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 <i>Leishmania</i> parasites...
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MDPI AG
2022-08-01
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| Online Access: | https://www.mdpi.com/1420-3049/27/17/5401 |
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| author | Patrícia S. M. Amado Inês C. C. Costa José A. Paixão Ricardo F. Mendes Sofia Cortes Maria L. S. Cristiano |
| author_facet | Patrícia S. M. Amado Inês C. C. Costa José A. Paixão Ricardo F. Mendes Sofia Cortes Maria L. S. Cristiano |
| author_sort | Patrícia S. M. Amado |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T01:32:00Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T01:32:00Z |
| publishDate | 2022-08-01 |
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| spelling | doaj.art-cf90b761f92443a19cc59940ce9b31812023-11-23T13:41:25ZengMDPI AGMolecules1420-30492022-08-012717540110.3390/molecules27175401Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole HybridsPatrícia S. M. Amado0Inês C. C. Costa1José A. Paixão2Ricardo F. Mendes3Sofia Cortes4Maria L. S. Cristiano5Center of Marine Sciences, CCMAR, Gambelas Campus, University of Algarve, UAlg, 8005-139 Faro, PortugalCenter of Marine Sciences, CCMAR, Gambelas Campus, University of Algarve, UAlg, 8005-139 Faro, PortugalCFisUC, Department of Physics, University of Coimbra, 3004-516 Coimbra, PortugalCICECO-Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, PortugalGlobal Health and Tropical Medicine-GHTM, Instituto de Higiene e Medicina Tropical-IHMT, Universidade Nova de Lisboa-NOVA, 1349-008 Lisboa, PortugalCenter of Marine Sciences, CCMAR, Gambelas Campus, University of Algarve, UAlg, 8005-139 Faro, PortugalLeishmaniases 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.https://www.mdpi.com/1420-3049/27/17/5401antileishmanial chemotherapy1,2,4-trioxanes1,2,4,5-tetraoxanespyrazolesendoperoxide–pyrazole hybridsprototropic tautomerism |
| spellingShingle | Patrícia S. M. Amado Inês C. C. Costa José A. Paixão Ricardo F. Mendes Sofia Cortes Maria L. S. Cristiano Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole Hybrids Molecules antileishmanial chemotherapy 1,2,4-trioxanes 1,2,4,5-tetraoxanes pyrazoles endoperoxide–pyrazole hybrids prototropic tautomerism |
| 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 | antileishmanial chemotherapy 1,2,4-trioxanes 1,2,4,5-tetraoxanes pyrazoles endoperoxide–pyrazole hybrids prototropic tautomerism |
| url | https://www.mdpi.com/1420-3049/27/17/5401 |
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