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. 2020 Aug 24;25(17):3838.
doi: 10.3390/molecules25173838.

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
Affiliations

Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites

Thibaud Reyser et al. Molecules. .

Abstract

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.

Keywords: alkoxyamine; alkylation; heme; malaria; radical chemistry; schistosomiasis.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Expected alkylation of heme after homolysis of alkoxyamines, leading to a lethal oxidative stress within blood parasites (the oval stands for the porphyrin macrocycle).
Figure 2
Figure 2
Structures of alkoxyamines 1a, 2F, 4F, 2G and 8F.
Scheme 1
Scheme 1
Synthesis of alkoxyamines (RR/SS)-6F and (RS/SR)-6F.
Scheme 2
Scheme 2
Synthesis of alkoxyamines (RR/SS)-2F, (RS/SR)-2F, (RR/SS)-4F and (RS/SR)-4F.
Scheme 3
Scheme 3
Synthesis of alkoxyamines (R/S)-8F.
Scheme 4
Scheme 4
Synthesis of alkoxyamines (RR/SS)-2G and (RS/SR)-2G.
Figure 3
Figure 3
Ortep drawing from X-ray analysis of (a) (RR/SS)-6F (Figure 3a) and (b) (RR/SS)-2G.
Scheme 5
Scheme 5
Reaction of (RR/SS)-2F or (RS/SR)-2F with heme under inert atmosphere (route a) or in the presence of air (route b). The blue and red labels stand for the 1H and 13C-NMR chemical shifts, respectively.
Scheme 6
Scheme 6
Computed free energy (B3lyp/3-21G*) of alkylation of heme at the β-meso position, by the alkyl radical derived from the homolysis of (RR/SS)-2F or (RS/SR)-2F.
Scheme 7
Scheme 7
Optimized structure of alkoxyamines.
See this image and copyright information in PMC

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