Design, Synthesis and Antiparasitic Evaluation of Click Phospholipids
| Autor: | Irini Fragiadaki, Theodora Calogeropoulou, Sheraz Gul, Chiara Borsari, Wanderley de Souza, Bernhard Ellinger, Paloma Tejera Nevado, Nuno Santarém, Pantelis Afroudakis, Julia Hachenberg, Marina Roussaki, Anabela Cordeiro da Silva, Emile Santos Barrias, Maria Kuzikov, George E. Magoulas, Kalliopi Georgikopoulou, Kyriakos C. Prousis, Theano Fotopoulou, Eugenia Bifeld, Joachim Clos, Effie Scoulica, Maria Paola Costi |
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| Přispěvatelé: | Publica |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
ether phospholipids
Pharmaceutical Science Organic chemistry Antiparasitic activity Analytical Chemistry chemistry.chemical_compound 0302 clinical medicine QD241-441 Drug Discovery Trypanosoma brucei Leishmania infantum Leishmaniasis Phospholipids Leishmania 0303 health sciences Antiparasitic Agents biology antiparasitic activity Biochemistry Chemistry (miscellaneous) Molecular Medicine Leishmania donovani medicine.drug Antiparasitic medicine.drug_class Trypanosoma cruzi 030231 tropical medicine Phospholipid Article Ether phospholipids Heterocyclic rings Chagas Disease Click Chemistry Humans Macrophages Structure-Activity Relationship Drug Design 03 medical and health sciences parasitic diseases medicine heterocyclic rings Physical and Theoretical Chemistry Amastigote 030304 developmental biology Miltefosine biology.organism_classification chemistry |
| Zdroj: | Molecules, Vol 26, Iss 4204, p 4204 (2021) Molecules Volume 26 Issue 14 |
| ISSN: | 1420-3049 |
| Popis: | 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 Leishmania infantum and Leishmania donovani intracellular amastigotes, against Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. 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 27 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 L. infantum strains and T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes, while its cytotoxicity concentration (CC50) 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. |
| Databáze: | OpenAIRE |
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