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Design, Synthesis of New 1,3,5-tris[(4-(Substituted-aminomethyl)phenoxy)methyl]benzene derivatives and Evaluation of their Antimalarial Activity
1 , * 1 , 2 , 3 , 3 , 4 , 1 , 1 , 5 , 6 , 6 , 7, 8 , 7, 8 , 3
1  Univ. Bordeaux, CNRS, INSERM, ARNA, UMR 5320, U1212, F-33000 Bordeaux, France
2  Aix-Marseille Univ., INSERM U1261, MCT-UMR MD1, Marseille, France
3  Université de Picardie Jules Verne, UFR des Sciences Pharmaceutiques, AGIR - EA4294, 1 rue des Louvels, F-80037 Amiens cedex 1, 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  Centre de Recherche Cardio-thoracique de Bordeaux (CRCTB), UMR U1045 INSERM, PTIB - Hôpital Xavier Arnozan, F-33600 Pessac, France
8  INRAE Bordeaux Aquitaine, France
Academic Editor: Alfredo Berzal-Herranz (registering DOI)

In order to fight malaria, a public health problem for which nearly half of the world’s population is at risk and responsible a life-threatening disease primarily found in tropical countries, for which the estimated number of deaths stood at 619 000 in 2021[1] and effective intersectoral coordination is recommended to facilitate concerted action [2], an original strategy is to design and synthesize new original drug candidates that are not recognized by the protein system involved in the drug efflux. Thus, taking into account our latest antimalarial derivatives described previously, namely new 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzenes [3], a series of novel structural analogues, the 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene compounds 1, were designed, prepared, and evaluated for their in vitro antimalarial activity against the CQ-sensitive (3D7) and the CQ-resistant (W2) strains of the malaria parasite Plasmodium falciparum. The pharmacological data showed antimalarial activity with IC50 values in the sub and μM range. In these new synthesized series, the 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzenes 1 bearing pyridinyl-alkylaminomethyl side chains at position 4 of the phenoxymethyl moieties displayed better activities than their homologs substituted with alkylaminoalkylaminomethyl side chains. Against the P. falciparum CQ-sensitive 3D7, the 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene 1p bearing pyridin-4-ylmethylaminomethyl side chains at position 4 of each of the phenoxymethyl groups was noticed to be the most active, with an IC50 of 0.078 μM, while compound 1m substituted by pyridin-3-ylmethylaminomethyl side chains was found the most active ligands against the W2 strain with an IC50 of 0. 073 µM. As the telomeres of P. falciparum have been previously reported as potential targets of these kinds of nitrogen heterocycles, some FRET melting assays have been carried out to test their ability to stabilize the parasitic telomeric G-quadruplexe.

[1] World malaria report 2022. Geneva: World Health Organization; 2022. Licence: CC BY-NC-SA 3.0 IGO.

[2] Ending the neglect to attain the Sustainable Development Goals: a road map for neglected tropical diseases 2021–2030. Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO.

[3] Drugs Drug Candidates 2023, 2, 653-672;

Keywords: antimalarial activity; 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene; G-quadruplexes; telomeres