Antimalarial pyrido [1,2‑a] benzimidazoles exert strong parasiticidal effects by achieving high cellular uptake and suppressing heme detoxification
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2022 |
| Outros Autores: | , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/54917 |
Resumo: | Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB). Fundação Oswaldo Cruz (Fiocruz) / Programa de Excelência em Pesquisa (PROEP). University of Cape Town. South African Medical Research Council. South African Research Chairs Initiative of the Department of Science and Innovation. South African National Research Foundation. |
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Sousa, Caroline CDziwornu, Godwin AkpekoQuadros, Helenita CAraújo Neto, João HonoratoChibale, KellyMoreira, Diogo R. M2022-09-28T17:54:26Z2022-09-28T17:54:26Z2022SOUSA, Caroline C. et al. Antimalarial pyrido [1,2‑a] benzimidazoles exert strong parasiticidal effects by achieving high cellular uptake and suppressing heme detoxification. ACS Infectious Diseases, v. 8, p. 1-11, 2022.2373-8227https://www.arca.fiocruz.br/handle/icict/5491710.1021/acsinfecdis.2c00326Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB). Fundação Oswaldo Cruz (Fiocruz) / Programa de Excelência em Pesquisa (PROEP). University of Cape Town. South African Medical Research Council. South African Research Chairs Initiative of the Department of Science and Innovation. South African National Research Foundation.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz, Salvador, BA, Brasil.South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Diseases and Molecular Medicine, University of Cape Town. Rondebosch, South AfricaFundação Oswaldo Cruz. Instituto Gonçalo Moniz, Salvador, BA, Brasil.Universidade de São Paulo. São Paulo, SP, Brasil.South African Medical Research Council Drug Discovery and Development Research Uni., Department of Chemistry and Institute of Infectious Diseases and Molecular Medicine. University of Cape Town. Rondebosch, South AfricaFundação Oswaldo Cruz. Instituto Gonçalo Moniz, Salvador, BA, Brasil.Pyrido[1,2-a]benzimidazoles (PBIs) are synthetic antiplasmodium agents with potent activity and are structurally differentiated from benchmark antimalarials. To study the cellular uptake of PBIs and understand the underlying phenotype of their antiplasmodium activity, their antiparasitic activities were examined in chloroquine (CQ)-susceptible and CQ-resistant Plasmodium falciparumin vitro. Moreover, drug uptake and heme detoxification suppression were examined in Plasmodium berghei-infected mice. The in vitro potency of PBIs is comparable to most 4-aminoquinolines. They have a speed of action in vitro that is superior to that of atovaquone and an ability to kill rings and trophozoites. The antiparasitic effects observed for the PBIs in cell culture and in infected mice are similar in terms of potency and efficacy and are comparable to CQ but with the added advantage of demonstrating equipotency against both CQ susceptible and resistant parasite strains. PBIs have a high rate of uptake by parasite cells and, conversely, a limited rate of uptake by host cells. The mechanism of cellular uptake of the PBIs