{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:23:02Z","timestamp":1792804982740,"version":"4.5.0"},"reference-count":161,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Deanship of Graduate Studies and Scientific Research at Jouf University\n\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/02zsyt821","award":["DGSSR-2024-02-02146"],"award-info":[{"award-number":["DGSSR-2024-02-02146"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In response to recent advances in computer-aided drug discovery (CADD) enabled by high-performance computing, computational approaches were employed to support and rationalize the investigation of a VEGFR-2-targeted anticancer candidate, combining molecular-level modeling with experimental validation. Initial in silico ADMET profiling and molecular docking were conducted to support the evaluation of drug-like properties and target engagement within a series of para-toluidine-based derivatives (1\u201314). The most biologically active compound was further evaluated through 100 ns molecular dynamics simulations and comprehensive DFT calculations to investigate binding stability and electronic characteristics. Based on a rational design strategy and supported by computational analyses, the compounds were synthesized and fully characterized using IR, MS, 1H\/13C NMR, and elemental analysis. Biological evaluation was performed against HepG-2, MCF-7, HCT-116, and normal WI-38 cells. Mechanistic studies included VEGFR-2 inhibition, wound-healing migration assays, cell-cycle distribution analysis, apoptosis assessment, and caspase-3 activation. Several derivatives exhibited micromolar cytotoxic activity, with compound 14 emerging as the most active against HepG-2 cells (IC50 = 7.84 \u00b1 0.5 \u00b5M), showing cytotoxic activity comparable to that of sorafenib (IC50 = 9.18 \u00b1 0.6 \u00b5M) and demonstrating favorable selectivity toward normal WI-38 cells (IC50 = 67.75 \u00b1 3.6 \u00b5M). Compound 14 showed moderate VEGFR-2 inhibitory activity (IC50 = 0.55 \u00b5M), significant suppression of cell migration, pronounced G0\/G1 cell-cycle arrest, and robust apoptosis induction supported by caspase-3 activation. Molecular docking and MD simulations supported a stable binding mode within the VEGFR-2 active site. This integrated framework highlights compound 14 as a selectively active VEGFR-2-oriented anticancer candidate scaffold with a favorable selectivity profile, supported by experimental and computational analyses, warranting further lead optimization.<\/jats:p>","DOI":"10.3390\/ijms27073018","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T13:48:41Z","timestamp":1774532921000},"page":"3018","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["From Synthesis to Mechanism: Biological Evaluation of a p-Toluidine-Based Thiazolidinone-Quinoline VEGFR-2 Candidate Supported by CADD"],"prefix":"10.3390","volume":"27","author":[{"given":"Emad","family":"Manni","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3664-2745","authenticated-orcid":false,"given":"Modather F.","family":"Hussein","sequence":"additional","affiliation":[{"name":"Chemistry Department, College of Science, Jouf University, P.O. Box 2014, Sakaka 72341, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Elkady","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adel A.-H.","family":"Abdel-Rahman","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed A.","family":"Hawata","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8232-1830","authenticated-orcid":false,"given":"Wael A.","family":"El-Sayed","sequence":"additional","affiliation":[{"name":"Photochemistry Department, National Research Centre, Dokki, Giza 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5312-4870","authenticated-orcid":false,"given":"Ahmed F.","family":"El-Sayed","sequence":"additional","affiliation":[{"name":"Microbial Genetics Department, Biotechnology Research Institute, National Research Centre, Giza 12622, Egypt"},{"name":"Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 11517, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3841-6122","authenticated-orcid":false,"given":"Hagar S.","family":"El-Hema","sequence":"additional","affiliation":[{"name":"Basic Science Department (Chemistry), Thebes Higher Institute for Engineering, Thebes Academy, Maadi 11434, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1016\/S0140-6736(25)01570-3","article-title":"Global cancer burden: Progress, projections, and challenges","volume":"406","author":"Luo","year":"2025","journal-title":"Lancet"},{"key":"ref_3","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1002\/ijc.33574","article-title":"Cancer in Iran 2008 to 2025: Recent incidence trends and short-term predictions of the future burden","volume":"149","author":"Roshandel","year":"2021","journal-title":"Int. J. Cancer"},{"key":"ref_5","first-page":"141","article-title":"Drug resistance and combating drug resistance in cancer","volume":"2","author":"Wang","year":"2019","journal-title":"Cancer Drug Resist."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e265","DOI":"10.1002\/mco2.265","article-title":"Understanding and targeting resistance mechanisms in cancer","volume":"4","author":"Lei","year":"2023","journal-title":"MedComm"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e2443198","DOI":"10.1001\/jamanetworkopen.2024.43198","article-title":"Global disparities of cancer and its projected burden in 2050","volume":"7","author":"Bizuayehu","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_8","first-page":"27","article-title":"Acquired resistance to molecularly targeted therapies for cancer","volume":"8","author":"Stubbs","year":"2025","journal-title":"Cancer Drug Resist."