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Chem."},{"issue":"30","key":"10.1016\/j.ejmech.2025.118219_bib157","doi-asserted-by":"crossref","first-page":"18872","DOI":"10.1021\/acsomega.0c02038","article-title":"Dual targeting of VEGFR2 and C-Met kinases via the design and synthesis of substituted 3-(Triazolo-thiadiazin-3-yl)indolin-2-one derivatives as angiogenesis inhibitors","volume":"5","author":"Mohamady","year":"2020","journal-title":"ACS Omega"},{"issue":"2","key":"10.1016\/j.ejmech.2025.118219_bib158","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1016\/j.bmc.2006.10.029","article-title":"Analgesic agents without gastric damage: design and synthesis of structurally simple benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors","volume":"15","author":"Zheng","year":"2007","journal-title":"Bioorg. Med. Chem."},{"issue":"1","key":"10.1016\/j.ejmech.2025.118219_bib159","doi-asserted-by":"crossref","DOI":"10.1080\/14756366.2023.2220570","article-title":"Design, synthesis, and antitumor efficacy of novel 5-deazaflavin derivatives backed by kinase screening, docking, and ADME studies","volume":"38","author":"Bedewy","year":"2023","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"10.1016\/j.ejmech.2025.118219_bib160","unstructured":"Tamer A. Elwaie, Safinaz E. Abbas, Riham F. George, Enayat I. Aly, Zakaria Y. Abd Elmageed, Constantinos M. Mikelis, Hamed I. Ali, Novel Pyrrolotriazine-Based VEGFR-2 Kinase Inhibitors as Promising Sorafenib Analogues Targeting Hepatocellular Carcinoma, Unpublished data."},{"key":"10.1016\/j.ejmech.2025.118219_bib161","unstructured":"Maryam M. El Ganainy, Nashwa Mohamed Saber, Abu Zeid A. Hassanien, Ishaq Khan, Tamer A. Elwaie, Hamed I. 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