Design, synthesis, and antiprotozoal evaluation 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 Article - Janvier 2020

Jean Guillon, Anita Cohen, Clotilde Boudot, Alessandra Valle, Vittoria Milano, Rabindra Nath Das, Aurore Guédin, Stéphane Moreau, Luisa Ronga, Solène Savrimoutou, Maxime Demourgues, Elodie Reviriego, Sandra Rubio, Sandie Ferriez, Patrice Agnamey, Cécile Pauc, Serge Moukha, Pascale Dozolme, Sophie Da Nascimento, Pierre Laumaille, Anne Bouchut, Nadine Azas, Jean-Louis Mergny, Catherine Mullié, Pascal Sonnet, Bertrand Courtioux

Jean Guillon, Anita Cohen, Clotilde Boudot, Alessandra Valle, Vittoria Milano, Rabindra Nath Das, Aurore Guédin, Stéphane Moreau, Luisa Ronga, Solène Savrimoutou, Maxime Demourgues, Elodie Reviriego, Sandra Rubio, Sandie Ferriez, Patrice Agnamey, Cécile Pauc, Serge Moukha, Pascale Dozolme, Sophie Da Nascimento, Pierre Laumaille, Anne Bouchut, Nadine Azas, Jean-Louis Mergny, Catherine Mullié, Pascal Sonnet, Bertrand Courtioux, « Design, synthesis, and antiprotozoal evaluation 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  », Journal of Enzyme Inhibition and Medicinal Chemistry, janvier 2020, pp. 432-459. ISSN 1475-6366

Abstract

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.

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