{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T10:30:13Z","timestamp":1776853813103,"version":"3.51.2"},"reference-count":40,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2020,10,19]],"date-time":"2020-10-19T00:00:00Z","timestamp":1603065600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["427078\/2016-4"],"award-info":[{"award-number":["427078\/2016-4"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006162","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Ci\u00eancia e Tecnologia do Estado de Pernambuco","doi-asserted-by":"publisher","award":["APQ-0350-4.03\/18"],"award-info":[{"award-number":["APQ-0350-4.03\/18"]}],"id":[{"id":"10.13039\/501100006162","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006162","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Ci\u00eancia e Tecnologia do Estado de Pernambuco","doi-asserted-by":"publisher","award":["APQ-0549-2.11\/14"],"award-info":[{"award-number":["APQ-0549-2.11\/14"]}],"id":[{"id":"10.13039\/501100006162","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2020,11,18]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chagas disease and malaria are two neglected tropical diseases (NTDs) that prevail in tropical and subtropical regions in 149\u2005countries. Chagas is also present in Europe, the US and Australia due to immigration of asymptomatic infected individuals. In the absence of an effective vaccine, the control of both diseases relies on chemotherapy. However, the emergence of parasite drug resistance is rendering currently available drugs obsolete. Hence, it is crucial to develop new molecules. Phthalimides, thiosemicarbazones, and 1,3\u2010thiazoles have been used as scaffolds to obtain antiplasmodial and anti\u2010<jats:italic>Trypanosoma cruzi<\/jats:italic> agents. Herein we present the synthesis of 24 phthalimido\u2010thiosemicarbazones (<jats:bold>3\u2009a<\/jats:bold>\u2013<jats:bold>x<\/jats:bold>) and 14 phthalimido\u2010thiazoles (<jats:bold>4\u2009a<\/jats:bold>\u2013<jats:bold>n<\/jats:bold>) and the corresponding biological activity against <jats:italic>T. cruzi, Plasmodium falciparum<\/jats:italic>, and cytotoxicity against mammalian cell lines. Some of these compounds showed potent inhibition of <jats:italic>T. cruzi<\/jats:italic> at low cytotoxic concentrations in RAW 264.7\u2005cells. The most active compounds, <jats:bold>3\u2009t<\/jats:bold> (IC<jats:sub>50<\/jats:sub>=3.60\u2005\u03bcM), <jats:bold>3\u2009h<\/jats:bold> (IC<jats:sub>50<\/jats:sub>=3.75\u2005\u03bcM), and <jats:bold>4\u2009j<\/jats:bold> (IC<jats:sub>50<\/jats:sub>=4.48\u2005\u03bcM), were more active than the control drug benznidazole (IC<jats:sub>50<\/jats:sub>=14.6\u2005\u03bcM). Overall, the phthalimido\u2010thiosemicarbazone derivatives were more potent than phthalimido\u2010thiazole derivatives against <jats:italic>T. cruzi<\/jats:italic>. Flow cytometry assay data showed that compound <jats:bold>4\u2009j<\/jats:bold> was able to induce necrosis and apoptosis in trypomastigotes. Analysis by scanning electron microscopy showed that <jats:italic>T. cruzi<\/jats:italic> trypomastigote cells treated with compounds <jats:bold>3\u2009h<\/jats:bold>, <jats:bold>3\u2009t<\/jats:bold>, and <jats:bold>4\u2009j<\/jats:bold> at IC<jats:sub>50<\/jats:sub> concentrations promoted changes in the shape, flagella, and surface of the parasite body similar to those observed in benznidazole\u2010treated cells. The compounds with the highest antimalarial activity were the phthalimido\u2010thiazoles <jats:bold>4\u2009l<\/jats:bold> (IC<jats:sub>50<\/jats:sub>=1.2\u2005\u03bcM), <jats:bold>4\u2009m<\/jats:bold> (IC<jats:sub>50<\/jats:sub>=1.7\u2005\u03bcM), and <jats:bold>4\u2009n<\/jats:bold> (IC<jats:sub>50<\/jats:sub>=2.4\u2005\u03bcM). Together, these data revealed that phthalimido derivatives possess a dual antiparasitic profile with potential effects against <jats:italic>T. cruzi<\/jats:italic> and lead\u2010like characteristics.<\/jats:p>","DOI":"10.1002\/cmdc.202000331","type":"journal-article","created":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T02:24:40Z","timestamp":1598581480000},"page":"2164-2175","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Dual Parasiticidal Activities of Phthalimides: Synthesis and Biological Profile against <i>Trypanosoma cruzi<\/i> and <i>Plasmodium falciparum<\/i>"],"prefix":"10.1002","volume":"15","author":[{"given":"Paulo Andr\u00e9","family":"Teixeira de Moraes Gomes","sequence":"first","affiliation":[{"name":"Departamento de Ci\u00eancias Farmac\u00eauticas Centro de Ci\u00eancias da Sa\u00fade Universidade Federal de Pernambuco  50740-535 Recife, PE Brazil"}]},{"given":"Marcos","family":"Ver\u00edssimo de Oliveira Cardoso","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Prospec\u00e7\u00e3o de Mol\u00e9culas Bioativas Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancia e Tecnologia Ambiental para o Semi\u00e1rido Universidade de Pernambuco  56328-903 Petrolina, PE Brazil"}]},{"given":"Ignes Regina","family":"dos Santos","sequence":"additional","affiliation":[{"name":"Departamento de Ci\u00eancias Farmac\u00eauticas Centro de Ci\u00eancias da Sa\u00fade Universidade Federal de Pernambuco  50740-535 Recife, PE Brazil"}]},{"given":"Fabiano","family":"Amaro de