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s43556-025-00352-w","article-title":"Drug resistance in cancer: Molecular mechanisms and emerging treatment strategies","volume":"6","author":"Li","year":"2025","journal-title":"Mol. Biomed."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Hoffmann, M.E., and K\u00fchn, F.E. (Chem. Soc. Rev., 2025). Au NHC complexes as anticancer agents: Milestones, strategies and future developments, Chem. Soc. Rev., in press.","DOI":"10.1039\/D5CS00924C"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/s41568-025-00824-9","article-title":"Acquired resistance in cancer: Towards targeted therapeutic strategies","volume":"25","author":"Soragni","year":"2025","journal-title":"Nat. Rev. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1159\/000530495","article-title":"Guidelines for the diagnosis and treatment of primary liver cancer (2022 edition)","volume":"12","author":"Zhou","year":"2023","journal-title":"Liver Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.jhep.2022.08.021","article-title":"Global burden of primary liver cancer in 2020 and predictions to 2040","volume":"77","author":"Rumgay","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/s41571-024-00868-0","article-title":"Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma","volume":"21","author":"Llovet","year":"2024","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Cano, L., Foucher, F., and Musso, O. (2025). Geographic diversity of human liver cancers mirrors global social inequalities. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1565692"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"102446","DOI":"10.1016\/j.jceh.2024.102446","article-title":"Global epidemiology of hepatocellular carcinoma","volume":"15","author":"Singh","year":"2025","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1200\/JCO.2025.43.4_suppl.529","article-title":"Hepatocellular carcinoma: A 30-year trend analysis of global burden stratified by risk factors and sociodemographic indexes","volume":"43","author":"Bhanushali","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/S0140-6736(25)01042-6","article-title":"The Lancet Commission on addressing the global hepatocellular carcinoma burden: Comprehensive strategies from prevention to treatment","volume":"406","author":"Chan","year":"2025","journal-title":"Lancet"},{"key":"ref_19","first-page":"r1587","article-title":"Majority of global liver cancer cases \u201cpreventable,\u201d Lancet commission finds","volume":"390","author":"Bowie","year":"2025","journal-title":"Lancet"},{"key":"ref_20","first-page":"40","article-title":"The Egyptian liver and schistosomiasis in 5000 years: The liver and river story","volume":"1","author":"Elgazzar","year":"2024","journal-title":"Egypt. J. Hist. Philos. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13120","DOI":"10.1038\/s41598-025-96615-1","article-title":"Long-term trends and future projections of liver cancer burden in China from 1990 to 2030","volume":"15","author":"Zhan","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"101571","DOI":"10.1016\/j.jhepr.2025.101571","article-title":"Hepatocellular carcinoma: Epidemiology, diagnosis and treatment","volume":"7","author":"Mauro","year":"2025","journal-title":"JHEP Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1097\/CM9.0000000000003264","article-title":"Global epidemiology of liver cancer 2022: An emphasis on geographic disparities","volume":"137","author":"Li","year":"2024","journal-title":"Chin. Med. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"355","DOI":"10.3350\/cmh.2023.0070","article-title":"The latest global burden of liver cancer: A past and present threat","volume":"29","author":"Oh","year":"2023","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Jiang, Z., Zeng, G., Dai, H., Bian, Y., Wang, L., Cao, W., and Yang, J. (2025). Global, regional and national burden of liver cancer 1990\u20132021: A systematic analysis of the global burden of disease study 2021. BMC Public Health, 25.","DOI":"10.1186\/s12889-025-22026-6"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.3748\/wjg.v10.i8.1079","article-title":"Curse of schistosomiasis on Egyptian liver","volume":"10","year":"2004","journal-title":"World J. Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"S46","DOI":"10.1038\/551S46a","article-title":"Egypt: The flatworm\u2019s revenge","volume":"551","author":"Sarant","year":"2017","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ebiom.2016.11.034","article-title":"Parasite infection, carcinogenesis and human malignancy","volume":"15","author":"Brindley","year":"2017","journal-title":"EBioMedicine"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13027-024-00569-4","article-title":"A prognostic model for Schistosoma japonicum infection-associated liver hepatocellular carcinoma: Strengthening the connection through initial biological experiments","volume":"19","author":"Sheng","year":"2024","journal-title":"Infect. Agents Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.bjid.2018.06.001","article-title":"Schistosomal liver fibrosis and hepatocellular carcinoma\u2014Case series of patients submitted to liver transplantation","volume":"22","author":"Filgueira","year":"2018","journal-title":"Braz. J. Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"260","DOI":"10.14218\/JCTH.2015.00027","article-title":"Hepatocellular carcinoma related to Schistosoma mansoni infection: Case series and literature review","volume":"3","author":"Toda","year":"2015","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"von Buelow, V., Lichtenberger, J., Grevelding, C.G., Falcone, F.H., Roeb, E., and Roderfeld, M. (2021). Does Schistosoma mansoni facilitate carcinogenesis?. Cells, 10.","DOI":"10.3390\/cells10081982"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e2445525","DOI":"10.1001\/jamanetworkopen.2024.45525","article-title":"Trends in hepatocellular carcinoma mortality rates in the US and projections through 2040","volume":"7","author":"Qiu","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"k2817","DOI":"10.1136\/bmj.k2817","article-title":"Mortality due to cirrhosis and liver cancer in the United States, 1999\u20132016: Observational study","volume":"362","author":"Tapper","year":"2018","journal-title":"BMJ"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Lee, Y.T., Wang, J.J., Danpanichkul, P., Kim, H.S., Kuo, A., Ayoub, W.S., Trivedi, H.D., Wang, Y., Vipani, A., and Martin, P. (Clin. Gastroenterol. Hepatol., 2025). Recent trends of incidence, mortality, treatment, and overall survival of hepatocellular carcinoma in the United States, Clin. Gastroenterol. Hepatol., in press.","DOI":"10.1016\/j.cgh.2025.10.012"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"100532","DOI":"10.1016\/j.clinme.2025.100532","article-title":"Hepatocellular carcinoma (HCC): An update on risk factors, surveillance, diagnosis and treatment strategies","volume":"25","author":"Mathew","year":"2025","journal-title":"Clin. Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Cabral, L.K.D., Tiribelli, C., and Sukowati, C.H.C. (2020). Sorafenib resistance in hepatocellular carcinoma: The relevance of genetic heterogeneity. Cancers, 12.","DOI":"10.3390\/cancers12061576"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1159\/000529824","article-title":"Survival trends in sorafenib for advanced hepatocellular carcinoma: A reconstructed individual patient data meta-analysis of randomized trials","volume":"12","author":"Tan","year":"2023","journal-title":"Liver Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s43066-023-00306-3","article-title":"Latest advances in hepatocellular carcinoma management and prevention through advanced technologies","volume":"14","author":"Addissouky","year":"2024","journal-title":"Egypt. Liver J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"112","DOI":"10.20517\/2394-5079.2017.03","article-title":"Management of advanced hepatocellular carcinoma: Review of current and potential therapies","volume":"3","author":"Gomaa","year":"2017","journal-title":"Hepatoma Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41392-024-02075-w","article-title":"Hepatocellular carcinoma: Signaling pathways and therapeutic advances","volume":"10","author":"Zheng","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Guo, L., Hu, C., Yao, M., and Han, G. (2023). Mechanism of sorafenib resistance associated with ferroptosis in HCC. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1207496"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.21037\/atm-2020-131","article-title":"Doxorubicin for the treatment of hepatocellular carcinoma: GAME OVER!","volume":"8","author":"Guiu","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e000238","DOI":"10.1136\/esmoopen-2017-000238","article-title":"Safety and efficacy of intra-arterial hepatic chemotherapy with doxorubicin-loaded nanoparticles in hepatocellular carcinoma","volume":"2","author":"Merle","year":"2017","journal-title":"ESMO Open"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Philippi, Z., Reddy, K.D., Malik, S., Al-Khalil, Z., and Dbouk, N. (2025). Systemic therapy for unresectable hepatocellular carcinoma: Current landscape and future directions. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26135994"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"25","DOI":"10.20892\/j.issn.2095-3941.2022.0449","article-title":"Angiogenesis in hepatocellular carcinoma: Mechanisms and anti-angiogenic therapies","volume":"20","author":"Yao","year":"2023","journal-title":"Cancer Biol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"77","DOI":"10.2147\/JHC.S224471","article-title":"Angiogenesis in hepatocellular carcinoma: Pathophysiology, targeted therapy, and role of imaging","volume":"7","author":"Moawad","year":"2020","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1158\/1078-0432.CCR-18-1254","article-title":"The role of angiogenesis in hepatocellular carcinoma","volume":"25","author":"Morse","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Pinto, E., Pelizzaro, F., Farinati, F., and Russo, F.P. (2023). Angiogenesis and hepatocellular carcinoma: From molecular mechanisms to systemic therapies. Medicina, 59.","DOI":"10.3390\/medicina59061115"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Wang, L., Liu, W.Q., Broussy, S., Han, B., and Fang, H. (2023). Recent advances of anti-angiogenic inhibitors targeting VEGF\/VEGFR axis. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1307860"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Wang, X., Bove, A.M., Simone, G., and Ma, B. (2020). Molecular bases of VEGFR-2-mediated physiological function and pathological role. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.599281"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s12079-016-0352-8","article-title":"VEGF-A\/VEGFR2 signaling network in endothelial cells relevant to angiogenesis","volume":"10","author":"Abhinand","year":"2016","journal-title":"J. Cell Commun. Signal."},{"key":"ref_53","first-page":"63","article-title":"The vascular endothelial growth factor receptor (VEGFR) and cancer","volume":"4","author":"Merde","year":"2018","journal-title":"Anatol. J. Pharm. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"25682","DOI":"10.1038\/s41598-024-76258-4","article-title":"Targeting the VEGFR2 signaling pathway for angiogenesis and fibrosis regulation in neovascular age-related macular degeneration","volume":"14","author":"Yu","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1007\/s12272-025-01545-1","article-title":"Targeting vascular endothelial growth factor receptor-2 (VEGFR-2): Structural biology, functional insights, and therapeutic resistance","volume":"48","author":"Shah","year":"2025","journal-title":"Arch. Pharm. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"100009","DOI":"10.1016\/j.medidd.2019.100009","article-title":"Vascular endothelial growth factor receptor (VEGFR-2)\/KDR inhibitors: Medicinal chemistry perspective","volume":"2","author":"Modi","year":"2019","journal-title":"Med. Drug Discov."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Marques, C.S., Brand\u00e3o, P., and Burke, A.J. (2024). Targeting vascular endothelial growth factor receptor 2 (VEGFR-2): Latest insights on synthetic strategies. Molecules, 29.","DOI":"10.3390\/molecules29225341"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1111\/cbdd.14196","article-title":"Molecular target interactions of quinoline derivatives as anticancer agents: A review","volume":"101","author":"Pradhan","year":"2023","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"El-Hema, H.S., El Fekey, H.M., Abdel-Rahman, A.A.-H., Morsy, A.R.I., Radwan, A.A., Nossier, E.S., Alshabani, L.A., Saleh, A., Hussein, M.F., and Hawata, M.A. (2026). Design and Multi-Level Biological Evaluation of Naphthyridine-Based Derivatives as Topoisomerase I\/II-Targeted Anticancer Agents with Anti-Fowlpox Virus Activity Supported by In Silico Analysis. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27052445"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1158\/1538-7445.AM2017-1914","article-title":"GNS561 is a new quinoline derivative with high efficacy on cancer stem cells from colorectal liver metastasis and hepatocellular carcinoma","volume":"77","author":"Bassissi","year":"2017","journal-title":"Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Abd Elrahman, S.F., Ahmed, A.A.S., Abd Elsatar, D., Elkady, S., Elgendy, A., Alnakeeb, F., Elmongy, E.I., Henidi, H.A., El-Gendy, S.M., and El Sayed, I.E.T. (2023). Cytotoxic potential of a novel quinoline derivative: 11-(1,4-bisaminopropylpiperazinyl)-5-methyl-5H-indolo [2,3-b]quinoline against different cancer cell lines via modulation of protein expression. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241814336"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.3892\/ijo.2016.3717","article-title":"An indolylquinoline derivative activates DNA damage response and apoptosis in human hepatocellular carcinoma cells","volume":"49","author":"Liu","year":"2016","journal-title":"Int. J. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4920","DOI":"10.1016\/j.arabjc.2016.10.009","article-title":"Comprehensive review on current developments of quinoline-based anticancer agents","volume":"12","author":"Jain","year":"2019","journal-title":"Arab. J. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e03182","DOI":"10.1002\/slct.202503182","article-title":"Synthesis of 8-hydroxyquinoline derivatives: A revolutionary target in medicinal chemistry (2020\u20132025)","volume":"10","author":"Sharma","year":"2025","journal-title":"ChemistrySelect"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"117681","DOI":"10.1016\/j.bmc.2024.117681","article-title":"Inhibition of cancer cells by quinoline-based compounds: A review with mechanistic insights","volume":"103","author":"Saxena","year":"2024","journal-title":"Bioorg. Med. Chem."},{"key":"ref_66","first-page":"217","article-title":"Designing of novel quinoline derivatives as hepatocellular carcinoma inhibitors using in silico approaches","volume":"13","author":"Khaldan","year":"2023","journal-title":"Biointerface Res. Appl. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"825","DOI":"10.2174\/1871520620666200516150345","article-title":"Recent progress in the development of quinoline derivatives for exploitation as anticancer agents","volume":"21","author":"Man","year":"2021","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"130","DOI":"10.21608\/ajps.2023.332171","article-title":"An overview of quinoline derivatives as anticancer agents","volume":"68","author":"Aref","year":"2023","journal-title":"Al-Azhar J. Pharm. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Martorana, A., La Monica, G., and Lauria, A. (2020). Quinoline-based molecules targeting c-Met, EGF, and VEGF receptors and proteins involved in related carcinogenic pathways. Molecules, 25.","DOI":"10.3390\/molecules25184279"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2100359","DOI":"10.1002\/ardp.202100359","article-title":"Targeting VEGFR-2 by new quinoxaline derivatives: Design, synthesis, antiproliferative assay, apoptosis induction, and in silico studies","volume":"355","author":"Alsaif","year":"2022","journal-title":"Arch. Pharm."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Elebiju, O.F., Ajani, O.O., Oduselu, G.O., Ogunnupebi, T.A., and Adebiyi, E. (2023). Recent advances in functionalized quinoline scaffolds and hybrids\u2014Exceptional pharmacophores in therapeutic medicine. Front. Chem., 10.","DOI":"10.3389\/fchem.2022.1074331"},{"key":"ref_72","first-page":"592879","article-title":"Pharmacophore modelling and synthesis of quinoline-3-carbohydrazides as antioxidants","volume":"2011","author":"Ismaili","year":"2011","journal-title":"Int. J. Med. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e202500279","DOI":"10.1002\/cmdc.202500279","article-title":"Recent advances of quinoline-based small molecules as kinase inhibitors (2020\u20132024)","volume":"20","author":"Sultan","year":"2025","journal-title":"ChemMedChem"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Czy\u017cnikowska, \u017b., Mys\u0142ek, M., Marciniak, A., P\u0142aczek, R., Kotynia, A., and Krzy\u017cak, E. (2025). In silico approach to design of new multi-targeted inhibitors based on a quinoline ring with potential anticancer properties. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26104620"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"104639","DOI":"10.1016\/j.bioorg.2021.104639","article-title":"Quinolines, a perpetual, multipurpose scaffold in medicinal chemistry","volume":"109","author":"Yadav","year":"2021","journal-title":"Bioorg. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"30576","DOI":"10.1039\/D5RA00534E","article-title":"Quinoline derivatives\u2019 biological interest for anti-malarial and anti-cancer activities: An overview","volume":"15","author":"Chavan","year":"2025","journal-title":"RSC Adv."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"109476","DOI":"10.1016\/j.bioorg.2026.109476","article-title":"Expanding the chemical and therapeutic landscape of 5H-indeno[1,2-b]pyridin-5-one derivatives: Novel anticancer activity, EGFR inhibition, and modulation of HIF\u2013VEGF and PI3K\/AKT\/mTOR pathways supported by computational insights","volume":"170","author":"Hawata","year":"2026","journal-title":"Bioorg. Chem."},{"key":"ref_78","unstructured":"U.S. Food and Drug Administration (2018). FDA Approves Lenvatinib for Unresectable Hepatocellular Carcinoma."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e484","DOI":"10.1002\/onco.13566","article-title":"FDA supplemental approval summary: Lenvatinib for the treatment of unresectable hepatocellular carcinoma","volume":"26","author":"Nair","year":"2021","journal-title":"Oncologist"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1007\/s12072-022-10398-5","article-title":"Lenvatinib for the treatment of hepatocellular carcinoma\u2014A real-world multicenter Australian cohort study","volume":"16","author":"Patwala","year":"2022","journal-title":"Hepatol. Int."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"78","DOI":"10.3892\/br.2022.1561","article-title":"Effect of lenvatinib treatment on the cell cycle and microRNA profile in hepatocellular carcinoma cells","volume":"17","author":"Nakahara","year":"2022","journal-title":"Biomed. Rep."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Sacco, R., Giannini, E.G., Tortora, R., Di Costanzo, G.G., Mega, A., Marzi, L., Pieri, G., Pasta, A., Daniele, B., and Federico, P. (2025). Lenvatinib is highly effective in patients with hepatocellular carcinoma related to both metabolic dysfunction-associated steatohepatitis and alcoholic etiology: A propensity score analysis. Cancers, 17.","DOI":"10.3390\/cancers17111808"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Hatanaka, T., Naganuma, A., and Kakizaki, S. (2021). Lenvatinib for hepatocellular carcinoma: A literature review. Pharmaceuticals, 14.","DOI":"10.3390\/ph14010036"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.4251\/wjgo.v13.i12.2076","article-title":"Prospect of lenvatinib for unresectable hepatocellular carcinoma in the new era of systemic chemotherapy","volume":"13","author":"Sho","year":"2021","journal-title":"World J. Gastrointest. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.2147\/JHC.S411806","article-title":"Application and resistance mechanisms of lenvatinib in patients with advanced hepatocellular carcinoma","volume":"10","author":"Tao","year":"2023","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/s13045-024-01647-1","article-title":"Lenvatinib and immune-checkpoint inhibitors in hepatocellular carcinoma: Mechanistic insights, clinical efficacy, and future perspectives","volume":"17","author":"Chen","year":"2024","journal-title":"J. Hematol. Oncol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1038\/s41401-022-01021-2","article-title":"Hepatocellular carcinoma cells lose lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation","volume":"44","author":"Mauriz","year":"2023","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"188391","DOI":"10.1016\/j.bbcan.2020.188391","article-title":"Lenvatinib for hepatocellular carcinoma: From preclinical mechanisms to anti-cancer therapy","volume":"1874","author":"Zhao","year":"2020","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"31","DOI":"10.2147\/JHC.S168953","article-title":"Lenvatinib for the treatment of unresectable hepatocellular carcinoma: Evidence to date","volume":"6","author":"Personeni","year":"2019","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Gawi Ermi, A., and Sarkar, D. (2024). Resistance to tyrosine kinase inhibitors in hepatocellular carcinoma (HCC): Clinical implications and potential strategies to overcome the resistance. Cancers, 16.","DOI":"10.3390\/cancers16233944"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1038\/s41416-020-0737-6","article-title":"A multicentre phase 1b\/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma","volume":"122","author":"Fountzilas","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_92","unstructured":"U.S. Food and Drug Administration (2021). FDA Approves Tivozanib for Relapsed or Refractory Advanced Renal Cell Carcinoma."