Synthesis, structure and antileishmanial evaluation of endoperoxide–pyrazole hybrids
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.1/18238 |
Resumo: | Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and pyrazole-containing chemotypes demonstrated activity against <i>Leishmania</i> parasites. This study reports the synthesis and structure of trioxolane–pyrazole (<b>OZ1</b>, <b>OZ2</b>) and tetraoxane–pyrazole (<b>T1</b>, <b>T2</b>) hybrids obtained from the reaction of 3(5)-aminopyrazole with endoperoxide-containing building blocks. Interestingly, only the endocyclic amine of 3(5)-aminopyrazole was found to act as nucleophile for amide coupling. However, the fate of the reaction was influenced by prototropic tautomerism of the pyrazole heterocycle, yielding 3- and 5-aminopyrazole containing hybrids which were characterized by different techniques, including X-ray crystallography. The compounds were evaluated for <i>in vitro</i> antileishmanial activity against promastigotes of <i>L. tropica</i> and <i>L. infantum</i>, and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of <i>L. infantum.</i> Trioxolane–pyrazole hybrids <b>OZ1</b> and <b>OZ2</b> exhibited some activity against <i>Leishmania</i> promastigotes, while tetraoxane–pyrazole hybrids proved inactive, most likely due to solubility issues. Eight salt forms, specifically tosylate, mesylate, and hydrochloride salts, were then prepared to improve the solubility of the corresponding peroxide hybrids and were uniformly tested. Biological evaluations in promastigotes showed that the compound <b>OZ1</b><b>•HCl</b> was the most active against both strains of <i>Leishmania</i>. Such finding was corroborated by the results obtained in assessments of the <i>L. infantum</i> amastigote susceptibility. It is noteworthy that the salt forms of the endoperoxide–pyrazole hybrids displayed a broader spectrum of action, showing activity in both strains of <i>Leishmania</i>. Our preliminary biological findings encourage further optimization of peroxide–pyrazole hybrids to identify a promising antileishmanial lead. |
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Synthesis, structure and antileishmanial evaluation of endoperoxide–pyrazole hybridsAntileishmanial chemotherapy1,2,4-trioxanes1,2,4,5-tetraoxanesPyrazolesEndoperoxide– pyrazole hybridsPrototropic tautomerismLeishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and pyrazole-containing chemotypes demonstrated activity against <i>Leishmania</i> parasites. This study reports the synthesis and structure of trioxolane–pyrazole (<b>OZ1</b>, <b>OZ2</b>) and tetraoxane–pyrazole (<b>T1</b>, <b>T2</b>) hybrids obtained from the reaction of 3(5)-aminopyrazole with endoperoxide-containing building blocks. Interestingly, only the endocyclic amine of 3(5)-aminopyrazole was found to act as nucleophile for amide coupling. However, the fate of the reaction was influenced by prototropic tautomerism of the pyrazole heterocycle, yielding 3- and 5-aminopyrazole containing hybrids which were characterized by different techniques, including X-ray crystallography. The compounds were evaluated for <i>in vitro</i> antileishmanial activity against promastigotes of <i>L. tropica</i> and <i>L. infantum</i>, and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of <i>L. infantum.</i> Trioxolane–pyrazole hybrids <b>OZ1</b> and <b>OZ2</b> exhibited some activity against <i>Leishmania</i> promastigotes, while tetraoxane–pyrazole hybrids proved inactive, most likely due to solubility issues. Eight salt forms, specifically tosylate, mesylate, and hydrochloride salts, were then prepared to improve the solubility of the corresponding peroxide hybrids and were uniformly tested. Biological evaluations in promastigotes showed that the compound <b>OZ1</b><b>•HCl</b> was the most active against both strains of <i>Leishmania</i>. Such finding was corroborated by the results obtained in assessments of the <i>L. infantum</i> amastigote susceptibility. It is noteworthy that the salt forms of the endoperoxide–pyrazole hybrids displayed a broader spectrum of action, showing activity in both strains of <i>Leishmania</i>. Our preliminary biological findings encourage further optimization of peroxide–pyrazole hybrids to identify a promising antileishmanial lead.ALG-01-0145-FEDER-022121; SFRH/BD/08242/2020MDPISapientiaAmado, Patrícia S. M.Costa, Inês C. C.Paixão, José A.Mendes, Ricardo F.Cortes, SofiaCristiano, Maria L.2022-09-09T10:06:12Z2022-08-242022-09-08T13:24:05Z2022-08-24T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.1/18238engMolecules 27 (17): 5401 (2022)1420-304910.3390/molecules27175401info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-13T02:07:57Zoai:sapientia.ualg.pt:10400.1/18238Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:08:00.606094Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Synthesis, structure and antileishmanial evaluation of endoperoxide–pyrazole hybrids |
