{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T18:38:27Z","timestamp":1787683107119,"version":"build-2784847793"},"reference-count":39,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T00:00:00Z","timestamp":1628467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["RTI2018-101818-B-I00"],"award-info":[{"award-number":["RTI2018-101818-B-I00"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003086","name":"Eusko Jaurlaritza","doi-asserted-by":"publisher","award":["IT 992-16"],"award-info":[{"award-number":["IT 992-16"]}],"id":[{"id":"10.13039\/501100003086","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"publisher","award":["SAF2017-83575-R"],"award-info":[{"award-number":["SAF2017-83575-R"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>This work describes, for the first time, the synthesis of dialkyl (2-arylquinolin-8-yl)phosphonate derivatives. The preparation was carried out through a direct and simple process as a multicomponent Povarov reaction of aminophenylphosphonates, aldehydes, and styrenes and subsequent oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or, alternatively, by a cycloaddition reaction between phosphonate aldimines and acetylenes. Based on phosphonate group structural characteristics, considered as phosphorous isosteres of carboxylic heterocycles, they may present interesting biological properties related to cell proliferation. In the current report, a new series of dialkyl (2-arylquinolin-8-yl)phosphonates have been synthesized and their antiproliferative effect evaluated on different human cancer and embryonic cells, as well as on Leishmania infantum parasites, a eukaryotic protist responsible for visceral leishmaniasis. Thereby, the antitumor effect was assessed in human lung adenocarcinoma cells (A549), human ovarian carcinoma cells (SKOV3), and human embryonic kidney cells (HEK293) versus the non-cancerous lung fibroblasts cell line (MRC5). On the other hand, the antileishmanial activity was tested against both stages of L. infantum cell cycle, namely free-living promastigotes and intramacrophage amastigotes, using a primary culture of Balb\/c splenocytes to calculate the selectivity index. Besides the antiproliferative and antileishmanial capacities, their behavior as topoisomerase 1B inhibitors has been evaluated as a possible mechanism of action.<\/jats:p>","DOI":"10.3390\/ph14080784","type":"journal-article","created":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T09:03:53Z","timestamp":1628499833000},"page":"784","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Hybrid Quinolinyl Phosphonates as Heterocyclic Carboxylate Isosteres: Synthesis and Biological Evaluation against Topoisomerase 1B (TOP1B)"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7327-668X","authenticated-orcid":false,"given":"Asier","family":"Selas","sequence":"first","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica I, Facultad de Farmacia and Centro de Investigaci\u00f3n Lascaray, Universidad del Pa\u00eds Vasco (UPV\/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Fuertes","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica I, Facultad de Farmacia and Centro de Investigaci\u00f3n Lascaray, Universidad del Pa\u00eds Vasco (UPV\/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9663-060X","authenticated-orcid":false,"given":"Estela","family":"Melc\u00f3n-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Facultad de Veterinaria, Universidad de Le\u00f3n, 24071 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"P\u00e9rez-Pertejo","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Facultad de Veterinaria, Universidad de Le\u00f3n, 24071 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9148-2997","authenticated-orcid":false,"given":"Rosa M.","family":"Reguera","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Facultad de Veterinaria, Universidad de Le\u00f3n, 24071 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0418-6116","authenticated-orcid":false,"given":"Rafael","family":"Bala\u00f1a-Fouce","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Facultad de Veterinaria, Universidad de Le\u00f3n, 24071 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgitta R.","family":"Knudsen","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Genetics and Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000 Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6365-0324","authenticated-orcid":false,"given":"Francisco","family":"Palacios","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica I, Facultad de Farmacia and Centro de Investigaci\u00f3n Lascaray, Universidad del Pa\u00eds Vasco (UPV\/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0866-3493","authenticated-orcid":false,"given":"Concepcion","family":"Alonso","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica I, Facultad de Farmacia and Centro de Investigaci\u00f3n Lascaray, Universidad del Pa\u00eds Vasco (UPV\/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,9]]},"reference":[{"key":"ref_1","unstructured":"(2020, November 13). International Agency for Research on Cancer, GLOBOCAN 2018. Available online: http:\/\/gco.iarc.fr\/today\/home."