differs from the ion-trap mechanism typically observed for 4-aminoquinolines, although they share key structural features. The high cellular uptake, attractive parasiticidal profile, and susceptibility of resistant strains to PBIs are desirable characteristics for new antimalarial agents.engAmerican Chemical SocietyMalariaPlasmodiumMaláriaPlasmodiumBenzimidazolParasiticidaHeme poolDesintoxicação do hemeMalariaPlasmodiumBenzimidazoleParasiticidalHeme poolHeme detoxificationAntimalarial pyrido [1,2‑a] benzimidazoles exert strong parasiticidal effects by achieving high cellular uptake and suppressing heme detoxificationinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/54917/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALSousa, Caroline C. - Antimalarial Pyrido[1,2‑a]benzimidazoles Exert Strong Parasiticidal.pdfSousa, Caroline C. - Antimalarial Pyrido[1,2‑a]benzimidazoles Exert Strong Parasiticidal.pdfapplication/pdf2955799https://www.arca.fiocruz.br/bitstream/icict/54917/2/Sousa%2c%20Caroline%20C.%20-%20Antimalarial%20Pyrido%5b1%2c2%e2%80%91a%5dbenzimidazoles%20Exert%20Strong%20Parasiticidal.pdfba06545f19ee7f5245f843619faad97fMD52icict/549172023-03-15 14:32:51.451oai:www.arca.fiocruz.br:icict/54917Q0VTU8ODTyBOw4NPIEVYQ0xVU0lWQSBERSBESVJFSVRPUyBBVVRPUkFJUwoKQW8gYWNlaXRhciBvcyBURVJNT1MgZSBDT05EScOHw5VFUyBkZXN0YSBDRVNTw4NPLCBvIEFVVE9SIGUvb3UgVElUVUxBUiBkZSBkaXJlaXRvcwphdXRvcmFpcyBzb2JyZSBhIE9CUkEgZGUgcXVlIHRyYXRhIGVzdGUgZG9jdW1lbnRvOgoKKDEpIENFREUgZSBUUkFOU0ZFUkUsIHRvdGFsIGUgZ3JhdHVpdGFtZW50ZSwgw6AgRklPQ1JVWiAtIEZVTkRBw4fDg08gT1NXQUxETyBDUlVaLCBlbQpjYXLDoXRlciBwZXJtYW5lbnRlLCBpcnJldm9nw6F2ZWwgZSBOw4NPIEVYQ0xVU0lWTywgdG9kb3Mgb3MgZGlyZWl0b3MgcGF0cmltb25pYWlzIE7Dg08KQ09NRVJDSUFJUyBkZSB1dGlsaXphw6fDo28gZGEgT0JSQSBhcnTDrXN0aWNhIGUvb3UgY2llbnTDrWZpY2EgaW5kaWNhZGEgYWNpbWEsIGluY2x1c2l2ZSBvcyBkaXJlaXRvcwpkZSB2b3ogZSBpbWFnZW0gdmluY3VsYWRvcyDDoCBPQlJBLCBkdXJhbnRlIHRvZG8gbyBwcmF6byBkZSBkdXJhw6fDo28gZG9zIGRpcmVpdG9zIGF1dG9yYWlzLCBlbQpxdWFscXVlciBpZGlvbWEgZSBlbSB0b2RvcyBvcyBwYcOtc2VzOwoKKDIpIEFDRUlUQSBxdWUgYSBjZXNzw6NvIHRvdGFsIG7Do28gZXhjbHVzaXZhLCBwZXJtYW5lbnRlIGUgaXJyZXZvZ8OhdmVsIGRvcyBkaXJlaXRvcyBhdXRvcmFpcwpwYXRyaW1vbmlhaXMgbsOjbyBjb21lcmNpYWlzIGRlIHV0aWxpemHDp8OjbyBkZSBxdWUgdHJhdGEgZXN0ZSBkb2N1bWVudG8gaW5jbHVpLCBleGVtcGxpZmljYXRpdmFtZW50ZSwKb3MgZGlyZWl0b3MgZGUgZGlzcG9uaWJpbGl6YcOnw6NvIGUgY29tdW5pY2HDp8OjbyBww7pibGljYSBkYSBPQlJBLCBlbSBxdWFscXVlciBtZWlvIG91IHZlw61jdWxvLAppbmNsdXNpdmUgZW0gUmVwb3NpdMOzcmlvcyBEaWdpdGFpcywgYmVtIGNvbW8gb3MgZGlyZWl0b3MgZGUgcmVwcm9kdcOnw6NvLCBleGliacOnw6NvLCBleGVjdcOnw6NvLApkZWNsYW1hw6fDo28sIHJlY2l0YcOnw6NvLCBleHBvc2nDp8OjbywgYXJxdWl2YW1lbnRvLCBpbmNsdXPDo28gZW0gYmFuY28gZGUgZGFkb3MsIHByZXNlcnZhw6fDo28sIGRpZnVzw6NvLApkaXN0cmlidWnDp8OjbywgZGl2dWxnYcOnw6NvLCBlbXByw6lzdGltbywgdHJhZHXDp8OjbywgZHVibGFnZW0sIGxlZ2VuZGFnZW0sIGluY2x1c8OjbyBlbSBub3ZhcyBvYnJhcyBvdQpjb2xldMOibmVhcywgcmV1dGlsaXphw6fDo28sIGVkacOnw6NvLCBwcm9kdcOnw6NvIGRlIG1hdGVyaWFsIGRpZMOhdGljbyBlIGN1cnNvcyBvdSBxdWFscXVlciBmb3JtYSBkZQp1dGlsaXphw6fDo28gbsOjbyBjb21lcmNpYWw7CgooMykgUkVDT05IRUNFIHF1ZSBhIGNlc3PDo28gYXF1aSBlc3BlY2lmaWNhZGEgY29uY2VkZSDDoCBGSU9DUlVaIC0gRlVOREHDh8ODTyBPU1dBTERPCkNSVVogbyBkaXJlaXRvIGRlIGF1dG9yaXphciBxdWFscXVlciBwZXNzb2Eg4oCTIGbDrXNpY2Egb3UganVyw61kaWNhLCBww7pibGljYSBvdSBwcml2YWRhLCBuYWNpb25hbCBvdQplc3RyYW5nZWlyYSDigJMgYSBhY2Vzc2FyIGUgdXRpbGl6YXIgYW1wbGFtZW50ZSBhIE9CUkEsIHNlbSBleGNsdXNpdmlkYWRlLCBwYXJhIHF1YWlzcXVlcgpmaW5hbGlkYWRlcyBuw6NvIGNvbWVyY2lhaXM7CgooNCkgREVDTEFSQSBxdWUgYSBvYnJhIMOpIGNyaWHDp8OjbyBvcmlnaW5hbCBlIHF1ZSDDqSBvIHRpdHVsYXIgZG9zIGRpcmVpdG9zIGFxdWkgY2VkaWRvcyBlIGF1dG9yaXphZG9zLApyZXNwb25zYWJpbGl6YW5kby1zZSBpbnRlZ3JhbG1lbnRlIHBlbG8gY29udGXDumRvIGUgb3V0cm9zIGVsZW1lbnRvcyBxdWUgZmF6ZW0gcGFydGUgZGEgT0JSQSwKaW5jbHVzaXZlIG9zIGRpcmVpdG9zIGRlIHZveiBlIGltYWdlbSB2aW5jdWxhZG9zIMOgIE9CUkEsIG9icmlnYW5kby1zZSBhIGluZGVuaXphciB0ZXJjZWlyb3MgcG9yCmRhbm9zLCBiZW0gY29tbyBpbmRlbml6YXIgZSByZXNzYXJjaXIgYSBGSU9DUlVaIC0gRlVOREHDh8ODTyBPU1dBTERPIENSVVogZGUKZXZlbnR1YWlzIGRlc3Blc2FzIHF1ZSB2aWVyZW0gYSBzdXBvcnRhciwgZW0gcmF6w6NvIGRlIHF1YWxxdWVyIG9mZW5zYSBhIGRpcmVpdG9zIGF1dG9yYWlzIG91CmRpcmVpdG9zIGRlIHZveiBvdSBpbWFnZW0sIHByaW5jaXBhbG1lbnRlIG5vIHF1ZSBkaXogcmVzcGVpdG8gYSBwbMOhZ2lvIGUgdmlvbGHDp8O1ZXMgZGUgZGlyZWl0b3M7CgooNSkgQUZJUk1BIHF1ZSBjb25oZWNlIGEgUG9sw610aWNhIEluc3RpdHVjaW9uYWwgZGUgQWNlc3NvIEFiZXJ0byBkYSBGSU9DUlVaIC0gRlVOREHDh8ODTwpPU1dBTERPIENSVVogZSBhcyBkaXJldHJpemVzIHBhcmEgbyBmdW5jaW9uYW1lbnRvIGRvIHJlcG9zaXTDs3JpbyBpbnN0aXR1Y2lvbmFsIEFSQ0EuCgpBIFBvbMOtdGljYSBJbnN0aXR1Y2lvbmFsIGRlIEFjZXNzbyBBYmVydG8gZGEgRklPQ1JVWiAtIEZVTkRBw4fDg08gT1NXQUxETyBDUlVaIHJlc2VydmEKZXhjbHVzaXZhbWVudGUgYW8gQVVUT1Igb3MgZGlyZWl0b3MgbW9yYWlzIGUgb3MgdXNvcyBjb21lcmNpYWlzIHNvYnJlIGFzIG9icmFzIGRlIHN1YSBhdXRvcmlhCmUvb3UgdGl0dWxhcmlkYWRlLCBzZW5kbyBvcyB0ZXJjZWlyb3MgdXN1w6FyaW9zIHJlc3BvbnPDoXZlaXMgcGVsYSBhdHJpYnVpw6fDo28gZGUgYXV0b3JpYSBlIG1hbnV0ZW7Dp8OjbwpkYSBpbnRlZ3JpZGFkZSBkYSBPQlJBIGVtIHF1YWxxdWVyIHV0aWxpemHDp8Ojby4KCkEgUG9sw610aWNhIEluc3RpdHVjaW9uYWwgZGUgQWNlc3NvIEFiZXJ0byBkYSBGSU9DUlVaIC0gRlVOREHDh8ODTyBPU1dBTERPIENSVVoKcmVzcGVpdGEgb3MgY29udHJhdG9zIGUgYWNvcmRvcyBwcmVleGlzdGVudGVzIGRvcyBBdXRvcmVzIGNvbSB0ZXJjZWlyb3MsIGNhYmVuZG8gYW9zIEF1dG9yZXMKaW5mb3JtYXIgw6AgSW5zdGl0dWnDp8OjbyBhcyBjb25kacOnw7VlcyBlIG91dHJhcyByZXN0cmnDp8O1ZXMgaW1wb3N0YXMgcG9yIGVzdGVzIGluc3RydW1lbnRvcy4KRepositório 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| dc.title.en_US.fl_str_mv |
Antimalarial pyrido [1,2‑a] benzimidazoles exert strong parasiticidal effects by achieving high cellular uptake and suppressing heme detoxification |
| title |
Antimalarial pyrido [1,2‑a] benzimidazoles exert strong parasiticidal effects by achieving high cellular uptake and suppressing heme detoxification |
| spellingShingle |
Antimalarial pyrido [1,2‑a] benzimidazoles exert strong parasiticidal effects by achieving high cellular uptake and suppressing heme detoxification Sousa, Caroline C Malaria Plasmodium Malária Plasmodium Benzimidazol Parasiticida Heme pool Desintoxicação do heme Malaria Plasmodium Benzimidazole Parasiticidal Heme pool Heme detoxification |
| title_short |
Antimalarial pyrido [1,2‑a] benzimidazoles exert strong parasiticidal effects by achieving high cellular uptake and suppressing heme detoxification |
| title_full |
Antimalarial pyrido [1,2‑a] benzimidazoles exert strong parasiticidal effects by achieving high cellular uptake and suppressing heme detoxification |
| title_fullStr |
Antimalarial pyrido [1,2‑a] benzimidazoles exert strong parasiticidal effects by achieving high cellular uptake and suppressing heme detoxification |
