G. M. Youssif Stefan Bräse Safwat M. Rabea Design, synthesis, and antiproliferative activity of new 5-ethylsulfonyl-indazole-3-carbohydrazides as dual EGFR/VEGFR-2 kinases inhibitors Journal of Enzyme Inhibition and Medicinal Chemistry Apoptosis DFT cancer EGFR VEGFR-2 |
| title | Design, synthesis, and antiproliferative activity of new 5-ethylsulfonyl-indazole-3-carbohydrazides as dual EGFR/VEGFR-2 kinases inhibitors |
| title_full | Design, synthesis, and antiproliferative activity of new 5-ethylsulfonyl-indazole-3-carbohydrazides as dual EGFR/VEGFR-2 kinases inhibitors |
| title_fullStr | Design, synthesis, and antiproliferative activity of new 5-ethylsulfonyl-indazole-3-carbohydrazides as dual EGFR/VEGFR-2 kinases inhibitors |
| title_full_unstemmed | Design, synthesis, and antiproliferative activity of new 5-ethylsulfonyl-indazole-3-carbohydrazides as dual EGFR/VEGFR-2 kinases inhibitors |
| title_short | Design, synthesis, and antiproliferative activity of new 5-ethylsulfonyl-indazole-3-carbohydrazides as dual EGFR/VEGFR-2 kinases inhibitors |
| title_sort | design synthesis and antiproliferative activity of new 5 ethylsulfonyl indazole 3 carbohydrazides as dual egfr vegfr 2 kinases inhibitors |
| topic | Apoptosis DFT cancer EGFR VEGFR-2 |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2025.2516075 |
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