Synthesis and Antiprotozoal Evaluation of New 2,9-bis[(pyridinylalkylaminomethyl) phenyl]-1,10-Phenanthroline Derivatives by Targeting G-quadruplex, an Interesting Pharmacophore Against Drug Efflux
Jean Guillon
(1)
,
Anita Cohen
(2)
,
Sarah Monic
(1, 3)
,
Clotilde Boudot
(4)
,
Solène Savrimoutou
(1)
,
Sandra Albenque-Rubio
(1)
,
Stéphane Moreau
(1)
,
Alexandra Dassonville-Klimpt
(5)
,
Jean-Louis Mergny
(6)
,
Luisa Ronga
(7)
,
Mikel Bernabeu de Maria
(7)
,
Nikita Tyurin-Schmitt
(1)
,
Paul Parrens
(1)
,
Adrien Labarthe
(1)
,
Valentin Gomez
(1)
,
Serge Moukha
(8, 9, 10)
,
Pascale Dozolme
(9, 11, 10)
,
Nadine Azas
(2, 12)
,
Valérie Gabelica
(1)
,
Patrice Agnamey
(5)
,
Céline Damiani
(5, 13)
,
Anne Totet
(5, 13)
,
Catherine Mullié
(5, 13)
,
Bertrand Courtioux
(4)
,
Pascal Sonnet
(5)
1
ARNA -
Acides Nucléiques : Régulations Naturelle et Artificielle
2 VITROME - Vecteurs - Infections tropicales et méditerranéennes
3 CAM - University of Cambridge [UK]
4 NET - Neuroépidémiologie Tropicale
5 AGIR - Agents infectieux, résistance et chimiothérapie - UR UPJV 4294
6 IP Paris - Institut Polytechnique de Paris
7 IPREM - Institut des sciences analytiques et de physico-chimie pour l'environnement et les materiaux
8 MycSA - Unité de recherche Mycologie et Sécurité des Aliments
9 CRCTB - Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux]
10 Hôpital Xavier Arnozan
11 INRAE - Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement
12 IHU Marseille - Institut Hospitalier Universitaire Méditerranée Infection
13 CHU Amiens-Picardie
2 VITROME - Vecteurs - Infections tropicales et méditerranéennes
3 CAM - University of Cambridge [UK]
4 NET - Neuroépidémiologie Tropicale
5 AGIR - Agents infectieux, résistance et chimiothérapie - UR UPJV 4294
6 IP Paris - Institut Polytechnique de Paris
7 IPREM - Institut des sciences analytiques et de physico-chimie pour l'environnement et les materiaux
8 MycSA - Unité de recherche Mycologie et Sécurité des Aliments
9 CRCTB - Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux]
10 Hôpital Xavier Arnozan
11 INRAE - Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement
12 IHU Marseille - Institut Hospitalier Universitaire Méditerranée Infection
13 CHU Amiens-Picardie
Jean Guillon
- Function : Author
- PersonId : 758555
- ORCID : 0000-0001-8577-3894
Alexandra Dassonville-Klimpt
- Function : Author
- PersonId : 755027
- IdHAL : alexandra-dassonville-klimpt
- ORCID : 0000-0002-2891-9102
- IdRef : 071013903
Jean-Louis Mergny
- Function : Author
- PersonId : 737331
- IdHAL : jean-louis-mergny
- ORCID : 0000-0003-3043-8401
- IdRef : 074248847
Luisa Ronga
- Function : Author
- PersonId : 14651
- IdHAL : luisa-ronga
- ORCID : 0000-0002-8485-6492
- IdRef : 121566811
Serge Moukha
- Function : Author
- PersonId : 1413106
- IdHAL : smoukha
Pascale Dozolme
- Function : Author
- PersonId : 1401880
- IdHAL : pdozolme
- ORCID : 0000-0001-8768-5329
Patrice Agnamey
- Function : Author
- PersonId : 1186064
- ORCID : 0000-0001-6515-173X
- IdRef : 077250443
Céline Damiani
- Function : Author
- PersonId : 1145690
- ORCID : 0000-0003-3532-6775
- IdRef : 139902953
Anne Totet
- Function : Author
- PersonId : 890610
- IdHAL : totetanne
- ORCID : 0000-0002-9784-575X
- IdRef : 079379257
Catherine Mullié
- Function : Author
- PersonId : 776160
- ORCID : 0000-0001-8986-9666
- IdRef : 069746370
Pascal Sonnet
- Function : Author
- PersonId : 753326
- IdHAL : pascal-sonnet
- ORCID : 0000-0003-0118-9151
- IdRef : 06984948X
Abstract
A series of new 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds were designed, synthesized, and evaluated in vitro against two parasites (Plasmodium falciparum and Leishmania donovani). The biological results showed antimalarial activity with IC50 values in the sub and μM range. The in vitro cytotoxicity of these new aza polyaromatic derivatives was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene 1m was found as one of the most potent and promising antimalarial candidates with a ratio of cytotoxic to antiprotozoal activities of 83.67 against the P. falciparum CQ-sensitive strain 3D7. In addition, derivative 1r was also identified as the most interesting antimalarial compound with a selectivity index (SI) of 17.28 on the W2 P. falciparum CQ-resistant strain. It was previously described that the telomeres of P. falciparum could be considered as potential targets of these kinds of aza heterocycles; thus, the ability of these new derivatives to stabilize the parasitic telomeric G-quadruplexes was measured through a FRET melting assay.