Design, Synthesis and Antiparasitic Evaluation of Click Phospholipids
A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluat...
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Language: | English |
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MDPI AG
2021-07-01
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Series: | Molecules |
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Online Access: | https://www.mdpi.com/1420-3049/26/14/4204 |
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doaj-445daea165834b30a0f90e3cf6bb94b0 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
George E. Magoulas Pantelis Afroudakis Kalliopi Georgikopoulou Marina Roussaki Chiara Borsari Theano Fotopoulou Nuno Santarem Emile Barrias Paloma Tejera Nevado Julia Hachenberg Eugenia Bifeld Bernhard Ellinger Maria Kuzikov Irini Fragiadaki Effie Scoulica Joachim Clos Sheraz Gul Maria Paola Costi Wanderley de Souza Kyriakos C. Prousis Anabela Cordeiro da Silva Theodora Calogeropoulou |
spellingShingle |
George E. Magoulas Pantelis Afroudakis Kalliopi Georgikopoulou Marina Roussaki Chiara Borsari Theano Fotopoulou Nuno Santarem Emile Barrias Paloma Tejera Nevado Julia Hachenberg Eugenia Bifeld Bernhard Ellinger Maria Kuzikov Irini Fragiadaki Effie Scoulica Joachim Clos Sheraz Gul Maria Paola Costi Wanderley de Souza Kyriakos C. Prousis Anabela Cordeiro da Silva Theodora Calogeropoulou Design, Synthesis and Antiparasitic Evaluation of Click Phospholipids Molecules ether phospholipids heterocyclic rings antiparasitic activity <i>Leishmania</i> <i>infantum</i> <i>Leishmania donovani</i> <i>Trypanosoma brucei</i> |
author_facet |
George E. Magoulas Pantelis Afroudakis Kalliopi Georgikopoulou Marina Roussaki Chiara Borsari Theano Fotopoulou Nuno Santarem Emile Barrias Paloma Tejera Nevado Julia Hachenberg Eugenia Bifeld Bernhard Ellinger Maria Kuzikov Irini Fragiadaki Effie Scoulica Joachim Clos Sheraz Gul Maria Paola Costi Wanderley de Souza Kyriakos C. Prousis Anabela Cordeiro da Silva Theodora Calogeropoulou |
author_sort |
George E. Magoulas |
title |
Design, Synthesis and Antiparasitic Evaluation of Click Phospholipids |
title_short |
Design, Synthesis and Antiparasitic Evaluation of Click Phospholipids |
title_full |
Design, Synthesis and Antiparasitic Evaluation of Click Phospholipids |
title_fullStr |
Design, Synthesis and Antiparasitic Evaluation of Click Phospholipids |
title_full_unstemmed |
Design, Synthesis and Antiparasitic Evaluation of Click Phospholipids |
title_sort |
design, synthesis and antiparasitic evaluation of click phospholipids |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2021-07-01 |
description |
A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against <i>Leishmania infantum</i> and <i>Leishmania donovani</i> intracellular amastigotes, against <i>Trypanosoma brucei brucei</i> and against different developmental stages of <i>Trypanosoma cruzi</i>. The nature of the substituents of the heterocyclic ring (tail) and the oligomethylene spacer between the head group and the heterocyclic ring was found to affect the activity and toxicity of these compounds leading to a significantly improved understanding of their structure–activity relationships. The early ADMET profile of the new derivatives did not reveal major liabilities for the potent compounds. The 1,2,3-triazole derivative <b>27</b> substituted by a decyl tail, an undecyl spacer and a choline head group exhibited broad spectrum antiparasitic activity. It possessed low micromolar activity against the intracellular amastigotes of two <i>L. infantum</i> strains and <i>T. cruzi Y</i> strain epimastigotes, intracellular amastigotes and trypomastigotes, while its cytotoxicity concentration (CC<sub>50</sub>) against THP-1 macrophages ranged between 50 and 100 μM. Altogether, our work paves the way for the development of improved ether phospholipid derivatives to control neglected tropical diseases. |
