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Synthesis, structure and antileishmanial evaluation of endoperoxide–pyrazole hybrids

2022-08-24Journal article Open access
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dc.contributor.authorAmado, Patrícia S. M.
dc.contributor.authorCosta, Inês C. C.
dc.contributor.authorPaixão, José A.
dc.contributor.authorMendes, Ricardo F.
dc.contributor.authorCortes, Sofia
dc.contributor.authorCristiano, Maria L.
dc.date.accessioned2022-09-09T10:06:12Z
dc.date.available2022-09-09T10:06:12Z
dc.date.issued2022-08-24
dc.date.updated2022-09-08T13:24:05Z
dc.description.abstractLeishmaniases 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.pt_PT
dc.description.sponsorshipALG-01-0145-FEDER-022121; SFRH/BD/08242/2020
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationMolecules 27 (17): 5401 (2022)pt_PT
dc.identifier.doi10.3390/molecules27175401pt_PT
dc.identifier.issn1420-3049
dc.identifier.urihttp://hdl.handle.net/10400.1/18238
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationAlgarve Centre for Marine Sciences
dc.relationAlgarve Centre for Marine Sciences
dc.relationCentre for Marine and Environmental Research
dc.relationCenter for Physics of the University of Coimbra
dc.relationCenter for Physics of the University of Coimbra
dc.relationGlobal Health and Tropical Medicine
dc.relationCICECO-Aveiro Institute of Materials
dc.relationCICECO-Aveiro Institute of Materials
dc.relationCICECO – Aveiro Institute of Materials
dc.relationA Chemical Proteomics Approach to Defining the Mechanism of Artemisinin Action and Resistance in PfK13 Resistant parasites
dc.relationA Chemical Proteomics Approach to Defining the Mechanism of Artemisinin Action and Resistance in PfK13 Resistant parasites
dc.relationNot Available
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAntileishmanial chemotherapypt_PT
dc.subject1,2,4-trioxanespt_PT
dc.subject1,2,4,5-tetraoxanespt_PT
dc.subjectPyrazolespt_PT
dc.subjectEndoperoxide– pyrazole hybridspt_PT
dc.subjectPrototropic tautomerismpt_PT
dc.titleSynthesis, structure and antileishmanial evaluation of endoperoxide–pyrazole hybridspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleAlgarve Centre for Marine Sciences
oaire.awardTitleAlgarve Centre for Marine Sciences
oaire.awardTitleCentre for Marine and Environmental Research
oaire.awardTitleCenter for Physics of the University of Coimbra
oaire.awardTitleCenter for Physics of the University of Coimbra
oaire.awardTitleGlobal Health and Tropical Medicine
oaire.awardTitleCICECO-Aveiro Institute of Materials
oaire.awardTitleCICECO-Aveiro Institute of Materials
oaire.awardTitleCICECO – Aveiro Institute of Materials
oaire.awardTitleA Chemical Proteomics Approach to Defining the Mechanism of Artemisinin Action and Resistance in PfK13 Resistant parasites
oaire.awardTitleA Chemical Proteomics Approach to Defining the Mechanism of Artemisinin Action and Resistance in PfK13 Resistant parasites
oaire.awardTitleNot Available
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oaire.citation.issue17pt_PT
oaire.citation.startPage5401pt_PT
oaire.citation.titleMoleculespt_PT
oaire.citation.volume27pt_PT
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person.familyNameMenalha Amado
person.familyNamePaixão
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person.givenNamePatrícia Sofia
person.givenNameJosé António
person.givenNameMaria de Lurdes
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