Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis of Alkoxyamines
2.2. Antimalarial Activity
2.3. Antischistosomal Activity
2.4. Cytotoxicity
2.5. Thermodynamic and Kinetic Data for the Homolysis of the NO–C Bond
2.6. Reactivity of Alkoxyamines Toward Heme
3. Conclusions
4. Materials and Methods
4.1. Synthesis of Alkoxyamines
4.1.1. Methods
4.1.2. Syntheses and Characterization
4.2. Evaluation against P. falciparum
4.2.1. Parasite Culture
4.2.2. In Vitro Antimalarial Activities
4.2.3. Recrudescence Assay
4.3. Evaluation against S. mansoni
4.3.1. Parasite Culture
4.3.2. In Vitro Antischistosomal Activities
4.4. Cytotoxicity Assays
4.5. Computational Studies
4.6. Reactivity of Alkoxyamines toward Heme
4.6.1. Materials and Analytical Conditions
4.6.2. Reaction of (RR/SS)-1a or (RS/SR)-1a with Fe(III)-heme
4.6.3. Reaction of (RS/SR)-2F and (RR/SS)-2F with Fe(III)-heme
4.6.4. Reaction of (R/S)-8F with Fe(III)-heme
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are not available from the authors. |
S. mansoni Mean Survival Time (h) | P. falciparum Strains Mean IC50 (µM) | Cytotoxicity Mean IC50 (µM) | Selectivity Index 4 | ||
---|---|---|---|---|---|
Adult S. mansoni | F32-TEM | F32-ART5 | Vero cell lines | ||
(RR/SS)-1a | >8 | 15 2 | 16 2 | 17 ± 7.0 | 1 |
(RS/SR)-1a | 1.2 ± 0.1 | 7.6 2 | 11 2 | 28 ± 29 | 3 |
(RS/SR)-2F | 2.1 ± 0.1 | 0.6 ± 0.1 | 0.5 ± 0.1 | 0.8 ± 0.3 | 1 |
(RR/SS)-2F | 2.5 ± 0.2 | 0.5 ± 0.1 | 0.4 ± 0.1 | 0.7 ± 0.3 | 1 |
(RS/SR)-4F (RR/SS)-4F | 5.2 ± 0.2 >8 | 2.9 2 4.6 1 | 4.7 2 4.6 1 | 15 ± 5.0 8.1 ± 3.3 | 4 2 |
(R/S)-8F | 5.0 ± 0.0 | 1.3 2 | 1.1 2 | 0.7 ± 0.4 | 0.5 |
(RS/SR)-7F | 2.7 ± 0.1 | 1.3 2 | 1.4 2 | 0.9 ± 0.4 | 0.6 |
(RR/SS)-7F | 2.5 ± 0.1 | 0.94 2 | 0.85 2 | 1.2 ± 1.3 | 1 |
1J | 1.1 ± 0.1 | 2.9 1 | 2.3 1 | 6.2 ± 1.2 | 2 |
1K | 1.1 ± 0.0 | 1.1 1 | 1.6 1 | 1.1 ± 0.7 | 1 |
2J | 1.0 ± 0.0 | 5.0 1 | 4.6 1 | 17 ± 6.3 | 3 |
(RS/SR)-1L | ND 3 | 11 2 | 18 2 | ND | ND |
(RR/SS)-1L | ND | 20 2 | 26 2 | 28 | 1 |
(RS/SR)-1M | ND | 5.8 2 | 4.9 2 | 13 ± 1.5 | 2 |
(RR/SS)-1M | ND | 4.8 2 | 6 2 | 6.5 ± 0.3 | 1 |
22 | >8 | 0.24 1 | 0.23 1 | 5.3 ± 4.5 | 22 |
9a | 3.0 ± 0.0 | 7.5 1 | 13 1 | 40 ± 13 | 3 |
(RS/SR)-1A | 1.0 ± 0.05 | ND | ND | 21 | |
(RR/SS)-1A | 1.0 ± 0.05 | ND | ND | >100 | |
(RR/SS)-1p | 1.0 ± 0.05 | ND | ND | >100 | |
(RR/SS)-1k | 1.0 ± 0.05 | ND | ND | ||
Praziquantel | 1.0 ± 0.05 | ND | ND | >>100 5 | >>100 |
Artemisinin | ND | 0.02 ± 0.001 6 | 0.02 ± 0.002 6 | 160 ± 12 | 8000 |
Chloroquine | ND | 0.06 ± 0.02 | 0.06 ± 0.03 | 190 ± 56 | 3000 |
Drug (Dose) | Median (Range) Recrudescence Time (Days) | Mean ± SEM Difference of Recrudescence Time (Days) | p-value | |
---|---|---|---|---|
F32-ART5 | F32-TEM | |||
Artemisinin (18 µM) (RS/SR)-2F (5 µM) | 9 (7–11) 16 (15–17) | >30 (16→30) 1 >30 1 | >16.3 ± 3.7 >14 ± 0.6 | 0.048 0.0017 |