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0140-6736(18)31204-2","article-title":"Leishmaniasis","volume":"392","author":"Burza","year":"2018","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5900","DOI":"10.2174\/0929867325666180518074959","article-title":"DNA Topoisomerases of Leishmania Parasites; Druggable Targets for Drug Discovery","volume":"26","author":"Reguera","year":"2019","journal-title":"Curr. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1111\/cas.12366","article-title":"Targeting DNA damage response in cancer therapy","volume":"105","author":"Hosoya","year":"2014","journal-title":"Cancer Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3521","DOI":"10.1074\/jbc.M203991200","article-title":"A novel active DNA topoisomerase I in Leishmania donovani","volume":"278","author":"Villa","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_6","first-page":"326","article-title":"Trypanosomatids topoisomerase re-visited. New structural findings and role in drug discovery","volume":"24","author":"Reguera","year":"2014","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1146\/annurev.biochem.70.1.369","article-title":"DNA Topoisomerases: Structure, Function, and Mechanism","volume":"70","author":"Champoux","year":"2001","journal-title":"Annu. Rev. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1080\/13543776.2021.1879051","article-title":"A patent review of topoisomerase I inhibitors (2016-present)","volume":"31","author":"Selas","year":"2021","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6379","DOI":"10.1021\/acs.joc.7b00977","article-title":"Study of the hetero-[4+2]-cycloaddition reaction of aldimines and alkynes. Synthesis of 1,5-naphthyridine and isoindolone derivatives","volume":"82","author":"Alonso","year":"2017","journal-title":"J. Org. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ejmech.2016.03.031","article-title":"Synthesis and biological evaluation of indeno[1,5]naphthyridines as topoisomerase I (TopI) inhibitors with antiproliferative activity","volume":"115","author":"Alonso","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.2174\/1568026614666141215152441","article-title":"Synthesis and biological evaluation of 1,5-naphthyridines as topoisomerase I inhibitors. A new family of antiproliferative agents","volume":"14","author":"Alonso","year":"2014","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.ejmech.2018.04.033","article-title":"Substituted 1,5-naphthyridine derivatives as novel antileishmanial agents. Synthesis and biological evaluation","volume":"152","author":"Tejeria","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.ejmech.2016.09.017","article-title":"Antileishmanial effect of new indeno-1,5-naphthyridines, selective inhibitors of Leishmania infantum type IB DNA topoisomerase","volume":"124","author":"Tejeria","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"103732","DOI":"10.1016\/j.bioorg.2020.103732","article-title":"Synthesis of neocryptolepines and Carbocycle-Fused Quinolines and Evaluation of Their Anticancer and Antiplasmodial Activities","volume":"98","author":"Akkachairin","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"111970","DOI":"10.1016\/j.ejmech.2019.111970","article-title":"Modification of 7-piperazinylquinolone antibacterials to promising anticancer lead compounds: Synthesis and in vitro studies","volume":"187","author":"Ahadi","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1080\/17460441.2017.1319357","article-title":"An overview of quinoline as a privileged scaffold in cancer drug discovery","volume":"12","author":"Musiol","year":"2017","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.ejmech.2014.07.044","article-title":"A review on anticancer potential of bioactive heterocycle quinolone","volume":"97","author":"Afzal","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Maslanka, M., and Mucha, A. (2019). Recent developments in peptidyl diaryl phoshonates as inhibitors and activity-based probes for serine proteases. Pharmaceuticals, 12.","DOI":"10.3390\/ph12020086"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1021\/cr950066q","article-title":"Bioisosterism: A Rational Approach in Drug Design","volume":"96","author":"Patani","year":"1996","journal-title":"Chem. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.2174\/092986705774933452","article-title":"Phosphate isosteres in medicinal chemistry","volume":"12","author":"Rye","year":"2005","journal-title":"Curr. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1517\/17460441.2016.1135125","article-title":"An overview of molecular hybrids in drug Discovery","volume":"11","author":"Berube","year":"2016","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1517\/17460441.2013.798296","article-title":"Advances in the development of hybrid anticancer drugs","volume":"8","author":"Fortin","year":"2013","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.ejmech.2018.02.058","article-title":"Novel topoisomerase I inhibitors. Syntheses and biological evaluation of phosphorus substituted quinoline derivates with antiproliferative activity","volume":"149","author":"Alonso","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ejmech.2018.10.065","article-title":"Antileishmanial activity of new hybrid tetrahydroquinoline and quinoline derivatives with phosphorus substituents","volume":"162","author":"Reguera","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.ddtec.2018.08.004","article-title":"Recent advances of the Povarov reaction in medicinal chemistry","volume":"29","author":"Ghashghaei","year":"2018","journal-title":"Drug Discov. Today"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Cadogan, J.I.G., Sears, D.J., and Smith, D.M. (1969). The reactivity of organophosphorus compounds. Part XXV. Displacement of activated aromatic nitro-groups by tervalent phosphorus reagents. J. Chem. Soc., 1314\u20131318.","DOI":"10.1039\/j39690001314"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1021\/jm049146p","article-title":"Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex","volume":"48","author":"Staker","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/nrd3404","article-title":"Interfacial inhibitors: Targeting macromolecular complexes","volume":"11","author":"Pommier","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1093\/nar\/gkn1009","article-title":"Structural studies of type I topoisomerases","volume":"37","author":"Baker","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1158\/1535-7163.MCT-05-0456","article-title":"A novel norindeniosoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex","volume":"5","author":"Marchand","year":"2006","journal-title":"Mol. Cancer Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nature05938","article-title":"Antitumour drugs impede DNA uncoiling by topoisomerase I","volume":"448","author":"Koster","year":"2007","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s00894-006-0159-2","article-title":"Molecular docking approach on the Topoisomerase I inhibitors series included in the NCI anti-cancer agents mechanism database","volume":"13","author":"Lauria","year":"2007","journal-title":"J. Mol. Model."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"10815","DOI":"10.1021\/bi980757r","article-title":"Camptothecins inhibit the utilization of hydrogen peroxide in the ligation step of topoisomerase I catalysis","volume":"37","author":"Lisby","year":"1998","journal-title":"Biochemistry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/0378-4347(96)00152-1","article-title":"Separation and functional analysis of eukaryotic DNA topoisomerases by chromatography and electrophoresis","volume":"684","author":"Knudsen","year":"1996","journal-title":"J. Chromatogr. B Biomed. Appl."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"(2015). Schr\u00f6dinger Release 2015-1: Maestro, Schr\u00f6dinger, L.L.C.. version 10.1.","DOI":"10.1063\/pt.5.031026"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"(2015). Schr\u00f6dinger Release 2015-1: Glide, Schr\u00f6dinger, L.L.C.. version 6.9.","DOI":"10.1063\/pt.5.031026"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_38","unstructured":"(2015). Schr\u00f6dinger Release 2015-1: Protein Preparation Wizard, Schr\u00f6dinger, L.L.C.. epik 3.1."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Calvo-\u00c1lvarez, E., Stamatakis, K., Punz\u00f3n, C., \u00c1lvarez-Velilla, R., Tejer\u00eda, A., Escudero-Mart\u00ednez, J.M., P\u00e9rez-Pertejo, Y., Fresno, M., Bala\u00f1a-Fouce, R., and Reguera, R.M. (2015). Infrared fluorescent imaging as a potent tool for in vitro, ex vivo and in vivo models of visceral leishmaniasis. PLoS Negl. Trop. Dis., 9.","DOI":"10.1371\/journal.pntd.0003666"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/8\/784\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:42:47Z","timestamp":1760164967000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/8\/784"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,9]]},"references-count":39,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ph14080784"],"URL":"https:\/\/doi.org\/10.3390\/ph14080784","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,9]]}}}