title |
Synthesis, structure and antileishmanial evaluation of endoperoxide–pyrazole hybrids |
spellingShingle |
Synthesis, structure and antileishmanial evaluation of endoperoxide–pyrazole hybrids Amado, Patrícia S. M. Antileishmanial chemotherapy 1,2,4-trioxanes 1,2,4,5-tetraoxanes Pyrazoles Endoperoxide– pyrazole hybrids Prototropic tautomerism |
title_short |
Synthesis, structure and antileishmanial evaluation of endoperoxide–pyrazole hybrids |
title_full |
Synthesis, structure and antileishmanial evaluation of endoperoxide–pyrazole hybrids |
title_fullStr |
Synthesis, structure and antileishmanial evaluation of endoperoxide–pyrazole hybrids |
title_full_unstemmed |
Synthesis, structure and antileishmanial evaluation of endoperoxide–pyrazole hybrids |
title_sort |
Synthesis, structure and antileishmanial evaluation of endoperoxide–pyrazole hybrids |
author |
Amado, Patrícia S. M. |
author_facet |
Amado, Patrícia S. M. Costa, Inês C. C. Paixão, José A. Mendes, Ricardo F. Cortes, Sofia Cristiano, Maria L. |
author_role |
author |
author2 |
Costa, Inês C. C. Paixão, José A. Mendes, Ricardo F. Cortes, Sofia Cristiano, Maria L. |
author2_role |
author author author author author |
dc.contributor.none.fl_str_mv |
Sapientia |
dc.contributor.author.fl_str_mv |
Amado, Patrícia S. M. Costa, Inês C. C. Paixão, José A. Mendes, Ricardo F. Cortes, Sofia Cristiano, Maria L. |
dc.subject.por.fl_str_mv |
Antileishmanial chemotherapy 1,2,4-trioxanes 1,2,4,5-tetraoxanes Pyrazoles Endoperoxide– pyrazole hybrids Prototropic tautomerism |
topic |
Antileishmanial chemotherapy 1,2,4-trioxanes 1,2,4,5-tetraoxanes Pyrazoles Endoperoxide– pyrazole hybrids Prototropic tautomerism |
description |
Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and pyrazole-containing chemotypes demonstrated activity against <i>Leishmania</i> parasites. This study reports the synthesis and structure of trioxolane–pyrazole (<b>OZ1</b>, <b>OZ2</b>) and tetraoxane–pyrazole (<b>T1</b>, <b>T2</b>) hybrids obtained from the reaction of 3(5)-aminopyrazole with endoperoxide-containing building blocks. Interestingly, only the endocyclic amine of 3(5)-aminopyrazole was found to act as nucleophile for amide coupling. However, the fate of the reaction was influenced by prototropic tautomerism of the pyrazole heterocycle, yielding 3- and 5-aminopyrazole containing hybrids which were characterized by different techniques, including X-ray crystallography. The compounds were evaluated for <i>in vitro</i> antileishmanial activity against promastigotes of <i>L. tropica</i> and <i>L. infantum</i>, and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of <i>L. infantum.</i> Trioxolane–pyrazole hybrids <b>OZ1</b> and <b>OZ2</b> exhibited some activity against <i>Leishmania</i> promastigotes, while tetraoxane–pyrazole hybrids proved inactive, most likely due to solubility issues. Eight salt forms, specifically tosylate, mesylate, and hydrochloride salts, were then prepared to improve the solubility of the corresponding peroxide hybrids and were uniformly tested. Biological evaluations in promastigotes showed that the compound <b>OZ1</b><b>•HCl</b> was the most active against both strains of <i>Leishmania</i>. Such finding was corroborated by the results obtained in assessments of the <i>L. infantum</i> amastigote susceptibility. It is noteworthy that the salt forms of the endoperoxide–pyrazole hybrids displayed a broader spectrum of action, showing activity in both strains of <i>Leishmania</i>. Our preliminary biological findings encourage further optimization of peroxide–pyrazole hybrids to identify a promising antileishmanial lead. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-09-09T10:06:12Z 2022-08-24 2022-09-08T13:24:05Z 2022-08-24T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.1/18238 |
url |
http://hdl.handle.net/10400.1/18238 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Molecules 27 (17): 5401 (2022) 1420-3049 10.3390/molecules27175401 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
MDPI |
publisher.none.fl_str_mv |
MDPI |
dc.source.none.fl_str_mv |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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