{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T16:29:07Z","timestamp":1774888147298,"version":"3.50.1"},"reference-count":44,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T00:00:00Z","timestamp":1669075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universidade de Vigo, Xunta de Galicia","award":["ED431C 2022\/20"],"award-info":[{"award-number":["ED431C 2022\/20"]}]},{"name":"Universidade de Vigo, Xunta de Galicia","award":["ED431G 2019\/02"],"award-info":[{"award-number":["ED431G 2019\/02"]}]},{"name":"European Regional Development Fund (ERDF)","award":["ED431C 2022\/20"],"award-info":[{"award-number":["ED431C 2022\/20"]}]},{"name":"European Regional Development Fund (ERDF)","award":["ED431G 2019\/02"],"award-info":[{"award-number":["ED431G 2019\/02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Nowadays, cancer disease seems to be the second most common cause of death worldwide. Molecular hybridization is a drug design strategy that has provided promising results against multifactorial diseases, including cancer. In this work, two series of phthalazinone-dithiocarbamate hybrids were described, compounds 6\u20138, which display the dithiocarbamate scaffold at N2, and compounds 9, in which this moiety was placed at C4. The proposed compounds were successfully synthesized via the corresponding aminoalkyl phthalazinone derivatives and using a one-pot reaction with carbon disulfide, anhydrous H3PO4, and different benzyl or propargyl bromides. The antiproliferative effects of the titled compounds were explored against three human cancer cell lines (A2780, NCI-H460, and MCF-7). The preliminary results revealed significant differences in activity and selectivity depending on the dithiocarbamate moiety location. Thus, in general terms, compounds 6\u20138 displayed better activity against the A-2780 and MCF-7 cell lines, while most of the analogues of the 9 group were selective toward the NCI-H460 cell line. Compounds 6e, 8e, 6g, 9a\u2013b, 9d, and 9g with IC50 values less than 10 \u00b5M were the most promising. The drug-likeness and toxicity properties of the novel phthalazinone-dithiocarbamate hybrids were predicted using Swiss-ADME and ProTox web servers, respectively.<\/jats:p>","DOI":"10.3390\/molecules27238115","type":"journal-article","created":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T08:29:58Z","timestamp":1669105798000},"page":"8115","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Novel Phthalazin-1(2H)-One Derivatives Displaying a Dithiocarbamate Moiety as Potential Anticancer Agents"],"prefix":"10.3390","volume":"27","author":[{"given":"Noem\u00ed","family":"Vila","sequence":"first","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Universidade de Vigo, 36310 Vigo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Galicia Sur, Hospital \u00c1lvaro Cunqueiro, 36213 Vigo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9985-9063","authenticated-orcid":false,"given":"Pedro","family":"Besada","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Universidade de Vigo, 36310 Vigo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Galicia Sur, Hospital \u00c1lvaro Cunqueiro, 36213 Vigo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5523-1979","authenticated-orcid":false,"given":"Jos\u00e9","family":"Brea","sequence":"additional","affiliation":[{"name":"Drug Screening Platform\/Biofarma Research Group, CIMUS Research Center, Departamento de Farmacolox\u00eda, Farmacia e Tecnolox\u00eda Farmac\u00e9utica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Isabel","family":"Loza","sequence":"additional","affiliation":[{"name":"Drug Screening Platform\/Biofarma Research Group, CIMUS Research Center, Departamento de Farmacolox\u00eda, Farmacia e Tecnolox\u00eda Farmac\u00e9utica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4377-3604","authenticated-orcid":false,"given":"Carmen","family":"Ter\u00e1n","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Universidade de Vigo, 36310 Vigo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Galicia Sur, Hospital \u00c1lvaro Cunqueiro, 36213 Vigo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/S0140-6736(19)32007-0","article-title":"Variations in common diseases, hospital admissions, and deaths in middle-aged adults in 21 countries from five continents (PURE): A prospective cohort study","volume":"395","author":"Dagenais","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.1021\/acs.chemrev.0c00383","article-title":"Challenges and Opportunities in Cancer Drug Resistance","volume":"121","author":"Ward","year":"2021","journal-title":"Chem. