A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiprotozoal activity with IC50 values in the µM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline 1c was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the P. falciparum CQ-sensitive strain 3D7. The quinazoline 3h was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on T. brucei brucei strain. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the Plasmodium and Trypanosoma telomeric G-quadruplexes by our best compounds through FRET melting assays.

INSERM U1094 Tropical Neuroepidemiology Institute of Neuroepidemiology and Tropical Neurology Université de Limoges Limoges France

INSERM U1212 UMR CNRS 5320 ARNA Laboratory UFR des Sciences Pharmaceutiques Université de Bordeaux Bordeaux France

Institut Curie Université Paris Saclay CNRS UMR 9187 INSERM U1196 Université Paris Saclay Orsay France

Institute of Biophysics of the CAS Brno Czech Republic

IRD AP HM SSA VITROME Aix Marseille University Marseille France

PREM UMR5254 UPPA CNRS Technopole Hélioparc Université de Pau Pau France

UFR de Pharmacie AGIR Université de Picardie Jules Verne Amiens France

Université de Bordeaux Laboratoire de Toxicologie et d'Hygiène Appliquée INRA UFR des Sciences Pharmaceutiques Bordeaux France

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G-quadruplexes in helminth parasites