Design, Synthesis, and In Vitro Antimalarial Evaluation of New 1,3,5-Tris[(4-(Substituted-Aminomethyl)Phenoxy)Methyl]Benzenes
2024
Albenque-Rubio, Sandra | Guillon, Jean | Agnamey, Patrice | Damiani, Céline | Savrimoutou, Solène | Mustière, Romain | Pinaud, Noël | Moreau, Stéphane | Mergny, Jean-Louis | Ronga, Luisa | Kanavos, Ioannis | Marchivie, Mathieu | Moukha, Serge | Dozolme, Pascale | Sonnet, Pascal | Cohen, Anita | Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA) ; Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS) | Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR) ; Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie | Institut des Sciences Moléculaires (ISM) ; Université de Bordeaux (UB)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS) | Laboratoire d'Optique et Biosciences (LOB) ; École polytechnique (X) ; Institut Polytechnique de Paris (IP Paris)-Institut Polytechnique de Paris (IP Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) | Institut des sciences analytiques et de physico-chimie pour l'environnement et les materiaux (IPREM) ; Université de Pau et des Pays de l'Adour (UPPA)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS) | Institut de Chimie de la Matière Condensée de Bordeaux (ICMCB) ; Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS) | Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB) ; Université de Bordeaux (UB)-Centre Hospitalier Universitaire de Bordeaux (CHU Bordeaux)-Institut National de la Santé et de la Recherche Médicale (INSERM) | Plateforme Technologique d'Innovation Biomédicale (PTIB) ; Hôpital Xavier Arnozan - CHU de Bordeaux ; Centre Hospitalier Universitaire de Bordeaux (CHU Bordeaux)-Centre Hospitalier Universitaire de Bordeaux (CHU Bordeaux) | Hôpital Xavier Arnozan - CHU de Bordeaux ; Centre Hospitalier Universitaire de Bordeaux (CHU Bordeaux) | Membranes et cibles thérapeutiques (MCT) ; Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
International audience
Mostrar más [+] Menos [-]Inglés. By taking into account our previously described series of 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds, we have now designed, prepared, and evaluated in vitro against Plasmodium falciparum a novel series of structural analogues of these molecules, i.e., the 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivatives. The pharmacological data showed antimalarial activity with IC50 values in the sub and μM range. The in vitro cytotoxicity of these new nitrogen polyphenoxymethylbenzene compounds was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivative 1m was found as one of the most potent and promising antimalarial candidates with favorable cytotoxic to antiprotozoal properties in the P. falciparum strains W2 and 3D7. In conclusion, this 1,3,5-tris[(4-(pyridin-3-ylmethylaminomethyl)phenoxyl)methyl]benzene 1m (IC50 = 0.07 μM on W2, 0.06 μM on 3D7, and 62.11 μM on HepG2) was identified as the most promising antimalarial derivative with selectivity indexes (SI) of 887.29 on the W2 P. falciparum chloroquine-resistant strain, and of 1035.17 on the chloroquine-sensitive and mefloquine decreased sensitivity strain 3D7. It has been previously described that the telomeres of P. falciparum could represent potential targets for these types of polyaromatic compounds; therefore, the capacity of our novel derivatives to stabilize the parasitic telomeric G-quadruplexes was assessed using a FRET melting assay. However, with regard to the stabilization of the protozoal G-quadruplex, we observed that the best substituted derivatives 1, which exhibited some interesting stabilization profiles, were not the most active antimalarial compounds against the two Plasmodium strains. Thus, there were no correlations between their antimalarial activities and selectivities of their respective binding to G-quadruplexes.
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