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However, many types of cancer and viral infections such as hepatitis B virus or SARS-CoV-2 are still treated ineffectively. Therefore, further development of effective and selective lead compounds as potential drugs is still highly demanded. In this study, we synthesized a novel series of piperazine-substituted pyranopyridines and evaluated their anticancer and antiviral properties. Antiproliferative activity was determined in a panel of various tumor cell lines as well as non-tumor hepatic HepaRG cells. Mechanisms of cytotoxicity were assessed by fluorescent microscopy techniques. Antiviral activity was analyzed towards DNA and RNA viruses in infectious cell culture systems. Several compounds showed antiproliferative activity towards various cancer cell lines at micromolar and submicromolar concentrations. Mechanisms of cytotoxicity involve the induction of apoptosis and are not mediated via ERK1\/2 pathway or oxidative stress. Several compounds exhibit selective activity against hepatitis B virus by preventing the formation of virion particles. This study led to the identification of a novel class of piperazine-substituted pyranopyridines with antiproliferative activity towards a wide range of tumor cell lines as well as the non-toxic inhibitor of HBV virion production.<\/jats:p>","DOI":"10.3390\/ijms26093991","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T10:40:48Z","timestamp":1745404848000},"page":"3991","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Piperazine-Substituted Pyranopyridines Exhibit Antiproliferative Activity and Act as Inhibitors of HBV Virion Production"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6739-509X","authenticated-orcid":false,"given":"Sona","family":"Buloyan","sequence":"first","affiliation":[{"name":"Scientific Technological Center of Organic and Pharmaceutical Chemistry, National Academy of Sciences of the Republic of Armenia, 0019 Yerevan, Armenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6089-8727","authenticated-orcid":false,"given":"Arpine","family":"Harutyunyan","sequence":"additional","affiliation":[{"name":"Scientific Technological Center of Organic and Pharmaceutical Chemistry, National Academy of Sciences of the Republic of Armenia, 0019 Yerevan, Armenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hrachik","family":"Gasparyan","sequence":"additional","affiliation":[{"name":"Scientific Technological Center of Organic and Pharmaceutical Chemistry, National Academy of Sciences of the Republic of Armenia, 0019 Yerevan, Armenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0246-6130","authenticated-orcid":false,"given":"Anahit","family":"Sakeyan","sequence":"additional","affiliation":[{"name":"Scientific Technological Center of Organic and Pharmaceutical Chemistry, National Academy of Sciences of the Republic of Armenia, 0019 Yerevan, Armenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astghik","family":"Shahkhatuni","sequence":"additional","affiliation":[{"name":"Scientific Technological Center of Organic and Pharmaceutical Chemistry, National Academy of Sciences of the Republic of Armenia, 0019 Yerevan, Armenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9704-6977","authenticated-orcid":false,"given":"Natalia F.","family":"Zakirova","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3056-4889","authenticated-orcid":false,"given":"Gaukhar","family":"Yusubalieva","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"},{"name":"Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, 115682 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilya M.","family":"Kirillov","sequence":"additional","affiliation":[{"name":"Gamaleya National Research Centre for Epidemiology and Microbiology of the Ministry of Russia, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina T.","family":"Fedyakina","sequence":"additional","affiliation":[{"name":"Gamaleya National Research Centre for Epidemiology and Microbiology of the Ministry of Russia, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5546-4975","authenticated-orcid":false,"given":"Pavel N.","family":"Solyev","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia V.","family":"Lipatova","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail A.","family":"Bogomolov","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2429-6649","authenticated-orcid":false,"given":"Vladimir S.","family":"Prassolov","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5966-0914","authenticated-orcid":false,"given":"Timofey 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Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102716","DOI":"10.1016\/j.canep.2024.102716","article-title":"Updated cancer burden in oldest old: A population-based study using 2022 Globocan estimates","volume":"95","author":"Shah","year":"2024","journal-title":"Cancer Epidemiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Sapio, L., and Naviglio, S. (2022). Innovation through Tradition: The Current Challenges in Cancer Treatment. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105296"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Nurgali, K., Rudd, J.A., Was, H., and Abalo, R. (2022). Editorial: Cancer therapy: The challenge of handling a double-edged sword. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1007762"},{"key":"ref_5","unstructured":"(2020). The global challenge of cancer. Nat. Cancer, 1, 1\u20132."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/s41392-024-01856-7","article-title":"Exploring treatment options in cancer: Tumor treatment strategies","volume":"9","author":"Liu","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41573-023-00692-8","article-title":"Accelerating antiviral drug discovery: Lessons from COVID-19","volume":"22","author":"Hall","year":"2023","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zhou, Z., Liu, X., and Kang, D. (2024). Antiviral Drug Discovery. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25137413"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/s41575-022-00608-8","article-title":"Breakthroughs in hepatitis C research: From discovery to cure","volume":"19","author":"Manns","year":"2022","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Montaner, J.S., Lima, V.D., Harrigan, P.R., Louren\u00e7o, L., Yip, B., Nosyk, B., Wood, E., Kerr, T., Shannon, K., and Moore, D. (2014). Expansion of HAART coverage is associated with sustained decreases in HIV\/AIDS morbidity, mortality and HIV transmission: The \u201cHIV Treatment as Prevention\u201d experience in a Canadian setting. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087872"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1021\/ar7000843","article-title":"Hybrid molecules with a dual mode of action: Dream or reality?","volume":"41","author":"Meunier","year":"2008","journal-title":"Acc. Chem. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sirakanyan, S.N., Spinelli, D., Petrou, A., Geronikaki, A., Kartsev, V.G., Hakobyan, E.K., Yegoryan, H.A., Zuppiroli, L., Zuppiroli, R., and Ayvazyan, A.G. (2023). New Bicyclic Pyridine-Based Hybrids Linked to the 1,2,3-Triazole Unit: Synthesis via Click Reaction and Evaluation of Neurotropic Activity and Molecular Docking. Molecules, 28.","DOI":"10.3390\/molecules28030921"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"773","DOI":"10.2174\/138955710791608280","article-title":"Recent progress in the development of synthetic hybrids of natural or unnatural bioactive compounds for medicinal chemistry","volume":"10","author":"Tsogoeva","year":"2010","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1080\/17460441.2022.2103535","article-title":"The piperazine scaffold for novel drug discovery efforts: The evidence to date","volume":"17","author":"Romanelli","year":"2022","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1016\/j.bmc.2005.10.032","article-title":"Synthesis and antimicrobial activity of N-alkyl and N-aryl piperazine derivatives","volume":"14","author":"Chaudhary","year":"2006","journal-title":"Bioorg. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1021\/acs.jmedchem.7b01138","article-title":"Alkylated Piperazines and Piperazine-Azole Hybrids as Antifungal Agents","volume":"61","author":"Shrestha","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4287","DOI":"10.1016\/j.bmcl.2004.05.091","article-title":"Antioxidative activities of novel diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter","volume":"14","author":"Kimura","year":"2004","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"119","DOI":"10.14715\/cmb\/2019.65.3.18","article-title":"Piperazine ferulate exerts antihypertensive effect and improves endothelial function in vitro and in vivo via the activation of endothelial nitric oxide synthase","volume":"65","author":"Jianzhi","year":"2019","journal-title":"Cell Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.1002\/cmdc.202100045","article-title":"Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure-Activity Relationships","volume":"16","author":"Kumar","year":"2021","journal-title":"ChemMedChem"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5140","DOI":"10.1016\/j.bmcl.2009.07.076","article-title":"Inhibitors of HIV-1 attachment. Part 4: A study of the effect of piperazine substitution patterns on antiviral potency in the context of indole-based derivatives","volume":"19","author":"Wang","year":"2009","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_21","first-page":"571","article-title":"Preliminary evaluation of anticonvulsant activity and neurotoxicity of some 1,4-substituted piperazine derivatives","volume":"66","author":"Marona","year":"2009","journal-title":"Acta Pol. Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1080\/14756366.2018.1491564","article-title":"Donepezil structure-based hybrids as potential multifunctional anti-Alzheimer\u2019s drug candidates","volume":"33","author":"Piemontese","year":"2018","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1016\/j.ejmech.2008.09.025","article-title":"Synthesis and in vitro antiproliferative activity of novel 1-benzhydrylpiperazine derivatives against human cancer cell lines","volume":"44","author":"Vinaya","year":"2009","journal-title":"Eur. J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"136089","DOI":"10.1016\/j.molstruc.2023.136089","article-title":"Green chemistry approach towards Piperazine: Anticancer agents","volume":"1292","author":"Sharma","year":"2023","journal-title":"J. Mol. Struct."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Tahir, T., Ashfaq, M., Saleem, M., Rafiq, M., Shahzad, M.I., Kotwica-Mojzych, K., and Mojzych, M. (2021). Pyridine Scaffolds, Phenols and Derivatives of Azo Moiety: Current Therapeutic Perspectives. Molecules, 26.","DOI":"10.3390\/molecules26164872"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3126","DOI":"10.1016\/j.bmcl.2014.05.002","article-title":"Studies on molecular properties prediction, antitubercular and antimicrobial activities of novel quinoline based pyrimidine motifs","volume":"24","author":"Desai","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1007\/s00044-007-9035-6","article-title":"Synthesis and antiviral activity of new 4-(phenylamino)\/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids derivatives","volume":"16","author":"Bernardino","year":"2007","journal-title":"Med. Chem. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"171","DOI":"10.3897\/pharmacia.66.e36764","article-title":"Antioxidant properties of some novel derivatives thiazolo[4,5-b] pyridine","volume":"66","author":"Chaban","year":"2019","journal-title":"Pharmacia"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Myriagkou, M., Papakonstantinou, E., Deligiannidou, G.E., Patsilinakos, A., Kontogiorgis, C., and Pontiki, E. (2023). Novel Pyrimidine Derivatives as Antioxidant and Anticancer Agents: Design, Synthesis and Molecular Modeling Studies. Molecules, 28.","DOI":"10.3390\/molecules28093913"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.bmcl.2008.09.067","article-title":"Synthesis and biological evaluation of novel 2,4,5-substituted pyrimidine derivatives for anticancer activity","volume":"19","author":"Xie","year":"2009","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Bassyouni, F., Tarek, M., Salama, A., Ibrahim, B., Salah El Dine, S., Yassin, N., Hassanein, A., Moharam, M., and Abdel-Rehim, M. (2021). Promising Antidiabetic and Antimicrobial Agents Based on Fused Pyrimidine Derivatives: Molecular Modeling and Biological Evaluation with Histopathological Effect. Molecules, 26.","DOI":"10.3390\/molecules26082370"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2584","DOI":"10.2174\/1389557521666210126143558","article-title":"Antiviral Activities of Pyridine Fused and Pyridine Containing Heterocycles, A Review (from 2000 to 2020)","volume":"21","author":"Alizadeh","year":"2021","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"114199","DOI":"10.1016\/j.ejmech.2022.114199","article-title":"A score years\u2019 update in the synthesis and biological evaluation of medicinally important 2-pyridones","volume":"232","author":"Sangwan","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Romanelli, M.N., Braconi, L., Gabellini, A., Manetti, D., Marotta, G., and Teodori, E. (2024). Synthetic Approaches to Piperazine-Containing Drugs Approved by FDA in the Period of 2011\u20132023. Molecules, 29.","DOI":"10.3390\/molecules29010068"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1007\/s00044-023-03040-y","article-title":"Recent updates on thienopyrimidine derivatives as anticancer agents","volume":"32","author":"Sayed","year":"2023","journal-title":"Med. Chem. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1007\/BF00780403","article-title":"Synthesis and antibacterial activity of pyrano-(thiopyrano)[3,4-c]pyridine-, 2,7-naphthyridine-, and 5,6,7,8-tetrahydro-isoquinoline-3(2h)-thione derivatives","volume":"27","author":"Paronikyan","year":"1993","journal-title":"Pharm. Chem. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1002\/hep.21536","article-title":"Transdifferentiation of hepatocyte-like cells from the human hepatoma HepaRG cell line through bipotent progenitor","volume":"45","author":"Cerec","year":"2007","journal-title":"Hepatology"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ivanova, O.N., Snezhkina, A.V., Krasnov, G.S., Valuev-Elliston, V.T., Khomich, O.A., Khomutov, A.R., Keinanen, T.A., Alhonen, L., Bartosch, B., and Kudryavtseva, A.V. (2018). Activation of Polyamine Catabolism by N(1),N(11)-Diethylnorspermine in Hepatic HepaRG Cells Induces Dedifferentiation and Mesenchymal-Like Phenotype. Cells, 7.","DOI":"10.3390\/cells7120275"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1124\/dmd.107.020016","article-title":"Evaluation of HepaRG cells as an in vitro model for human drug metabolism studies","volume":"36","author":"Kanebratt","year":"2008","journal-title":"Drug Metab. Dispos."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1475-2859-2-2","article-title":"Cheese whey-induced high-cell-density production of recombinant proteins in Escherichia coli","volume":"2","author":"Viitanen","year":"2003","journal-title":"Microb. Cell Fact."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41420-024-01950-3","article-title":"Improving the power of drug toxicity measurements by quantitative nuclei imaging","volume":"10","author":"Mikheeva","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1038\/s41592-022-01663-4","article-title":"Cellpose 2.0: How to train your own model","volume":"19","author":"Pachitariu","year":"2022","journal-title":"Nat. Methods"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Stirling, D.R., Swain-Bowden, M.J., Lucas, A.M., Carpenter, A.E., Cimini, B.A., and Goodman, A. (2021). CellProfiler 4: Improvements in speed, utility and usability. BMC Bioinform., 22.","DOI":"10.1186\/s12859-021-04344-9"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1080\/15384101.2018.1547001","article-title":"Accurate delineation of cell cycle phase transitions in living cells with PIP-FUCCI","volume":"17","author":"Grant","year":"2018","journal-title":"Cell Cycle"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1016\/j.cell.2014.04.039","article-title":"High-sensitivity measurements of multiple kinase activities in live single cells","volume":"157","author":"Regot","year":"2014","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Lebedev, T.D., Khabusheva, E.R., Mareeva, S.R., Ivanenko, K.A., Morozov, A.V., Spirin, P.V., Rubtsov, P.M., Snezhkina, A.V., Kudryavtseva, A.V., and Sorokin, M.I. (2022). Identification of cell type-specific correlations between ERK activity and cell viability upon treatment with ERK1\/2 inhibitors. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.102226"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"8910396","DOI":"10.1155\/2016\/8910396","article-title":"Oxidative Stress during HIV Infection: Mechanisms and Consequences","volume":"2016","author":"Ivanov","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/s41419-023-06326-6","article-title":"Lysosomes, caspase-mediated apoptosis, and cytoplasmic activation of P21, but not cell senescence, participate in a redundant fashion in embryonic morphogenetic cell death","volume":"14","author":"Moran","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1080\/01926230701311344","article-title":"Emerging role of Nrf2 in protecting against hepatic and gastrointestinal disease","volume":"35","author":"Aleksunes","year":"2007","journal-title":"Toxicol. Pathol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1016\/j.drudis.2022.02.005","article-title":"Recent advances in developing polymeric micelles for treating cancer: Breakthroughs and bottlenecks in their clinical translation","volume":"27","author":"Kaur","year":"2022","journal-title":"Drug Discov. Today"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Ioele, G., Chieffallo, M., Occhiuzzi, M.A., De Luca, M., Garofalo, A., Ragno, G., and Grande, F. (2022). Anticancer Drugs: Recent Strategies to Improve Stability Profile, Pharmacokinetic and Pharmacodynamic Properties. Molecules, 27.","DOI":"10.3390\/molecules27175436"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1158\/2159-8290.CD-13-0611","article-title":"Rapid Induction of Apoptosis by PI3K