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Design, synthesis, biophysical and antiprotozoal evaluation of new promising 2,9-bis[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline derivatives by targeting G-quadruplex
* 1 , 2 , 3 , 1 , 1 , 1 , 1 , 4 , 5 , 6 , 6 , 7 , 7 , 8, 9 , 8, 9 , 4 , 4 , 3 , 4
1  Univ. Bordeaux, CNRS, INSERM, ARNA, UMR 5320, U1212, F-33000 Bordeaux, France
2  Aix-Marseille Univ., IRD, AP-HM, SSA, VITROME, Marseille, France
3  INSERM U1094, Université de Limoges, Institute of Neuroepidemiology and Tropical Neurology, Limoges, France
4  Université de Picardie Jules Verne, Agents Infectieux, Résistance et Chimiothérapie (AGIR), UR 4294, UFR de Pharmacie, Amiens, France
5  Ecole Polytechnique, Laboratoire d’Optique et Biosciences, CNRS, INSERM, Institut Polytechnique de Paris, Palaiseau, France
6  Université de Pau et des Pays de l'Adour, E2S UPPA, CNRS, IPREM, Pau, France
7  Univ. Bordeaux, CNRS, INSERM, ARNA, UMR 5320, U1212, IECB, F-33600 Pessac, France
8  Centre de Recherche Cardio-thoracique de Bordeaux (CRCTB), UMR U1045 INSERM, PTIB - Hôpital Xavier Arnozan, F-33600 Pessac, France
9  INRAE Bordeaux Aquitaine, France
Academic Editor: Maria Emília Sousa (registering DOI)

A series of new 2,9-bis[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline derivatives was designed, synthesized, 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 sub and mM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The substituted diphenylphenanthroline 1l was identified as the most potent antiplasmodial candidate with a ratio of cytotoxic to antiparasitic activities of 505.7 against the P. falciparum CQ-resistant strain W2. Against the promastigote forms of L. donovani, the phenanthrolines 1h, 1j, 1n and 1o were found the most active compounds with IC50 from 2.52 to 4.50 mM. The phenanthroline derivative 1o was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 91 on T. brucei brucei strain. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma could be considered as possible targets of this kind of nitrogen heterocyclic derivatives, their ability to stabilize the parasitic telomeric G-quadruplexes have been determined through the FRET melting assay and by native mass spectrometry.

Keywords: antiplasmodial activity; phenanthroline; G-quadruplex; antileishmanial activity; antitrypanosomal activity