Solvent | T (°C) a | kd′ (10−4s−1) b | Ea (kJ/mol) c,d | kd (10−3 s−1) d | t1/2 (day) e | |||||
---|---|---|---|---|---|---|---|---|---|---|
RS/SR f | RR/SS f | RS/SR f | RR/SS f | RS/SR f | RR/SS f | RS/SR f | RR/SS f | |||
6F | t-BuPh | 81 | 2.7 | 1.4 | 121.7 | 123.8 | 16.3 | 8.5 | 10 | 24 |
2F | t-BuPh | 81 | 5.3 | 7.0 | 119.7 | 118.9 | 29.9 | 38.4 | 4.8 | 3.5 |
2FH+ | t-BuPh + 2eq TFA g | 80 | 8.7 | 6.7 | 117.9 | 118.2 | 51.8 | 40.9 | 2.4 | 3.3 |
2F | MeOH/water 1:1 pH = 7.4 h | 81 | 8.7 | 7.1 | 118.2 | 118.8 | 46.7 | 38.9 | 2.7 | 3.5 |
2FH+ | MeOH/water 1:1 pH = 1.0 h | 51 | 2.1 | 12.0 | 111.9 | 107.4 | 310.1 | 1305 | 5.6 h | 1.0 h |
2FFe2+ | MeOH/water 1:1 pH = 7.4 h FeCl2 | 60 | 17.8 | -i | 109.2 | -j | 732.0 | -j | 2 h | -j |
2FFe2+ | MeOH/water 1:1 pH = 7.4 h FeCl2 | 51 | -i | 6.5 | -j | 109.0 | -j | 787.0 | -j | 1.8 h |
2FFe3+ | MeOH/water 1:1 pH = 7.4 h FeCl3 | 51 | 3.9 | -i | 116.4 | -j | 83.4 | -j | 1.3 | -j |
2FFe3+ | MeOH/water 1:1 pH = 7.4 h FeCl3 | 61 | -i | 2.0 | -j | 115.1 | -j | 120.6 | -j | 8.1 |
9F | t-BuPh | 111 | 3.7 k | 131.0 k | 0.95 k | 385 k | ||||
9FH+ | t-BuPh + 2 eq. TFA g | 101 | 3.0 k | 128.2 k | 2.2 k | 385 k | ||||
9F | MeOH/water 1:1 pH = 7.4 h | 90 | 0.25 k | 131.9 k | 0.7 k | 385 k | ||||
8F | t-BuPh | 111 | 1.9 | 133.3 k | 0.46 | 941k | ||||
6G | t-BuPh | 92 | 3.5 | 2.7 | 124.7 | 125.5 | 6.50 | 5.10 | 45.3 | 33.4 |
2G | t-BuPh | 81 | 3.7 | 3.8 | 120.8 | 120.8 | 21.6 | 21.1 | 7.5 | 7.5 |
2G | MeOH/water 2:1 pH = 7.0 h | 81 | 2.3 | 3.3 | 122.1 | 121.1 | 14.4 | 19.5 | 12.7 | 12.3 |
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Reyser, T.; To, T.H.; Egwu, C.; Paloque, L.; Nguyen, M.; Hamouy, A.; Stigliani, J.-L.; Bijani, C.; Augereau, J.-M.; Joly, J.-P.; et al. Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites. Molecules 2020, 25, 3838. https://doi.org/10.3390/molecules25173838
Reyser T, To TH, Egwu C, Paloque L, Nguyen M, Hamouy A, Stigliani J-L, Bijani C, Augereau J-M, Joly J-P, et al. Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites. Molecules. 2020; 25(17):3838. https://doi.org/10.3390/molecules25173838
Chicago/Turabian StyleReyser, Thibaud, Tung H. To, Chinedu Egwu, Lucie Paloque, Michel Nguyen, Alexandre Hamouy, Jean-Luc Stigliani, Christian Bijani, Jean-Michel Augereau, Jean-Patrick Joly, and et al. 2020. "Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites" Molecules 25, no. 17: 3838. https://doi.org/10.3390/molecules25173838
APA StyleReyser, T., To, T. H., Egwu, C., Paloque, L., Nguyen, M., Hamouy, A., Stigliani, J. -L., Bijani, C., Augereau, J. -M., Joly, J. -P., Portela, J., Havot, J., Marque, S. R. A., Boissier, J., Robert, A., Benoit-Vical, F., & Audran, G. (2020). Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites. Molecules, 25(17), 3838. https://doi.org/10.3390/molecules25173838