| Summary: | 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.
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