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.21037\/atm-20-3526","article-title":"Tivozanib in advanced inoperable hepatocellular carcinoma: Considerations for patients with liver cirrhosis","volume":"8","author":"Oh","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1200\/JCO.2022.40.4_suppl.462","article-title":"Phase 1b\/2 study of tivozanib in combination with durvalumab in subjects with advanced hepatocellular carcinoma (Deductive): Efficacy results in previously untreated patients","volume":"40","author":"Iyer","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1056\/NEJMoa1717002","article-title":"Cabozantinib in patients with advanced and progressing hepatocellular carcinoma","volume":"379","author":"Meyer","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1089\/thy.2013.0137","article-title":"In vitro and in vivo activity of cabozantinib (XL184), an inhibitor of RET, MET, and VEGFR2, in a model of medullary thyroid cancer","volume":"23","author":"Bentzien","year":"2013","journal-title":"Thyroid"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e453","DOI":"10.1093\/oncolo\/oyab076","article-title":"A phase Ib study of lucitanib (AL3810) in a cohort of patients with recurrent and metastatic nasopharyngeal carcinoma","volume":"27","author":"Zhang","year":"2022","journal-title":"Oncologist"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"145685","DOI":"10.1016\/j.molstruc.2026.145685","article-title":"Thienyl-based pyrimidine hybrids as multi-target anticancer agents: Design, synthesis, and integrated experimental\u2013computational insights into CDK4 inhibition and apoptosis","volume":"1361","author":"Modather","year":"2026","journal-title":"J. Mol. Struct."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.forsciint.2012.05.020","article-title":"Gas at postmortem computed tomography\u2014An evaluation of 73 non-putrefied trauma and non-trauma cases","volume":"222","author":"Gebhart","year":"2012","journal-title":"Forensic Sci. Int."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1001\/archsurg.2011.296","article-title":"Predicting in-hospital mortality in patients undergoing complex gastrointestinal surgery: Determining the optimal risk adjustment method","volume":"147","author":"Grendar","year":"2012","journal-title":"Arch. Surg."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s13304-019-00658-9","article-title":"A stepwise learning curve to define the standard for technical improvement in laparoscopic liver resections: Complexity-based analysis in 1032 procedures","volume":"71","author":"Aldrighetti","year":"2019","journal-title":"Updates Surg."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Saoudi Gonzalez, N., Castet, F., Elez, E., Macarulla, T., and Tabernero, J. (2022). Current and emerging anti-angiogenic therapies in gastrointestinal and hepatobiliary cancers. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1021772"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1056\/NEJMoa0708857","article-title":"Sorafenib in advanced hepatocellular carcinoma","volume":"359","author":"Llovet","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/S0140-6736(16)32453-9","article-title":"Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial","volume":"389","author":"Bruix","year":"2017","journal-title":"Lancet"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.jcf.2019.03.005","article-title":"A two-center analysis of hyperpolarized 129Xe lung MRI in stable pediatric cystic fibrosis: Potential as a biomarker for multi-site trials","volume":"18","author":"Couch","year":"2019","journal-title":"J. Cyst. Fibros."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1200\/JCO.2012.45.8976","article-title":"Competing roads to larynx preservation","volume":"31","author":"Vokes","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"e1012","DOI":"10.1093\/oncolo\/oyae073","article-title":"A phase IV study to evaluate the safety of fruquintinib in Chinese patients in real-world clinical practice","volume":"29","author":"Li","year":"2024","journal-title":"Oncologist"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"461","DOI":"10.5582\/bst.2019.01243","article-title":"Rapid advances in research on and development of anticancer drugs in China","volume":"13","author":"Yao","year":"2019","journal-title":"Biosci. Trends"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1080\/14756366.2022.2110869","article-title":"New quinoline and isatin derivatives as apoptotic VEGFR-2 inhibitors: Design, synthesis, anti-proliferative activity, docking, ADMET, toxicity, and MD simulation studies","volume":"37","author":"Elkaeed","year":"2022","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"4042","DOI":"10.1158\/1078-0432.CCR-10-3387","article-title":"Foretinib (GSK1363089), an orally available multikinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer metastasis","volume":"17","author":"Zillhardt","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"7099","DOI":"10.1158\/0008-5472.CAN-04-1443","article-title":"BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF\/MEK\/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis","volume":"64","author":"Wilhelm","year":"2004","journal-title":"Cancer Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"11346","DOI":"10.1038\/s41598-023-38264-w","article-title":"New proapoptotic chemotherapeutic agents based on the quinolone-3-carboxamide scaffold acting by VEGFR-2 inhibition","volume":"13","author":"Nissan","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"6653","DOI":"10.1016\/j.bmcl.2010.09.014","article-title":"Design, synthesis and biological evaluation of quinoline amide derivatives as novel VEGFR-2 inhibitors","volume":"20","author":"Yang","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"e24005","DOI":"10.1016\/j.heliyon.2024.e24005","article-title":"Discovery of new thiazolidine-2,4-dione derivatives as potential VEGFR-2 inhibitors: In vitro and in silico studies","volume":"10","author":"Eissa","year":"2024","journal-title":"Heliyon"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1080\/14756366.2022.2085693","article-title":"Design and synthesis of thiazolidine-2,4-diones hybrids with 1,2-dihydroquinolones and 2-oxindoles as potential VEGFR-2 inhibitors: In vitro anticancer evaluation and in silico studies","volume":"37","author":"Taghour","year":"2022","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"27801","DOI":"10.1039\/D3RA05689A","article-title":"Synthesis, biological evaluation and computer-aided discovery of new thiazolidine-2,4-dione derivatives as potential antitumor VEGFR-2 inhibitors","volume":"13","author":"Elkady","year":"2023","journal-title":"RSC Adv."