Design, Synthesis and Antiparasitic Evaluation of Click Phospholipids

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.

Valorizing Constituents of Cashew Nut Shell Liquid toward the Sustainable Development of New Drugs against Chagas Disease

“…The synthesis of the new ether phospholipids 16 – 21 (Scheme ) was realized using a procedure established by Calogeropoulou and co-workers, − which involves a three-step protocol: (a) phosphorylation of the aliphatic alcohols 7 – 9 or phenols 11 and 15 with POCl 3 in THF in the presence of Et 3 N to furnish the corresponding phosphoric acids after hydrolysis; (b) transformation of the phosphoric acids to the corresponding pyridinium salts; and finally (c) reaction with choline p -toluene­sulfonate in the presence of 1-(mesitylene-2-sulfonyl)-3-nitro-1 H -1,2,4-triazole (MSNT) as condensing agent.…”

Discovery of 1,3,4-Oxadiazole Derivatives as Broad-Spectrum Antiparasitic Agents

“…Phenotypic approaches in VBPD drug discovery are powerful, as they allow identification of compounds that are active against the entire parasite, as they simultaneously take into account not only the ability of compounds to modulate a disease-causing target at the molecular level but also membrane permeability, cell uptake, and efflux mechanisms. − To this end, phenotypic screening has been successfully applied in the field of VBPDs, as demonstrated by the discovery of fexinidazole and acoziborole for the treatment of HAT, GSK3186899 and DNDI-0690 for Leishmaniasis, and cipargamin for the treatment of malaria. Fexinidazole (Figure A) is an orally available 2-substituted 5-nitroimidazole compound that was identified through a phenotypic screening of a DNDi chemical library by Swiss TPH and further developed by Hoechst (now Sanofi).…”