{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T01:35:36Z","timestamp":1780450536235,"version":"3.54.1"},"reference-count":43,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,26]],"date-time":"2022-08-26T00:00:00Z","timestamp":1661472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The synthesis of alkyl 2-(4-hydroxyquinolin-2-yl) acetates and 1-phenyl-4-(phenylamino)pyridine-2,6(1H,3H)-dione was optimised. Starting from 4-hydroxyquinolines (4HQs), aminomethylation was carried out via the modified Mannich reaction (mMr) applying formaldehyde and piperidine, but a second paraformaldehyde molecule was incorporated into the Mannich product. The reaction also afforded the formation of bisquinoline derivatives. A new 1H-azeto [1,2-a]quinoline derivative was synthesised in two different ways; namely starting from the aminomethylated product or from the ester-hydrolysed 4HQ. When the aldehyde component was replaced with aromatic aldehydes, Knoevenagel condensation took place affording the formation of the corresponding benzylidene derivatives, with the concomitant generation of bisquinolines. The reactivity of salicylaldehyde and hydroxynaphthaldehydes was tested; under these conditions, partially saturated lactones were formed through spontaneous ring closure. The activity of the derivatives was assessed using doxorubicin-sensitive and -resistant colon adenocarcinoma cell lines and normal human fibroblasts. Some derivatives possessed selective toxicity towards resistant cancer cells compared to doxorubicin-sensitive cancer cells and normal fibroblasts. Cytotoxic activity of the benzylidene derivatives and the corresponding Hammett\u2013Brown substituent were correlated.<\/jats:p>","DOI":"10.3390\/ijms23179688","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T01:39:19Z","timestamp":1661737159000},"page":"9688","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Synthesis of 4-Hydroxyquinolines as Potential Cytotoxic Agents"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4866-4546","authenticated-orcid":false,"given":"Oszk\u00e1r","family":"Csuvik","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, University of Szeged, E\u00f6tv\u00f6s u. 6, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8638-5815","authenticated-orcid":false,"given":"Nikoletta","family":"Szemer\u00e9di","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Albert Szent-Gy\u00f6rgyi Health Center and Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8085-0950","authenticated-orcid":false,"given":"Gabriella","family":"Spengler","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Albert Szent-Gy\u00f6rgyi Health Center and Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8571-5229","authenticated-orcid":false,"given":"Istv\u00e1n","family":"Szatm\u00e1ri","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, University of Szeged, E\u00f6tv\u00f6s u. 6, H-6720 Szeged, Hungary"},{"name":"Stereochemistry Research Group, E\u00f6tv\u00f6s Lor\u00e1nd Research Network, University of Szeged, E\u00f6tv\u00f6s u. 6, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1021\/jm00354a005","article-title":"\u03b2-Adrenergic Blocking Agents. 24. Heterocyclic Substituted 1-(Aryloxy)-3-[[(amido)alkyl]amino]propan-2-ols","volume":"25","author":"Large","year":"1982","journal-title":"J. Med. Chem."},{"key":"ref_2","unstructured":"Baxter, A.D., Owen, D.A., Watson, R.J., Hannah, D., and Batty, D. (2000). Preparation of Hydroxamic and Carboxylic Acid Derivatives for Treating Condition Associated with Matrix Metalloproteinase, ADAM or ADAM-TS Enzymes. (No. WO2000069827), WIPO (PCT)."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4874","DOI":"10.1021\/jm501881c","article-title":"Origins of the Quinolone Class of Antibacterials: An Expanded \u201cDiscovery Story\u201d","volume":"58","author":"Bisacchi","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/S0006-291X(02)02917-0","article-title":"Electrochemical and in vitro evaluation of the redox-properties of kynurenine species","volume":"300","author":"Giles","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1002\/ardp.19122500151","article-title":"About a condensation product of formaldehyde, ammonia and antipyrine","volume":"250","author":"Mannich","year":"1912","journal-title":"Archiv der Pharmazie"},{"key":"ref_6","first-page":"301","article-title":"On the addition of benzyl amine to naphthol","volume":"30","author":"Betti","year":"1900","journal-title":"Gazz. Chim. Ital."},{"key":"ref_7","first-page":"310","article-title":"General condensation reaction between \u03b2-naphthol, aldehydes and amines","volume":"30","author":"Betti","year":"1900","journal-title":"Gazz. Chim. Ital."