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.

Design, synthesis and antiparasitic evaluation of click phospholipids / G.E. Magoulas, P. Afroudakis, K. Georgikopoulou, M. Roussaki, C. Borsari, T. Fotopoulou, N. Santarem, E. Barrias, P. Tejera Nevado, J. Hachenberg, E. Bifeld, B. Ellinger, M. Kuzikov, I. Fragiadaki, E. Scoulica, J. Clos, S. Gul, M.P. Costi, W. de Souza, K.C. Prousis, A.C. da Silva, T. Calogeropoulou. - In: MOLECULES. - ISSN 1420-3049. - 26:14(2021), pp. 4204.1-4204.37. [10.3390/molecules26144204]

Design, synthesis and antiparasitic evaluation of click phospholipids

C. Borsari;
2021

Abstract

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.
Antiparasitic activity; Ether phospholipids; Heterocyclic rings; Leishmania donovani; Leishmania infantum; Trypanosoma brucei; Trypanosoma cruzi
Settore CHIM/08 - Chimica Farmaceutica
   New Medicines for Trypanosomatidic Infections
   NMTRYPI
   European Commission
   SEVENTH FRAMEWORK PROGRAMME
   603240
2021
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1016648
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