Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites

Thibaud Reyser (1, 2) , Tung H To (3) , Chinedu Egwu (1, 2) , Lucie Paloque (1, 2) , Michel Nguyen (1) , Alexandre Hamouy (1) , Jean-Luc Stigliani (1) , Christian Bijani (1) , Jean-Michel Augereau (1, 2) , Jean-Patrick Joly (3) , Julien Portela (4) , Jeffrey Havot (3) , Sylvain R A Marque (3) , Jérôme Boissier (5) , Anne Robert (1) , Françoise Benoit-Vical (1, 2, 6) , Gérard Audran (3)

1 LCC - Laboratoire de chimie de coordination
2 IPBS - Institut de pharmacologie et de biologie structurale
3 ICR - Institut de Chimie Radicalaire
4 S.A.S ParaDev
5 IHPE - Interactions Hôtes-Pathogènes-Environnements
6 INSERM - Institut National de la Santé et de la Recherche Médicale

Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and subtropical 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 IC 50 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 k d for CON 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.

Mots clés: Alkoxyamine; Alkylation; Heme; Malaria; Radical chemistry; Schistosomiasis

Domaines: Chimie thérapeutique

Thibaud Reyser, Tung H To, Chinedu Egwu, Lucie Paloque, Michel Nguyen, et al.. Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites. Molecules, 2020, 25 (17), pp.3838. ⟨10.3390/molecules25173838⟩. ⟨hal-02948878⟩