topic |
ether phospholipids heterocyclic rings antiparasitic activity <i>Leishmania</i> <i>infantum</i> <i>Leishmania donovani</i> <i>Trypanosoma brucei</i> |
url |
https://www.mdpi.com/1420-3049/26/14/4204 |
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doaj-445daea165834b30a0f90e3cf6bb94b02021-07-23T13:56:25ZengMDPI AGMolecules1420-30492021-07-01264204420410.3390/molecules26144204Design, Synthesis and Antiparasitic Evaluation of Click PhospholipidsGeorge E. Magoulas0Pantelis Afroudakis1Kalliopi Georgikopoulou2Marina Roussaki3Chiara Borsari4Theano Fotopoulou5Nuno Santarem6Emile Barrias7Paloma Tejera Nevado8Julia Hachenberg9Eugenia Bifeld10Bernhard Ellinger11Maria Kuzikov12Irini Fragiadaki13Effie Scoulica14Joachim Clos15Sheraz Gul16Maria Paola Costi17Wanderley de Souza18Kyriakos C. Prousis19Anabela Cordeiro da Silva20Theodora Calogeropoulou21National Hellenic Research Foundation, Institute of Chemical Biology, 11653 Athens, GreeceNational Hellenic Research Foundation, Institute of Chemical Biology, 11653 Athens, GreeceNational Hellenic Research Foundation, Institute of Chemical Biology, 11653 Athens, GreeceNational Hellenic Research Foundation, Institute of Chemical Biology, 11653 Athens, GreeceDepartment of Biomedicine, University of Basel, 4058 Basel, SwitzerlandNational Hellenic Research Foundation, Institute of Chemical Biology, 11653 Athens, Greecei3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalInstituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, BrazilBernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, GermanyBernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, GermanyBernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, GermanyDepartment of Clinical Microbiology and Microbial Pathogenesis, Faculty of Medicine, University of Crete, 70013 Heraklion, GreeceDepartment of Clinical Microbiology and Microbial Pathogenesis, Faculty of Medicine, University of Crete, 70013 Heraklion, GreeceBernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, GermanyDepartment of Pharmacy, Università degli Studi di Modena e Reggio Emilia, 41125 Modena, ItalyInstituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, BrazilNational Hellenic Research Foundation, Institute of Chemical Biology, 11653 Athens, Greecei3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalNational Hellenic Research Foundation, Institute of Chemical Biology, 11653 Athens, GreeceA library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against <i>Leishmania infantum</i> and <i>Leishmania donovani</i> intracellular amastigotes, against <i>Trypanosoma brucei brucei</i> and against different developmental stages of <i>Trypanosoma cruzi</i>. The nature of the substituents of the heterocyclic ring (tail) and the oligomethylene spacer between the head group and the heterocyclic ring was found to affect the activity and toxicity of these compounds leading to a significantly improved understanding of their structure–activity relationships. The early ADMET profile of the new derivatives did not reveal major liabilities for the potent compounds. The 1,2,3-triazole derivative <b>27</b> substituted by a decyl tail, an undecyl spacer and a choline head group exhibited broad spectrum antiparasitic activity. It possessed low micromolar activity against the intracellular amastigotes of two <i>L. infantum</i> strains and <i>T. cruzi Y</i> strain epimastigotes, intracellular amastigotes and trypomastigotes, while its cytotoxicity concentration (CC<sub>50</sub>) against THP-1 macrophages ranged between 50 and 100 μM. Altogether, our work paves the way for the development of improved ether phospholipid derivatives to control neglected tropical diseases.https://www.mdpi.com/1420-3049/26/14/4204ether phospholipidsheterocyclic ringsantiparasitic activity<i>Leishmania</i> <i>infantum</i><i>Leishmania donovani</i><i>Trypanosoma brucei</i> |