| title_full_unstemmed |
Antimalarial pyrido [1,2‑a] benzimidazoles exert strong parasiticidal effects by achieving high cellular uptake and suppressing heme detoxification |
| title_sort |
Antimalarial pyrido [1,2‑a] benzimidazoles exert strong parasiticidal effects by achieving high cellular uptake and suppressing heme detoxification |
| author |
Sousa, Caroline C |
| author_facet |
Sousa, Caroline C Dziwornu, Godwin Akpeko Quadros, Helenita C Araújo Neto, João Honorato Chibale, Kelly Moreira, Diogo R. M |
| author_role |
author |
| author2 |
Dziwornu, Godwin Akpeko Quadros, Helenita C Araújo Neto, João Honorato Chibale, Kelly Moreira, Diogo R. M |
| author2_role |
author author author author author |
| dc.contributor.author.fl_str_mv |
Sousa, Caroline C Dziwornu, Godwin Akpeko Quadros, Helenita C Araújo Neto, João Honorato Chibale, Kelly Moreira, Diogo R. M |
| dc.subject.mesh.en_US.fl_str_mv |
Malaria Plasmodium |
| topic |
Malaria Plasmodium Malária Plasmodium Benzimidazol Parasiticida Heme pool Desintoxicação do heme Malaria Plasmodium Benzimidazole Parasiticidal Heme pool Heme detoxification |
| dc.subject.other.en_US.fl_str_mv |
Malária Plasmodium Benzimidazol Parasiticida Heme pool Desintoxicação do heme |
| dc.subject.en.en_US.fl_str_mv |
Malaria Plasmodium Benzimidazole Parasiticidal Heme pool Heme detoxification |
| description |
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB). Fundação Oswaldo Cruz (Fiocruz) / Programa de Excelência em Pesquisa (PROEP). University of Cape Town. South African Medical Research Council. South African Research Chairs Initiative of the Department of Science and Innovation. South African National Research Foundation. |
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2022 |
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2022-09-28T17:54:26Z |
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2022-09-28T17:54:26Z |
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2022 |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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SOUSA, Caroline C. et al. Antimalarial pyrido [1,2‑a] benzimidazoles exert strong parasiticidal effects by achieving high cellular uptake and suppressing heme detoxification. ACS Infectious Diseases, v. 8, p. 1-11, 2022. |
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https://www.arca.fiocruz.br/handle/icict/54917 |
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2373-8227 |
| dc.identifier.doi.none.fl_str_mv |
10.1021/acsinfecdis.2c00326 |
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SOUSA, Caroline C. et al. Antimalarial pyrido [1,2‑a] benzimidazoles exert strong parasiticidal effects by achieving high cellular uptake and suppressing heme detoxification. ACS Infectious Diseases, v. 8, p. 1-11, 2022. 2373-8227 10.1021/acsinfecdis.2c00326 |
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eng |
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eng |
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American Chemical Society |
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American Chemical Society |
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