Inhibitors Is Dependent upon Their Transient Inhibition of RAS\u2013ERK Signaling","volume":"4","author":"Will","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"69","DOI":"10.2174\/1389557521666210112142136","article-title":"Exploring Quinolone Scaffold: Unravelling the Chemistry of Anticancer Drug Design","volume":"22","author":"Sharma","year":"2022","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5845","DOI":"10.1021\/jm4017625","article-title":"Rings in Drugs","volume":"57","author":"Taylor","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_55","first-page":"758","article-title":"Alterations of Some Heavy Metals and Trace Elements Levels in Breast Cancer","volume":"7","author":"Ismail","year":"2017","journal-title":"Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1080\/14756366.2021.1931861","article-title":"Piperazine skeleton in the structural modification of natural products: A review","volume":"36","author":"Zhang","year":"2021","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.ejmech.2012.04.028","article-title":"Synthesis and biological activity assays of some new N1-(flavon-7-yl)amidrazone derivatives and related congeners","volume":"54","author":"Mustafa","year":"2012","journal-title":"Eur. J. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e1900051","DOI":"10.1002\/ardp.201900051","article-title":"Sulfonylpiperazines based on a flavone as antioxidant and cytotoxic agents","volume":"352","author":"Patel","year":"2019","journal-title":"Arch. Pharm."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"7723","DOI":"10.1039\/C5RA20197G","article-title":"Synthesis and biological evaluation of novel hybrid compounds between chalcone and piperazine as potential antitumor agents","volume":"6","author":"Mao","year":"2016","journal-title":"RSC Adv."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"237","DOI":"10.6023\/cjoc201605021","article-title":"Synthesis and Anti-tumor Activities of Novel 4\u2019-(N-Substitued-1-piperazinyl) chalcone Derivatives","volume":"37","author":"Lin","year":"2017","journal-title":"Chin. J. Org. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.bmcl.2014.11.049","article-title":"Design, synthesis and biological evaluation of novel arylpiperazine derivatives on human prostate cancer cell lines","volume":"25","author":"Chen","year":"2015","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Zsoldos, B., Nagy, N., Donk\u00f3-T\u00f3th, V., Keglevich, P., Weber, M., D\u00e9k\u00e1ny, M., Nehr-Majoros, A., Sz\u0151ke, \u00c9., Helyes, Z., and Hazai, L. (2024). Novel Piperazine Derivatives of Vindoline as Anticancer Agents. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25147929"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Xu, A.P., Xu, L.B., Smith, E.R., Fleishman, J.S., Chen, Z.-S., and Xu, X.-X. (2024). Cell death in cancer chemotherapy using taxanes. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1338633"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1634\/theoncologist.11-4-342","article-title":"Chemotherapeutic approaches for targeting cell death pathways","volume":"11","author":"Ricci","year":"2006","journal-title":"Oncologist"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.trecan.2017.03.002","article-title":"Necroptosis and Cancer","volume":"3","author":"Najafov","year":"2017","journal-title":"Trends Cancer"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.4161\/cc.8.8.8147","article-title":"How ERK1\/2 activation controls cell proliferation and cell death: Is subcellular localization the answer?","volume":"8","author":"Mebratu","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/cdd.2008.148","article-title":"Tumour cell survival signalling by the ERK1\/2 pathway","volume":"16","author":"Balmanno","year":"2009","journal-title":"Cell Death Differ."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1097\/WOX.0b013e3182439613","article-title":"Oxidative stress and antioxidant defense","volume":"5","author":"Birben","year":"2012","journal-title":"World Allergy Organ. J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"6175804","DOI":"10.1155\/2019\/6175804","article-title":"ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells","volume":"2019","author":"Snezhkina","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_70","first-page":"200","article-title":"Mitochondrial metabolism of reactive oxygen species","volume":"70","author":"Andreyev","year":"2005","journal-title":"Biochemistry"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/nrn3168","article-title":"Understanding calcium waves and sparks in central neurons","volume":"13","author":"Ross","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Trybus, W., Trybus, E., and Kr\u00f3l, T. (2023). Lysosomes as a Target of Anticancer Therapy. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032176"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1016\/j.apsb.2020.07.003","article-title":"The role of lysosome in regulated necrosis","volume":"10","author":"Alu","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/nrm3737","article-title":"Regulated necrosis: The expanding network of non-apoptotic cell death pathways","volume":"15","author":"Berghe","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"He, H., Shao, X., Li, Y., Gihu, R., Xie, H., Zhou, J., and Yan, H. (2021). Targeting Signaling Pathway Networks in Several Malignant Tumors: Progresses and Challenges. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.675675"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Sirico, M., D\u2019Angelo, A., Gianni, C., Casadei, C., Merloni, F., and De Giorgi, U. (2023). Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy. Cancers, 15.","DOI":"10.3390\/cancers15030703"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/nature04869","article-title":"Ras, PI(3)K and mTOR signalling controls tumour cell growth","volume":"441","author":"Shaw","year":"2006","journal-title":"Nature"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Mishra, R., Patel, H., Alanazi, S., Kilroy, M.K., and Garrett, J.T. (2021). PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073464"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/nrc2664","article-title":"Targeting PI3K signalling in cancer: Opportunities, challenges and limitations","volume":"9","author":"Engelman","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1158\/2159-8290.CD-18-1175","article-title":"Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors","volume":"9","author":"Hanker","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.gene.2012.04.011","article-title":"Relationships between single nucleotide polymorphisms of antioxidant enzymes and disease","volume":"501","author":"Crawford","year":"2012","journal-title":"Gene"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.gene.2016.03.052","article-title":"Rice protein suppresses ROS generation and stimulates antioxidant gene expression via Nrf2 activation in adult rats","volume":"585","author":"Li","year":"2016","journal-title":"Gene"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Wufuer, R., Fan, Z., Liu, K., and Zhang, Y. (2021). Differential Yet Integral Contributions of Nrf1 and Nrf2 in the Human HepG2 Cells on Antioxidant Cytoprotective Response against Tert-Butylhydroquinone as a Pro-Oxidative Stressor. Antioxidants, 10.","DOI":"10.3390\/antiox10101610"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Yang, L., Yang, F., Teng, L., and Katayama, I. (2020). 6-Shogaol Protects Human Melanocytes against Oxidative Stress through Activation of the Nrf2-Antioxidant Response Element Signaling Pathway. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103537"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"13291","DOI":"10.1074\/jbc.R900010200","article-title":"The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress","volume":"284","author":"Nguyen","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Correa-Padilla, E., Hern\u00e1ndez-Cano, A., Cuevas, G., Acevedo-Betancur, Y., Esquivel-Guadarrama, F., and Martinez-Mayorga, K. (2023). Modifications in the piperazine ring of nucleozin affect anti-influenza activity. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0277073"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1016\/j.ijbiomac.2018.08.047","article-title":"Berberine-piperazine conjugates as potent influenza neuraminidase blocker","volume":"119","author":"Enkhtaivan","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Chu, Y., Raja Sekhara Reddy, B., Pratap Reddy Gajulapalli, V., Sudhakar Babu, K., Kim, E., and Lee, S. (2020). Design, synthesis, and biological evaluation of N-arylpiperazine derivatives as interferon inducers. Bioorg. Med. Chem. Lett., 30.","DOI":"10.1016\/j.bmcl.2020.127613"},{"key":"ref_89","unstructured":"WHO Factsheet (2025, January 28). Hepatitis B. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/hepatitis-b."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"5878","DOI":"10.3390\/molecules15095878","article-title":"Discovery and Development of Anti-HBV Agents and Their Resistance","volume":"15","author":"Kim","year":"2010","journal-title":"Molecules"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Yasutake, Y., Hattori, S.