{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:11:13Z","timestamp":1760163073856,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,2,27]],"date-time":"2021-02-27T00:00:00Z","timestamp":1614384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>The discovery of novel antiparasitic drugs for neglected tropical diseases (NTDs) constitutes a global urgency and requires a range of innovative strategies to ensure a sustainable pipeline of lead compounds. Thus far, primaquine (PQ) is the only transmission-blocking antimalarial that is clinically available, displaying marked activity against gametocytes of all causative species of human malaria (Plasmodium spp.). Chagas disease, caused by Trypanosoma cruzi, is another PQ-sensitive illness besides malaria. One of the major drawbacks of PQ is its metabolism into carboxyprimaquine (CPQ), which is less active than the parent drug. In this study, we developed different synthetic pathways to confer N-protection to PQ through introduction of thioxo-imidazolidin-4-one. The introduction of this group prevents the formation of CPQ, counteracting one major drawback of the parent drug. After that, we evaluated the potential biological activity of the novel 2-thioxo-imidazolidin-4-one derivative of PQ, which showed relevant in vitro activity against Trypanosoma cruzi (IC50 1.4 \u03bcM) compared to PQ (IC50 1.7 \u03bcM) and the reference drug benznidazole (IC50 1.6 \u03bcM). Noting its acceptable pharmacokinetic profile, this PQ conjugate may be a potential scaffold for novel drug exploration against Chagas disease.<\/jats:p>","DOI":"10.3390\/ph14030196","type":"journal-article","created":{"date-parts":[[2021,2,27]],"date-time":"2021-02-27T20:55:44Z","timestamp":1614459344000},"page":"196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Synthesis, Biological Activity and In Silico Pharmacokinetic Prediction of a New 2-Thioxo-Imidazoldidin-4-One of Primaquine"],"prefix":"10.3390","volume":"14","author":[{"given":"Mariana","family":"Pereira","sequence":"first","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4870-3202","authenticated-orcid":false,"given":"Guy","family":"Caljon","sequence":"additional","affiliation":[{"name":"Laboratory of Parasitology, Microbiology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteiplein 1, 2610 Antwerp, Belgium"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3747-5520","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Gouveia","sequence":"additional","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2324-9509","authenticated-orcid":false,"given":"Louis","family":"Maes","sequence":"additional","affiliation":[{"name":"Laboratory of Parasitology, Microbiology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteiplein 1, 2610 Antwerp, Belgium"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Faculty of Medicine, University of Porto, Al. Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,27]]},"reference":[{"key":"ref_1","unstructured":"Chris, B., Singh, S., and Sudarshi, D. (2011). Neglected tropical diseases, conflict, and the right to health. The Causes and Impacts of Neglected Tropical and Zoonotic Diseases: Opportunities for Integrated Intervention Strategies, National Academies Press (US)."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mitra, A.K., and Mawson, A.R. (2017). Neglected tropical diseases: Epidemiology and global burden. Trop. Med. Infect. Dis., 2.","DOI":"10.3390\/tropicalmed2030036"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1038\/s41591-019-0514-3","article-title":"Turning up the heat on neglected diseases","volume":"25","author":"Wetsman","year":"2019","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1086\/424663","article-title":"Primaquine therapy for malaria","volume":"39","author":"Baird","year":"2004","journal-title":"Clin. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"402","DOI":"10.4269\/ajtmh.2006.75.402","article-title":"Primaquine: Report from CDC expert meeting on malaria chemoprophylaxis I","volume":"75","author":"Hill","year":"2006","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.ejmech.2008.08.011","article-title":"Primaquine revisited six decades after its discovery","volume":"44","author":"Vale","year":"2009","journal-title":"Eur. J. Med. Chem."},{"key":"ref_7","unstructured":"World Health Organization (2015). Guidelines for the Treatment of Malaria, World Health Organization."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/j.1365-2125.1980.tb01777.x","article-title":"Plasma kinetics and urinary excretion of primaquine in man","volume":"10","author":"Greaves","year":"1980","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1007\/BF02980134","article-title":"Pharmacokinetics of primaquine and carboxyprimaquine in Korean patients with vivax malaria","volume":"27","author":"Kim","year":"2004","journal-title":"Arch. Pharm. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1002\/jps.2600730418","article-title":"Excretion, distribution, and metabolism of primaquine in rats","volume":"73","author":"Clark","year":"1984","journal-title":"J. Pharm. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1186\/1475-2875-13-418","article-title":"Primaquine: The risks and the benefits","volume":"13","author":"Ashley","year":"2014","journal-title":"Malar. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1186\/s12936-019-2981-x","article-title":"Prevalence and distribution of G6PD deficiency: Implication for the use of primaquine in malaria treatment in Ethiopia","volume":"18","author":"Lo","year":"2019","journal-title":"Malar. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1186\/1475-2875-12-212","article-title":"The metabolism of primaquine to its active metabolite is dependent on CYP 2D6","volume":"12","author":"Pybus","year":"2013","journal-title":"Malar. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1093\/infdis\/jiz386","article-title":"Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population","volume":"220","author":"Spring","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1186\/1475-2875-11-259","article-title":"CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine","volume":"11","author":"Pybus","year":"2012","journal-title":"Malar. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1111\/j.1365-2125.1984.tb02369.x","article-title":"Pharmacokinetics of primaquine in man: Identification of the carboxylic acid derivative as a major plasma metabolite","volume":"17","author":"Mihaly","year":"1984","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S0940-2993(99)80010-4","article-title":"Metabolism of primaquine by liver homogenate fractions. Evidence for monoamine oxidase and cytochrome P450 involvement in the oxidative deamination of primaquine to carboxyprimaquine","volume":"51","author":"Constantino","year":"1999","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3226","DOI":"10.1038\/s41467-019-11239-0","article-title":"Antimalarial activity of primaquine operates via a two-step biochemical relay","volume":"10","author":"Camarda","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1128\/AAC.00015-15","article-title":"Differential CYP 2D6 metabolism alters primaquine pharmacokinetics","volume":"59","author":"Potter","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1186\/s12936-018-2433-z","article-title":"Metabolism of primaquine in normal human volunteers: Investigation of phase I and phase II metabolites from plasma and urine using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry","volume":"17","author":"Avula","year":"2018","journal-title":"Malar. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1021\/jm0494624","article-title":"Imidazolidin-4-one derivatives of primaquine as novel transmission-blocking antimalarials","volume":"48","author":"Bom","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.bmcl.2007.11.105","article-title":"Anti-Pneumocystis carinii and antiplasmodial activities of primaquine-derived imidazolidin-4-ones","volume":"18","author":"Vale","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1021\/jm00216a001","article-title":"In search of anti-Trypanosoma cruzi drugs: New leads from a mouse model","volume":"20","author":"Kinnamon","year":"1977","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0302-4598(00)00093-3","article-title":"Dissociation and electrooxidation of primaquine diphosphate as an approach to the study of anti-chagas prodrugs mechanism of action","volume":"53","author":"Chin","year":"2001","journal-title":"Bioelectrochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.clinthera.2014.02.002","article-title":"Adverse event management in mass drug administration for neglected tropical diseases","volume":"36","author":"Caplan","year":"2014","journal-title":"Clin. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1111\/j.1365-2125.1985.tb02709.x","article-title":"Pharmacokinetics of primaquine in man. I. Studies of the absolute bioavailability and effects of dose size","volume":"19","author":"Mihaly","year":"1985","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1093\/jac\/dkh224","article-title":"Effects of specific treatment on parasitological and histopathological parameters in mice infected with different Trypanosoma cruzi clonal genotypes","volume":"53","author":"Toledo","year":"2004","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1007\/s11095-016-1951-z","article-title":"Evaluation of the GastroPlus\u2122 Advanced Compartmental and Transit (ACAT) Model in Early Discovery","volume":"33","author":"Gobeau","year":"2016","journal-title":"Pharm. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.jep.2006.04.003","article-title":"Anti-infective potential of natural products: How to develop a stronger in vitro \u2019proof-of-concept\u2019","volume":"106","author":"Cos","year":"2006","journal-title":"J. Ethnopharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S0001-706X(97)00079-X","article-title":"The Alamar Blue assay to determine drug sensitivity of African trypanosomes (T.b. rhodesiense and T.b. gambiense) in vitro","volume":"68","author":"Iten","year":"1997","journal-title":"Acta Trop."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1007\/s00280-018-3545-4","article-title":"Monitoring of erlotinib in pancreatic cancer patients during long-time administration and comparison to a physiologically based pharmacokinetic model","volume":"81","author":"Gruber","year":"2018","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Duque, M.D., Silva, D.A., Issa, M.G., Porta, V., L\u00f6benberg, R., and Ferraz, H.G. (2019). In silico prediction of plasma concentrations of flucona-zole capsules with different dissolution profiles and bioequivalence study using population simulation. Pharmaceuticals, 11.","DOI":"10.3390\/pharmaceutics11050215"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ferreira, A., Lapa, R., and Vale, N. (2019). Combination of Gemcitabine with Cell-Penetrating Peptides: A Pharmacokinetic Approach Using in Silico Tools. Biomolecules, 9.","DOI":"10.3390\/biom9110693"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ferreira, A., Martins, H., Oliveira, J.C., Lapa, R., and Vale, N. (2021). In silico pharmacokinetic study of vancomycin using PBPK modeling and therapeutic drug monitoring. Curr. Drug Metabol.","DOI":"10.2174\/1389200221999210101232417"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/3\/196\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:29:58Z","timestamp":1760160598000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/3\/196"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,27]]},"references-count":34,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["ph14030196"],"URL":"https:\/\/doi.org\/10.3390\/ph14030196","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2021,2,27]]}}}