Sousa","sequence":"additional","affiliation":[{"name":"Departamento de Ci\u00eancias Farmac\u00eauticas Centro de Ci\u00eancias da Sa\u00fade Universidade Federal de Pernambuco  50740-535 Recife, PE Brazil"}]},{"given":"Juliana Maria","family":"da Concei\u00e7\u00e3o","sequence":"additional","affiliation":[{"name":"Departamento de Ci\u00eancias Farmac\u00eauticas Centro de Ci\u00eancias da Sa\u00fade Universidade Federal de Pernambuco  50740-535 Recife, PE Brazil"}]},{"given":"Vanessa","family":"Gouveia de Melo Silva","sequence":"additional","affiliation":[{"name":"Departamento de Ci\u00eancias Farmac\u00eauticas Centro de Ci\u00eancias da Sa\u00fade Universidade Federal de Pernambuco  50740-535 Recife, PE Brazil"}]},{"given":"Denise","family":"Duarte","sequence":"additional","affiliation":[{"name":"Unidade de Ensino e Investiga\u00e7\u00e3o de Parasitologia M\u00e9dica, Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical Universidade Nova de Lisboa, UNL  Rua da Junqueira no 100 1349-008 Lisboa Portugal"}]},{"given":"Raquel","family":"Pereira","sequence":"additional","affiliation":[{"name":"Unidade de Ensino e Investiga\u00e7\u00e3o de Parasitologia M\u00e9dica, Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical Universidade Nova de Lisboa, UNL  Rua da Junqueira no 100 1349-008 Lisboa Portugal"}]},{"given":"Rafael","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Unidade de Ensino e Investiga\u00e7\u00e3o de Parasitologia M\u00e9dica, Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical Universidade Nova de Lisboa, UNL  Rua da Junqueira no 100 1349-008 Lisboa Portugal"}]},{"given":"F\u00e1tima","family":"Nogueira","sequence":"additional","affiliation":[{"name":"Unidade de Ensino e Investiga\u00e7\u00e3o de Parasitologia M\u00e9dica, Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical Universidade Nova de Lisboa, UNL  Rua da Junqueira no 100 1349-008 Lisboa Portugal"}]},{"given":"Luiz Carlos","family":"Alves","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de imunopatologia Keizo Asami (LIKA) Campus UFPE  50670-901 Recife PE Brazil"},{"name":"Instituto Aggeu Magalh\u00e3es Funda\u00e7\u00e3o Oswaldo Cruz  50670-420 Recife, PE Brazil"}]},{"given":"Fabio Andr\u00e9","family":"Brayner","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de imunopatologia Keizo Asami (LIKA) Campus UFPE  50670-901 Recife PE Brazil"},{"name":"Instituto Aggeu Magalh\u00e3es Funda\u00e7\u00e3o Oswaldo Cruz  50670-420 Recife, PE Brazil"}]},{"given":"Aline Caroline","family":"da Silva Santos","sequence":"additional","affiliation":[{"name":"Instituto Aggeu Magalh\u00e3es Funda\u00e7\u00e3o Oswaldo Cruz  50670-420 Recife, PE Brazil"}]},{"given":"Val\u00e9ria","family":"R\u00eago Alves Pereira","sequence":"additional","affiliation":[{"name":"Instituto Aggeu Magalh\u00e3es Funda\u00e7\u00e3o Oswaldo Cruz  50670-420 Recife, PE Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9346-2292","authenticated-orcid":false,"given":"Ana Cristina","family":"Lima Leite","sequence":"additional","affiliation":[{"name":"Departamento de Ci\u00eancias Farmac\u00eauticas Centro de Ci\u00eancias da Sa\u00fade Universidade Federal de Pernambuco  50740-535 Recife, PE Brazil"}]}],"member":"311","published-online":{"date-parts":[[2020,10,19]]},"reference":[{"key":"e_1_2_7_1_1","unstructured":"WHO \u201cChagas disease (American trypanosomiasis) \u201d2019."},{"key":"e_1_2_7_2_1","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.ejmech.2018.06.040","volume":"155","author":"Scarim C. B.","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"e_1_2_7_3_1","unstructured":"\u201cWHO What is Chagas disease? \u201d https:\/\/www.who.int\/chagas\/disease\/en\/2019."},{"key":"e_1_2_7_4_1","unstructured":"W.\u2005H. Organization \u201cMalaria (2019) \u201d https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/malaria2019."},{"key":"e_1_2_7_5_1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.ejim.2017.05.001","volume":"43","author":"Antinori S.","year":"2017","journal-title":"Eur. J. Intern. Med."},{"key":"e_1_2_7_6_1","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1093\/cid\/ciw477","volume":"63","author":"Forsyth C. J.","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"e_1_2_7_7_1","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1056\/NEJMp1108322","volume":"365","author":"Dondorp A. M.","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"e_1_2_7_8_1","doi-asserted-by":"crossref","first-page":"e82","DOI":"10.1086\/657120","volume":"51","author":"Noedl H.","year":"2010","journal-title":"Clin. Infect. Dis."},{"key":"e_1_2_7_9_1","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1186\/1475-2875-13-452","volume":"13","author":"Lubell Y.","year":"2014","journal-title":"Malar. J."},{"key":"e_1_2_7_10_1","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/S1473-3099(15)70032-0","volume":"15","author":"Tun K. M.","year":"2015","journal-title":"Lancet Infect. Dis."},{"key":"e_1_2_7_11_1","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/nrd4573","volume":"14","author":"Wells T. N. C.","year":"2015","journal-title":"Nat. Rev. Drug Discovery"},{"key":"e_1_2_7_12_1","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.pt.2017.04.007","volume":"33","author":"Pierce R. 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