-I., Kumamoto, H., Tamura, N., Maeda, K., and Mitsuya, H. (2024). Deviated binding of anti-HBV nucleoside analog E-CFCP-TP to the reverse transcriptase active site attenuates the effect of drug-resistant mutations. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-66505-z"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1134\/S002689332004010X","article-title":"The State of The Jak\/Stat Pathway Affects the Sensitivity of Tumor Cells to Oncolytic Enteroviruses","volume":"54","author":"Le","year":"2020","journal-title":"Mol. Biol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Lipatova, A.V., Soboleva, A.V., Gorshkov, V.A., Bubis, J.A., Solovyeva, E.M., Krasnov, G.S., Kochetkov, D.V., Vorobyev, P.O., Ilina, I.Y., and Moshkovskii, S.A. (2021). Multi-Omics Analysis of Glioblastoma Cells\u2019 Sensitivity to Oncolytic Viruses. Cancers, 13.","DOI":"10.3390\/cancers13215268"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Vorobyev, P.O., Kochetkov, D.V., Chumakov, P.M., Zakirova, N.F., Zotova-Nefedorova, S.I., Vasilenko, K.V., Alekseeva, O.N., Kochetkov, S.N., Bartosch, B., and Lipatova, A.V. (2022). 2-Deoxyglucose, an Inhibitor of Glycolysis, Enhances the Oncolytic Effect of Coxsackievirus. Cancers, 14.","DOI":"10.3390\/cancers14225611"},{"key":"ref_95","unstructured":"Markossian, S., Grossman, A., Arkin, M., Auld, D., Austin, C., Baell, J., Brimacombe, K., Chung, T.D.Y., Coussens, N.P., and Dahlin, J.L. (2004). Cell Viability Assays. Assay Guidance Manual, Eli Lilly & Company and the National Center for Advancing Translational Sciences."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/978-1-61779-080-5_20","article-title":"Cell sensitivity assays: The MTT assay","volume":"731","author":"Kaspers","year":"2011","journal-title":"Methods Mol. Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/j.tiv.2013.01.016","article-title":"Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay: A quantitative method for oxidative stress assessment of nanoparticle-treated cells","volume":"27","author":"Aranda","year":"2013","journal-title":"Toxicol. In Vitro"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"6362426","DOI":"10.1155\/2018\/6362426","article-title":"Reactive Oxygen Species Generation in Human Cells by a Novel Magnetic Resonance Imaging Contrast Agent","volume":"2018","author":"Wang","year":"2018","journal-title":"J. Toxicol."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Golikov, M.V., Karpenko, I.L., Lipatova, A.V., Ivanova, O.N., Fedyakina, I.T., Larichev, V.F., Zakirova, N.F., Leonova, O.G., Popenko, V.I., and Bartosch, B. (2022). Cultivation of Cells in a Physiological Plasmax Medium Increases Mitochondrial Respiratory Capacity and Reduces Replication Levels of RNA Viruses. Antioxidants, 11.","DOI":"10.3390\/antiox11010097"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Ivanova, O.N., Gavlina, A.V., Karpenko, I.L., Zenov, M.A., Antseva, S.S., Zakirova, N.F., Valuev-Elliston, V.T., Krasnov, G.S., Fedyakina, I.T., and Vorobyev, P.O. (2024). Polyamine Catabolism Revisited: Acetylpolyamine Oxidase Plays a Minor Role due to Low Expression. Cells, 13.","DOI":"10.3390\/cells13131134"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Smith, S.M., Wunder, M.A.B., Norris, D.A., and Shellman, Y.G. (2011). A simple protocol for using a LDH-based cytotoxicity assay to assess the effects of death and growth inhibition at the same time. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0026908"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Smirnova, O.A., Ivanova, O.N., Mukhtarov, F., Valuev-Elliston, V.T., Fedulov, A.P., Rubtsov, P.M., Zakirova, N.F., Kochetkov, S.N., Bartosch, B., and Ivanov, A.V. (2023). Hepatitis Delta Virus Antigens Trigger Oxidative Stress, Activate Antioxidant Nrf2\/ARE Pathway, and Induce Unfolded Protein Response. Antioxidants, 12.","DOI":"10.3390\/antiox12040974"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.antiviral.2016.10.006","article-title":"HDV RNA replication is associated with HBV repression and interferon-stimulated genes induction in super-infected hepatocytes","volume":"136","author":"Alfaiate","year":"2016","journal-title":"Antiviral Res."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Shakiba, Y., Vorobyev, P.O., Naumenko, V.A., Kochetkov, D.V., Zajtseva, K.V., Valikhov, M.P., Yusubalieva, G.M., Gumennaya, Y.D., Emelyanov, E.A., and Semkina, A.S. (2023). Oncolytic Efficacy of a Recombinant Vaccinia Virus Strain Expressing Bacterial Flagellin in Solid Tumor Models. 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