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"405","DOI":"10.2174\/138955710791330918","article-title":"Search for new and novel chemotherapeutics for the treatment of human malignancies","volume":"10","author":"Kamal","year":"2010","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.2174\/1568026616666160927160620","article-title":"Hybrid compounds as direct multitarget ligands: A review","volume":"17","author":"Ishiki","year":"2017","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.ejmech.2014.03.018","article-title":"Rational approaches, design strategies, structure activity relationship and mechanistic insights for anticancer hybrids","volume":"77","author":"Nepali","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2228","DOI":"10.2174\/1871520620666200807220146","article-title":"Phthalazinone scaffold: Emerging tool in the development of target based novel anticancer agents","volume":"20","author":"Singh","year":"2020","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.ejmech.2014.11.043","article-title":"Phthalazin-1(2H)-one as a remarkable scaffold in drug Discovery","volume":"97","author":"Vila","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.ejmech.2018.10.047","article-title":"Recent advances in the synthesis of phthalazin-1(2H)-one core as a relevant pharmacophore in medicinal chemistry","volume":"161","author":"Besada","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6581","DOI":"10.1021\/jm8001263","article-title":"4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1","volume":"51","author":"Menear","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.bioorg.2018.01.034","article-title":"Development of novel synthesized phthalazinone-based PARP-1 inhibitors with apoptosis inducing mechanism in lung cancer","volume":"77","author":"Almahli","year":"2018","journal-title":"Bioorg. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.4155\/fmc-2020-0009","article-title":"Design and synthesis of novel phthalazinone derivatives as potent poly(ADP-ribose)polymerase 1 inhibitors","volume":"12","author":"Xin","year":"2020","journal-title":"Future Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1021\/jm101346r","article-title":"Phthalazinone pyrazoles as potent, selective, and orally bioavailable inhibitors of Aurora-A kinase","volume":"54","author":"Prime","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3675","DOI":"10.1039\/C9RA09016A","article-title":"Synthesis of new oxadiazol-phthalazinone derivatives with anti-proliferative activity; molecular docking, pro-apoptotic, and enzyme inhibition profile","volume":"10","author":"Hekal","year":"2020","journal-title":"RSC Adv."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"102092","DOI":"10.1016\/j.isci.2021.102092","article-title":"The revival of dithiocarbamates: From pesticides to innovative medical treatments","volume":"24","author":"Kaul","year":"2021","journal-title":"iScience"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"104347","DOI":"10.1016\/j.bioorg.2020.104346","article-title":"An insight into medicinal attributes of dithiocarbamates: Bird\u2019s eye view","volume":"105","author":"Shinde","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1021\/jm0508888","article-title":"Structure-activity study of brassinin derivatives as indoleamine 2,3-dioxygenase inhibitors","volume":"49","author":"Gaspari","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2851","DOI":"10.1038\/sj.onc.1210939","article-title":"A key in vivo antitumor mechanism of action of natural product-based brassinins is inhibition of indoleamine 2,3-dioxygenase","volume":"27","author":"Banerjee","year":"2008","journal-title":"Oncogene"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"103593","DOI":"10.1016\/j.bioorg.2020.103593","article-title":"Benzoxazole derivatives as new generation of anti-breast cancer agents","volume":"96","author":"Omar","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8543","DOI":"10.1021\/jm401002r","article-title":"Triazole-dithiocarbamate based selective lysine specific demethylase 1 (LSD1) inactivators inhibit gastric cancer cell growth, invasion, and migration","volume":"56","author":"Zheng","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.ejmech.2019.05.048","article-title":"Discovery of 2,4-diarylaminopyrimidine derivatives bearing dithiocarbamate moiety as novel FAK inhibitors with antitumor and anti-angiogenesis activities","volume":"177","author":"Su","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.ejmech.2015.11.044","article-title":"Synthesis and biological evaluation of quinazolin-4(3H)-one derivatives bearing dithiocarbamate side chain at C2-position as potential antitumor agents","volume":"108","author":"Ding","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3850","DOI":"10.1016\/j.ejmech.2010.05.038","article-title":"Synthesis and cytotoxic activity of N-((2-methyl-4(3H)-quinazolinon-6-yl)methyl)dithiocarbamates","volume":"45","author":"Cao","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3918","DOI":"10.1016\/j.bmcl.2016.07.012","article-title":"Design, synthesis and antiproliferative activity studies of novel dithiocarbamate-chalcone derivatives","volume":"26","author":"Fu","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_25","unstructured":"Ter\u00e1n, C., Besada, P., Costas, T., Vila, N., and Costas-Lago, M.C. (2015). Compuestos de Estructura H\u00edbrida Piridaziona Ditiocarbamato Con Actividad Antineopl\u00e1sica. (ES2469990B1), Spanish Patent."