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.tetasy.2010.03.020","article-title":"The Betti base: The awakening of a sleeping beauty","volume":"21","author":"Cardellicchio","year":"2010","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6977","DOI":"10.1016\/j.tet.2017.10.063","article-title":"Multicomponent Mannich reactions: General aspects, methodologies and applications","volume":"73","author":"Filho","year":"2017","journal-title":"Tetrahedron"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1080\/17460441.2018.1403420","article-title":"Recent developments concerning the application of the Mannich reaction for drug design","volume":"13","author":"Biersack","year":"2018","journal-title":"Expert Opin. Drug. Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e202200258","DOI":"10.1002\/cmdc.202200258","article-title":"Anticancer Activity of Mannich Bases: A Review of Recent Literature","volume":"17","author":"Roman","year":"2022","journal-title":"ChemMedChem"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"735","DOI":"10.2174\/1573406418666211220124119","article-title":"Mannich Bases: Centrality in Cytotoxic Drug Design","volume":"18","author":"Bhilare","year":"2022","journal-title":"Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1016\/j.tet.2012.11.055","article-title":"Syntheses, transformations and applications of aminonaphthol derivatives prepared via modified Mannich reactions","volume":"69","year":"2013","journal-title":"Tetrahedron"},{"key":"ref_14","first-page":"368","article-title":"Search for New Antispasmodics. Part IV","volume":"29","author":"Ghosh","year":"1952","journal-title":"J. Indian Chem. Soc."},{"key":"ref_15","first-page":"1","article-title":"Synthesis and antimicrobial activity of 3-aminomethyl substituted quinolones","volume":"1","author":"Zubkov","year":"2003","journal-title":"Visnik Farmatsii"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"L\u0151rinczi, B., Cs\u00e1mpai, A., F\u00fcl\u00f6p, F., and Szatm\u00e1ri, I. (2020). Synthesis of New C-3 Substituted Kynurenic Acid Derivatives. Molecules, 25.","DOI":"10.3390\/molecules25040937"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1039\/D0RA08325A","article-title":"Synthetic- and DFT modelling studies on regioselective modified Mannich reactions of hydroxy-KYNA derivatives","volume":"11","year":"2021","journal-title":"RSC Adv."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1021\/jo01146a011","article-title":"Substituted Quinolineacetic Acids","volume":"16","author":"Kaslow","year":"1951","journal-title":"J. Org. Chem."},{"key":"ref_19","first-page":"23","article-title":"Use of ethyl acetonedicarboxylate in the Conrad\u2013Limpach reaction. Preparation of substituted ethyl 4-hydroxyquinoline-2-acetates","volume":"1","author":"Munavalli","year":"1956","journal-title":"J. Karnatak Univ."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1021\/ml3001006","article-title":"4-Quinolones as Noncovalent Inhibitors of High Molecular Mass Penicillin-Binding Proteins","volume":"9","author":"Shilabin","year":"2012","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1039\/b901092k","article-title":"Synthesis of chromones and 4-hydroxyquinolines based on uncatalyzed condensations of 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene with 2-alkoxy- and 2-nitrobenzoyl chlorides and related reactions","volume":"7","author":"Rahn","year":"2009","journal-title":"Org. Biomol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1021\/jo00902a031","article-title":"1-Phenylpiperidine-2,4,6-Trione","volume":"40","author":"Mee","year":"1975","journal-title":"J. Org. Chem."},{"key":"ref_23","first-page":"108","article-title":"Synthesis of quinoline derivatives by acid catalyzed microwave-assisted approach","volume":"6","author":"Nadaraj","year":"2010","journal-title":"Org. Chem. Indian J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1246\/bcsj.48.2473","article-title":"Optical Activity and Absolute Configuration of 2,3:6,7-Dibenzobicyclo [3.3.1]nona-2,6-diene Derivatives","volume":"48","author":"Tatemitsu","year":"1975","journal-title":"Bull. Chem. Soc. Jpn."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10","DOI":"10.4236\/ijoc.2019.91002","article-title":"Studies and Mechanism of Olefination Reaction in Aryl-Enolates with Paraformaldehyde","volume":"9","author":"Escalante","year":"2019","journal-title":"Int. J. Org. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1016\/S0960-894X(01)00383-3","article-title":"Synthesis, Antimalarial Activity and Inhibition of Haem Detoxification of Novel Bisquinolines","volume":"11","author":"Ayad","year":"2001","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8618","DOI":"10.1002\/anie.201104452","article-title":"Iridium-Catalyzed Reactions of \u03c9-Arylalkanols to \u03b1,\u03c9-Diarylalkanes","volume":"50","author":"Obora","year":"2011","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1016\/S0040-4020(98)83014-7","article-title":"Synthesis of Some Quinolizine Derivatives","volume":"54","author":"Chen","year":"1998","journal-title":"Tetrahedron"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"141","DOI":"10.2174\/1573406415666190603103012","article-title":"Styrylquinoline\u2014A Versatile Scaffold in Medicinal Chemistry","volume":"16","author":"Musiol","year":"2020","journal-title":"Med. Chem."},{"key":"ref_30","first-page":"588","article-title":"Effect of compounds related to 4-(p-dimethylaminostyryl) quinolone methiodide on lymphoma 8","volume":"15","author":"Bahner","year":"1955","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3407","DOI":"10.1021\/ja01151a120","article-title":"Quaternary Salts of Styryl Pyridines and Quinolines","volume":"73","author":"Bahner","year":"1951","journal-title":"J. Am. Chem. Soc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.ejmech.2019.05.061","article-title":"The synthesis and anticancer activity of 2-styrylquinoline derivatives. A P53 independent mechanism of action","volume":"177","author":"Kuczak","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6138","DOI":"10.1016\/j.bmcl.2007.09.040","article-title":"Investigating the antiproliferative activity of quinoline-5,8-diones and styrylquinolinecarboxylic acids on tumor cell lines","volume":"17","author":"Podeszwa","year":"2007","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s10600-005-0198-4","article-title":"3-(2-Quinolyl)- and 3-(5-carbethoxyfuryl-2)coumarins","volume":"41","author":"Shablykina","year":"2005","journal-title":"Chem. Nat. Compd."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2858","DOI":"10.1055\/s-0032-1317488","article-title":"A Convenient Method of Facilitating Aryl\u2013Aryl Bond-Formation Reactions in the Synthesis of Biquinoline- and Quinoline-Bearing Chromene Derivatives","volume":"23","author":"Sankaran","year":"2012","journal-title":"Synlett"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7619","DOI":"10.1039\/C8OB02047G","article-title":"The fluorescent biomarkers for lipid droplets with quinolone-coumarin unit","volume":"16","author":"Chen","year":"2018","journal-title":"Org. Biomol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1002\/cbic.201900728","article-title":"Design and Expeditious Synthesis of Quinoline-Pyrene-Based Ratiometric Fluorescent Probes for Targeting Lysosomal pH","volume":"21","author":"Hande","year":"2020","journal-title":"ChemBioChem"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.bmcl.2017.01.033","article-title":"Selenoesters and selenoanhydrides as novel multidrug resistance reversing agents: A confirmation study in a colon cancer MDR cell line","volume":"27","author":"Spengler","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1021\/cr00002a004","article-title":"A Survey of Hammett Substituent Constants and Resonance and Field Parameters","volume":"91","author":"Hansch","year":"1991","journal-title":"Chem. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Ackroyd, J., and Scheinmann, F. (1981). A New Route to 1H-1,5-Benzodiazepinones. J. Chem. Soc. Chem. Commun., 339\u2013340.","DOI":"10.1039\/c39810000339"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1002\/cber.19891220429","article-title":"Cyclopentenone Derivatives, XIV. Stereoselective Formation of Prostacyclin Intermediates","volume":"122","author":"Balkenhohl","year":"1989","journal-title":"Chemische Berichte"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6129","DOI":"10.1016\/0040-4039(91)80770-7","article-title":"Preparation of Spiroindolines as Potential Intermediates in Aspidosperma Alkaloid Synthesis","volume":"32","author":"Troin","year":"1991","journal-title":"Tetrahedron Lett."},{"key":"ref_43","first-page":"271","article-title":"Isomerization of N-Aryl Substituted Diethyl 3-Aminoglutaconates. Part I","volume":"377","author":"Humpa","year":"1996","journal-title":"J. Mol. Struct."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/9688\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:15:55Z","timestamp":1760141755000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/9688"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,26]]},"references-count":43,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms23179688"],"URL":"https:\/\/doi.org\/10.3390\/ijms23179688","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,26]]}}}