{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T10:30:11Z","timestamp":1776853811552,"version":"3.51.2"},"reference-count":21,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T00:00:00Z","timestamp":1567123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003074","name":"Agencia Nacional de Promoci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["PICT2015-1713"],"award-info":[{"award-number":["PICT2015-1713"]}],"id":[{"id":"10.13039\/501100003074","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The current chemotherapy of Chagas disease needs to be urgently improved. With this aim, a series of 16 hybrids of Cinchona alkaloids and bile acids were prepared by functionalization at position C-2 of the quinoline nucleus by a radical attack of a norcholane substituent via a Barton\u2013Zard decarboxylation reaction. The antitrypanosomal activity of the hybrids was tested on different stages and strains of T. cruzi. In particular, eight out of 16 hybrids presented an IC50 \u22641 \u03bcg\/mL against trypomastigotes of the CL Brener strain and\/or a selectivity index higher than 10. These promising hybrids yielded similar results when tested on trypomastigotes from the RA strain of T. cruzi (discrete typing unit\u2014DTU\u2014VI). Surprisingly, trypomastigotes of the Y strain (DTU II) were more resistant to benznidazole and to most of the hybrids than those of the CL Brener and RA strains. However, the peracetylated and non-acetylated forms of the cinchonine\/chenodeoxycholic bile acid conjugate 4f and 5f were the most trypanocidal hybrids against Y strain trypomastigotes, with IC50 values of 0.5 and 0.65 \u03bcg\/mL, respectively. More importantly, promising results were observed in invasion assays using the Y strain, where hybrids 5f and 4f induced a significant reduction in intracellular amastigotes and on the release of trypomastigotes from infected cells.<\/jats:p>","DOI":"10.3390\/molecules24173168","type":"journal-article","created":{"date-parts":[[2019,9,2]],"date-time":"2019-09-02T03:16:12Z","timestamp":1567394172000},"page":"3168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Hybrids of Cinchona Alkaloids and Bile Acids as Antiparasitic Agents Against Trypanosoma cruzi"],"prefix":"10.3390","volume":"24","author":[{"given":"Daniel","family":"Musikant","sequence":"first","affiliation":[{"name":"Departamento de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Ciudad deBuenos Aires, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aur\u00e9lie","family":"Leverrier","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Ciudad de Buenos Aires, Argentina"},{"name":"CONICET-Universidad de Buenos Aires, Unidad de Microan\u00e1lisis y M\u00e9todos F\u00edsicos en Qu\u00edmica Org\u00e1nica (UMYMFOR), 1428 Ciudad de Buenos Aires, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Bernal","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Ciudad deBuenos Aires, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel","family":"Ferri","sequence":"additional","affiliation":[{"name":"CONICET-Universidad de Buenos Aires, Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), 1428 Ciudad de Buenos Aires, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge A.","family":"Palermo","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Ciudad de Buenos Aires, Argentina"},{"name":"CONICET-Universidad de Buenos Aires, Unidad de Microan\u00e1lisis y M\u00e9todos F\u00edsicos en Qu\u00edmica Org\u00e1nica (UMYMFOR), 1428 Ciudad de Buenos Aires, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9120-2649","authenticated-orcid":false,"given":"Martin M.","family":"Edreira","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Ciudad deBuenos Aires, Argentina"},{"name":"CONICET-Universidad de Buenos Aires, Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), 1428 Ciudad de Buenos Aires, Argentina"},{"name":"Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,30]]},"reference":[{"key":"ref_1","first-page":"154","article-title":"Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi","volume":"6","author":"Lechuga","year":"2016","journal-title":"Int. J. Parasitol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1080\/00034983.1996.11813071","article-title":"Primaquine analogues that are potent anti-Trypanosoma cruzi agents in a mouse model","volume":"90","author":"Kinnamon","year":"1996","journal-title":"Ann. Trop. Med. Parasitol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0163-7258(98)00012-6","article-title":"Quinoline antimalarials: Mechanisms of action and resistance and prospects for new agents","volume":"79","author":"Foley","year":"1998","journal-title":"Pharmacol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.ijid.2011.03.021","article-title":"Recent advances in leishmaniasis treatment","volume":"15","author":"Tiuman","year":"2011","journal-title":"Int. J. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1111\/cbdd.13346","article-title":"Cytotoxic and trypanocidal activities of Cinchona alkaloid derivatives","volume":"92","author":"Kacprzak","year":"2018","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5013","DOI":"10.1016\/j.bmc.2003.09.007","article-title":"Synthesis and biological evaluation of substituted quinolines: Potential treatment of protozoal and retroviral co-infections","volume":"11","author":"Fakhfakh","year":"2003","journal-title":"Bioorganic Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ramawat, K.G., and M\u00e9rillon, J.-M. (2013). Chemistry and Biology of Cinchona Alkaloids. Natural Products: Phytochemistry, Botany and Metabolism of Alkaloids, Phenolics and Terpenes, Springer.","DOI":"10.1007\/978-3-642-22144-6"},{"key":"ref_8","first-page":"162","article-title":"Spectrum of biological properties of Cinchona alkaloids: A brief review","volume":"6","author":"Pranay","year":"2017","journal-title":"J. Pharmacogn. Phytochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/978-3-642-14541-4_4","article-title":"Role of the intestinal bile acid transporters in bile acid and drug disposition","volume":"201","author":"Dawson","year":"2011","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.ejmech.2013.06.004","article-title":"Antiparasitic hybrids of Cinchona alkaloids and bile acids","volume":"66","author":"Leverrier","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.molbiopara.2016.10.003","article-title":"Host Epac1 is required for cAMP-mediated invasion by Trypanosoma cruzi","volume":"211","author":"Musikant","year":"2017","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1590\/S0074-02762009000700021","article-title":"A new consensus for Trypanosoma cruzi intraspecific nomenclature: Second revision meeting recommends TcI to TcVI","volume":"104","author":"Zingales","year":"2009","journal-title":"Memorias do Instituto Oswaldo Cruz"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1590\/S0074-02762010000700014","article-title":"Trypanosoma cruzi benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease","volume":"105","author":"Moreno","year":"2010","journal-title":"Memorias do Instituto Oswaldo Cruz"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.exppara.2004.07.001","article-title":"Lack of correlation between in vitro susceptibility to Benznidazole and phylogenetic diversity of Trypanosoma cruzi, the agent of Chagas disease","volume":"108","author":"Villarreal","year":"2004","journal-title":"Exp. Parasitol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1128\/AAC.47.1.223-230.2003","article-title":"Chemotherapy with benznidazole and itraconazole for mice infected with different Trypanosoma cruzi clonal genotypes","volume":"47","author":"Toledo","year":"2003","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0166-6851(98)00037-1","article-title":"Molecular characterization of susceptible and naturally resistant strains of Trypanosoma cruzi to benznidazole and nifurtimox","volume":"93","author":"Murta","year":"1998","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/0035-9203(87)90020-4","article-title":"Susceptibility and natural resistance of Trypanosoma cruzi strains to drugs used clinically in Chagas disease","volume":"81","author":"Filardi","year":"1987","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1590\/0074-0276140156","article-title":"Drug discovery for Chagas disease should consider Trypanosoma cruzi strain diversity","volume":"109","author":"Zingales","year":"2014","journal-title":"Memorias do Instituto Oswaldo Cruz"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Quebrada Palacio, L.P., Gonzalez, M.N., Hernandez-Vasquez, Y., Perrone, A.E., Parodi-Talice, A., Bua, J., and Postan, M. (2018). Phenotypic diversity and drug susceptibility of Trypanosoma cruzi TcV clinical isolates. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0203462"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3367","DOI":"10.1007\/s00436-018-6084-3","article-title":"Experimental models in Chagas disease: A review of the methodologies applied for screening compounds against Trypanosoma cruzi","volume":"117","author":"Aran","year":"2018","journal-title":"Parasitol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ejmech.2015.05.044","article-title":"Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities","volume":"100","author":"Leverrier","year":"2015","journal-title":"Eur. J. Med. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/17\/3168\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:15:32Z","timestamp":1760188532000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/17\/3168"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,30]]},"references-count":21,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["molecules24173168"],"URL":"https:\/\/doi.org\/10.3390\/molecules24173168","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,30]]}}}