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.2174\/1389557518666180903153254","article-title":"New 1-phthalazinone scaffold based compounds: Design, cytotoxicity and protein kinase inhibition activity","volume":"18","author":"George","year":"2018","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1021\/acsmedchemlett.1c00633","article-title":"Novel pyridazin-3(2H)-one-based guanidine derivatives as potential DNA minor groove binders with anticancer activity","volume":"13","author":"Vila","year":"2022","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1002\/cmdc.201600182","article-title":"A BOILED-Egg to predict gastrointestinal absorption and brain penetration of small molecules","volume":"11","author":"Daina","year":"2016","journal-title":"ChemMedChem"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.addr.2015.03.001","article-title":"Prediction of drug-ABC-transporter interaction-recent advances and future challenges","volume":"86","author":"Montarani","year":"2015","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"105","DOI":"10.2217\/14622416.9.1.105","article-title":"ABC multidrug transporters: Structure, function and role in chemoresistence","volume":"9","author":"Sharom","year":"2008","journal-title":"Pharmacohenomics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and premeabilty in drug discoveryand development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug. Deliv. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1021\/cc9800071","article-title":"A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases","volume":"1","author":"Ghose","year":"1999","journal-title":"J Comb. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1021\/jm020017n","article-title":"Molecular properties that influence the oral bioavailability of drug candidates","volume":"45","author":"Veber","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3867","DOI":"10.1021\/jm000292e","article-title":"Prediction of drug absorption using multivariate statistics","volume":"43","author":"Egan","year":"2000","journal-title":"J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1021\/jm015507e","article-title":"Simple selection criteria for drug-like chemical matter","volume":"44","author":"Muegge","year":"2001","journal-title":"J. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"W257","DOI":"10.1093\/nar\/gky318","article-title":"ProTox-II: A webserver for the prediction of toxicity of chemicals","volume":"46","author":"Banerjee","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"46170","DOI":"10.1039\/C6RA03841G","article-title":"Synthesis, biological evaluation and molecular modeling studies of phthalazin-1(2H)-one derivatives as novel cholinesterase inhibitors","volume":"6","author":"Vila","year":"2016","journal-title":"RSC Adv."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"105203","DOI":"10.1016\/j.bioorg.2021.105203","article-title":"Pyridazinones containing dithiocarbamoyl moieties as a new class of selective MAO-B inhibitors","volume":"115","author":"Besada","year":"2021","journal-title":"Bioorg. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3927","DOI":"10.1016\/j.bmcl.2003.09.011","article-title":"Synthesis of 17-beta-estradiol platinum(II) complexes: Biological evaluation on breast cancer cell lines","volume":"13","author":"Mathieu","year":"2003","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6692","DOI":"10.1021\/jm070897b","article-title":"Novel di- and tetracarboxylatoplatinum(IV) complexes. synthesis, characterization, cytotoxic activity, and DNA platination","volume":"50","author":"Reithofer","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1002\/cbic.200500108","article-title":"Synthesis, characterization and biological activity of trans-platinum(II) and trans-platinum(IV) complexes with 4-hydroxymethylpyridine","volume":"6","author":"Martinez","year":"2005","journal-title":"ChemBioChem"},{"key":"ref_43","unstructured":"(2022, September 26). SwissADME. Available online: http:\/\/www.swissadme.ch."},{"key":"ref_44","unstructured":"(2022, September 27). ProTox-II. Available online: https:\/\/tox-new.charite.de\/protox_II\/."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/23\/8115\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:23:23Z","timestamp":1760145803000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/23\/8115"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,22]]},"references-count":44,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["molecules27238115"],"URL":"https:\/\/doi.org\/10.3390\/molecules27238115","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,22]]}}}