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"36134","DOI":"10.1021\/acsomega.5c03795","article-title":"Targeting cancer with new morpholine-benzimidazole-oxadiazole derivatives: Synthesis, biological evaluation, and computational insights","volume":"10","author":"Osmaniye","year":"2025","journal-title":"ACS Omega"},{"key":"ref_118","first-page":"145461","article-title":"From benzo[g]quinoline multitargeted anticancer scaffold to a potent benzo[g]pyrimido[4,5-b]quinoline lead targeting wild-type and mutant EGFR: Insights from integrated computational studies, molecular signaling modulation, and gene expression networks","volume":"1395","author":"Hawata","year":"2026","journal-title":"J. Mol. Struct."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Duan, M., Mahal, A., Alkouri, A., Wang, C., Zhang, Z., Ren, J., and Obaidullah, A.J. (2024). Synthesis, anticancer activity, and molecular docking of new 1,2,3-triazole linked tetrahydrocurcumin derivatives. Molecules, 29.","DOI":"10.3390\/molecules29133010"},{"key":"ref_120","first-page":"100294","article-title":"Molecules with alkyne fragment in medicinal chemistry: The path from neurotoxins to drugs","volume":"15","author":"Zelisko","year":"2025","journal-title":"Eur. J. Med. Chem. Rep."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Janowska, S., Paneth, A., and Wujec, M. (2020). Cytotoxic properties of 1,3,4-thiadiazole derivatives\u2014A review. Molecules, 25.","DOI":"10.3390\/molecules25184309"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Alsalim, T.A.Q., Nasir, N.M., El-Arabey, A.A., and Abdalla, M. (2022). Anticancer and antioxidant activities and molecular docking study of thiazolidine-4-one and thiadiazole derivatives. Molecules, 27.","DOI":"10.21203\/rs.3.rs-1200559\/v1"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1002\/med.21634","article-title":"Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine-containing bioactive molecules","volume":"40","author":"Kourounakis","year":"2020","journal-title":"Med. Res. Rev."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1039\/D2MD00023G","article-title":"Morpholine substituted quinazoline derivatives as anticancer agents against MCF-7, A549 and SHSY-5Y cancer cell lines and mechanistic studies","volume":"13","author":"Dwivedi","year":"2022","journal-title":"RSC Med. Chem."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.ejmech.2019.02.015","article-title":"Revealing quinquennial anticancer journey of morpholine: A SAR-based review","volume":"167","author":"Arshad","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"104168","DOI":"10.1016\/j.arabjc.2022.104168","article-title":"Review on recent development of quinoline for anticancer activities","volume":"15","author":"Ilakiyalakshmi","year":"2022","journal-title":"Arab. J. Chem."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.3390\/molecules27061985","article-title":"In Silico Structure-Based Approach for Group Efficiency Estimation in Fragment-Based Drug Design Using Evaluation of Fragment Contributions","volume":"27","author":"Shulga","year":"2022","journal-title":"Molecules"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13321-019-0330-2","article-title":"The Nature of Ligand Efficiency","volume":"11","author":"Kenny","year":"2019","journal-title":"J. Cheminform."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1002\/cmdc.200800132","article-title":"Group Efficiency: A Guideline for Hits-to-Leads Chemistry","volume":"3","author":"Verdonk","year":"2008","journal-title":"ChemMedChem"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"107817","DOI":"10.1016\/j.bioorg.2024.107817","article-title":"Tetrahydrocarbazoles incorporating 5-arylidene-4-thiazolinones as potential antileukemia and antilymphoma targeting tyrosine kinase and tubulin polymerase enzymes: Design, synthesis, structural, biological and molecular docking studies","volume":"153","author":"Ali","year":"2024","journal-title":"Bioorg. Chem."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"S1980","DOI":"10.1016\/j.arabjc.2013.07.026","article-title":"Molecular modeling studies of quinoline derivatives as VEGFR-2 tyrosine kinase inhibitors using pharmacophore-based 3D-QSAR and docking approach","volume":"10","author":"Ugale","year":"2017","journal-title":"Arab. J. Chem."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"118930","DOI":"10.1016\/j.biopha.2025.118930","article-title":"Targeting tumors and inflammation: A quinoline\u2013chalcone ruthenium complex with therapeutic promise","volume":"194","author":"Tatar","year":"2026","journal-title":"Biomed. Pharmacother."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1080\/14756366.2021.1899168","article-title":"Discovery of novel quinoline-based analogues of combretastatin A-4 as tubulin polymerisation inhibitors with apoptosis-inducing activity and potent anticancer effect","volume":"36","author":"Ibrahim","year":"2021","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.1016\/j.arabjc.2015.04.030","article-title":"Novel 2,5-disubstituted-1,3,4-oxadiazole derivatives induce apoptosis in HepG2 cells through p53-mediated intrinsic pathway","volume":"12","author":"Sankhe","year":"2019","journal-title":"Arab. J. Chem."