Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites

Type Article
Date 2020-09
Language English
Author(s) Reyser Thibaud1, 2, To Tung H.3, Egwu Chinedu1, 2, Paloque Lucie1, 2, Nguyen Michel1, Hamouy Alexandre1, Stigliani Jean-Luc1, Bijani Christian1, Augereau Jean-Michel1, 2, Joly Jean-Patrick3, Portela Julien4, Havot Jeffrey3, Marque Sylvain R. A.3, Boissier Jérôme5, Robert Anne1, Benoit-Vical Françoise1, 2, 6, Audran Gérard3
Affiliation(s) 1 : Laboratoire de Chimie de Coordination du CNRS, LCC-CNRS, Université de Toulouse, CNRS, 31555 Toulouse, France
2 : Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, 31077 Toulouse, France
3 : Aix Marseille University, CNRS, ICR, UMR 7273, Case 551, Avenue Escadrille Normandie-Niemen, 13397 Marseille CEDEX 20, France
4 : S.A.S ParaDev, 52 Avenue Paul Alduy, 66860 Perpignan, France
5 : Laboratoire Interactions Hôtes-Pathogènes-Environnements (IHPE), UMR 5244 CNRS, University of Perpignan, IFREMER, Univ. Montpellier, F-66860 Perpignan, France
6 : INSERM, Institut National de la Santé et de la Recherche Médicale, 31024 Toulouse, France
Source Molecules (1420-3049) (MDPI AG), 2020-09 , Vol. 25 , N. 17 , P. 3838 (23p.)
DOI 10.3390/molecules25173838
WOS© Times Cited 8
Note This article belongs to the Special Issue Stable Radicals: Synthesis, Structure and Applications
Keyword(s) alkoxyamine, alkylation, heme, malaria, radical chemistry, schistosomiasis

Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and sub-tropical areas. Due to the widespread drug resistance of the parasites, the availability of new efficient and affordable drugs for these endemic pathologies is now a critical public health issue. In this study, we report the design, the synthesis and the preliminary biological evaluation of a series of alkoxyamine derivatives as potential drugs against Plasmodium and Schistosoma parasites. The compounds (RS/SR)-2F, (RR/SS)-2F, and 8F, having IC50 values in nanomolar range against drug-resistant P. falciparum strains, but also five other alkoxyamines, inducing the death of all adult worms of S. mansoni in only 1 h, can be considered as interesting chemical starting points of the series for improvement of the activity, and further structure activity, relationship studies. Moreover, investigation of the mode of action and the rate constants kd for C-ON bond homolysis of new alkoxyamines is reported, showing a possible alkyl radical mediated biological activity. A theoretical chemistry study allowed us to design new structures of alkoxyamines in order to improve the selectivity index of these drugs

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Reyser Thibaud, To Tung H., Egwu Chinedu, Paloque Lucie, Nguyen Michel, Hamouy Alexandre, Stigliani Jean-Luc, Bijani Christian, Augereau Jean-Michel, Joly Jean-Patrick, Portela Julien, Havot Jeffrey, Marque Sylvain R. A., Boissier Jérôme, Robert Anne, Benoit-Vical Françoise, Audran Gérard (2020). Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites. Molecules, 25(17), 3838 (23p.). Publisher's official version : , Open Access version :