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Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole Hybrids

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 Leishmania parasites. This study report...

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Autores principales: Amado, Patrícia S. M., Costa, Inês C. C., Paixão, José A., Mendes, Ricardo F., Cortes, Sofia, Cristiano, Maria L. S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9457810/
https://www.ncbi.nlm.nih.gov/pubmed/36080174
http://dx.doi.org/10.3390/molecules27175401
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author Amado, Patrícia S. M.
Costa, Inês C. C.
Paixão, José A.
Mendes, Ricardo F.
Cortes, Sofia
Cristiano, Maria L. S.
author_facet Amado, Patrícia S. M.
Costa, Inês C. C.
Paixão, José A.
Mendes, Ricardo F.
Cortes, Sofia
Cristiano, Maria L. S.
author_sort Amado, Patrícia S. M.
collection PubMed
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 Leishmania parasites. This study reports the synthesis and structure of trioxolane–pyrazole (OZ1, OZ2) and tetraoxane–pyrazole (T1, T2) 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 in vitro antileishmanial activity against promastigotes of L. tropica and L. infantum, and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of L. infantum. Trioxolane–pyrazole hybrids OZ1 and OZ2 exhibited some activity against Leishmania 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 OZ1•HCl was the most active against both strains of Leishmania. Such finding was corroborated by the results obtained in assessments of the L. infantum 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 Leishmania. Our preliminary biological findings encourage further optimization of peroxide–pyrazole hybrids to identify a promising antileishmanial lead.
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spelling pubmed-94578102022-09-09 Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole Hybrids Amado, Patrícia S. M. Costa, Inês C. C. Paixão, José A. Mendes, Ricardo F. Cortes, Sofia Cristiano, Maria L. S. Molecules Article 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 Leishmania parasites. This study reports the synthesis and structure of trioxolane–pyrazole (OZ1, OZ2) and tetraoxane–pyrazole (T1, T2) 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 in vitro antileishmanial activity against promastigotes of L. tropica and L. infantum, and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of L. infantum. Trioxolane–pyrazole hybrids OZ1 and OZ2 exhibited some activity against Leishmania 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 OZ1•HCl was the most active against both strains of Leishmania. Such finding was corroborated by the results obtained in assessments of the L. infantum 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 Leishmania. Our preliminary biological findings encourage further optimization of peroxide–pyrazole hybrids to identify a promising antileishmanial lead. MDPI 2022-08-24 /pmc/articles/PMC9457810/ /pubmed/36080174 http://dx.doi.org/10.3390/molecules27175401 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Amado, Patrícia S. M.
Costa, Inês C. C.
Paixão, José A.
Mendes, Ricardo F.
Cortes, Sofia
Cristiano, Maria L. S.
Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole Hybrids
title 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_short Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole Hybrids
title_sort synthesis, structure and antileishmanial evaluation of endoperoxide–pyrazole hybrids
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9457810/
https://www.ncbi.nlm.nih.gov/pubmed/36080174
http://dx.doi.org/10.3390/molecules27175401
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