},{"key":"ref_135","first-page":"1751","article-title":"Heterogeneity of malignant cells from a human colonic carcinoma","volume":"41","author":"Brattain","year":"1981","journal-title":"Cancer Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/282615a0","article-title":"Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line","volume":"282","author":"Aden","year":"1979","journal-title":"Nature"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1093\/jnci\/51.5.1409","article-title":"A human cell line from a pleural effusion derived from a breast carcinoma","volume":"51","author":"Soule","year":"1973","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"143790","DOI":"10.1016\/j.molstruc.2025.143790","article-title":"Novel pyrimidopyridothiazine-based derivatives as potential anticancer and antibacterial agents: A step towards design and synthesis of multi-targeted therapeutics","volume":"1349","author":"Mady","year":"2026","journal-title":"J. Mol. Struct."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/0014-4827(61)90192-6","article-title":"The serial cultivation of human diploid cell strains","volume":"25","author":"Hayflick","year":"1961","journal-title":"Exp. Cell Res."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"},{"key":"ref_141","first-page":"936","article-title":"Evaluation of a tetrazolium-based semiautomated colorimetric assay: Assessment of chemosensitivity testing","volume":"47","author":"Carmichael","year":"1987","journal-title":"Cancer Res."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1089\/adt.2009.0222","article-title":"ADP-Glo: A bioluminescent and homogeneous ADP monitoring assay for kinases","volume":"7","author":"Zegzouti","year":"2009","journal-title":"Assay Drug Dev. Technol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"27992","DOI":"10.1038\/s41598-025-12140-1","article-title":"Design, antiproliferative potency, and in silico studies of novel 5-(methylfuran-3-ylthio)-3-phenylquinazolin-4(3H)-one derivatives as potential EGFR inhibitors","volume":"15","author":"Soliman","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nprot.2007.30","article-title":"In vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro","volume":"2","author":"Liang","year":"2007","journal-title":"Nat. Protoc."},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"El-Hema, H.S., Shehata, H.E., Hawata, M.A., Nossier, E.S., El-Sayed, A.F., Altwaijry, N.A., and Abdel-Rahman, A.A.H. (2025). Innovative amino-functionalization of pyrido[2,3-d]pyrimidine scaffolds for broad therapeutic applications supported by computational analyses. Pharmaceuticals, 18.","DOI":"10.3390\/ph18101472"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1186\/s12935-022-02568-0","article-title":"MicroRNA-146a promotes proliferation, migration, and invasion of HepG2 via regulating FLAP","volume":"22","author":"Wang","year":"2022","journal-title":"Cancer Cell Int."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1038\/nprot.2006.238","article-title":"Analysis of apoptosis by propidium iodide staining and flow cytometry","volume":"1","author":"Riccardi","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0022-1759(95)00072-I","article-title":"A novel assay for apoptosis: Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein-labelled annexin V","volume":"184","author":"Vermes","year":"1995","journal-title":"J. Immunol. Methods"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/sj.cdd.4400476","article-title":"Emerging roles of caspase-3 in apoptosis","volume":"6","author":"Porter","year":"1999","journal-title":"Cell Death Differ."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1006\/abio.1997.2220","article-title":"Fluorometric and colorimetric detection of caspase activity associated with apoptosis","volume":"251","author":"Gurtu","year":"1997","journal-title":"Anal. Biochem."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"W5","DOI":"10.1093\/nar\/gkab255","article-title":"ADMETlab 2.0: An integrated online platform for accurate and comprehensive predictions of ADMET properties","volume":"49","author":"Xiong","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_152","unstructured":"Schr\u00f6dinger LLC (The PyMOL Molecular Graphics System, 2015). The PyMOL Molecular Graphics System, Version 1.8."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_155","unstructured":"Dassault Syst\u00e8mes BIOVIA (Discovery Studio Modeling Environment, 2017). Discovery Studio Modeling Environment, Release 4."},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"P\u00e1ll, S., Abraham, M.J., Kutzner, C., Hess, B., and Lindahl, E. (2014). Tackling exascale software challenges in molecular dynamics simulations. Proceedings of the International Conference on Exascale Applications and Software, Springer.","DOI":"10.1007\/978-3-319-15976-8_1"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1002\/jcc.23354","article-title":"CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data","volume":"34","author":"Huang","year":"2013","journal-title":"J. Comput. Chem."},{"key":"ref_159","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., and Petersson, G.A. (Gaussian 09, 2009). Gaussian 09, Revision D.01."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"5648","DOI":"10.1063\/1.464913","article-title":"Density-functional thermochemistry. III. The role of exact exchange","volume":"98","author":"Becke","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1103\/PhysRevB.37.785","article-title":"Development of the Colle\u2013Salvetti correlation-energy formula into a functional of the electron density","volume":"37","author":"Lee","year":"1988","journal-title":"Phys. Rev. B"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/7\/3018\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T13:52:53Z","timestamp":1774533173000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/7\/3018"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,26]]},"references-count":161,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27073018"],"URL":"https:\/\/doi.org\/10.3390\/ijms27073018","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,26]]}}}