Antiplasmodial Activity of Nitroaromatic Compounds: Correlation with Their Reduction Potential and Inhibitory Action on Plasmodium falciparum Glutathione Reductase
Abstract
:1. Introduction
2. Results
2.1. Relationship between Antiplasmodial Activity of Nitroaromatic Compounds and Their Single-Electron Reduction Midpoint Potential
2.2. Single-Electron Reduction of Nitroaromatics by PfFNR and PfGR
2.3. Inhibition of P. falciparum Glutathione Reductase by Nitroaromatic Compounds
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Methods
4.2.1. Enzyme Kinetic Studies
4.2.2. Antiplasmodial In Vitro Activity Studies
4.2.3. Statistical Analysis and Calculations
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ArNO2 | Nitroaromatic compound |
E17 | Single-electron reduction midpoint potential of nitroaromatic compound (redox potential of ArNO2/ArNO2−. couple) at pH 7.0 |
HGR | Human erythrocyte glutathione reductase |
IC50 | Compound concentration causing 50% parasite growth inhibition |
kcat | Enzyme catalytic constant |
kcat/Km | Enzyme bimolecular rate constant (catalytic efficiency) |
Ki | Enzyme inhibition constant |
log D | Octanol/water distribution coefficient at pH 7.0 |
PfFNR | P. falciparum ferredoxin:NADP+ oxidoreductase |
PfGR | P. falciparum glutathione reductase |
ROS | Reactive oxygen species |
TNT | 2,4,6-Trinitrotoluene |
TR | Trypanothione reductase |
References
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Sample Availability: Samples of the compounds 3,15–22 (Table 1) are available from the authors. |
No. | Compound | E17 (V) [35] | IC50 (µM) [19] | log D | kcat/Km (M−1·s−1) |
---|---|---|---|---|---|
1 | Nitrobenzene | −0.485 | 473 ± 113 | 1.91 | 5.5 ± 0.8 × 101 |
2 | 4-Nitrobenzoic acid | −0.425 | 360 ± 16; 450 ± 70.7 b | −1.66 | 4.5 ± 0.6 × 102 |
3 | CB-1954 | −0.380 | 48.5 ± 5.0 b | 0.64 | 2.8 ± 0.3 × 103 |
4 | 4-Nitroacetophenone | −0.355 | 172 ± 8.0 | 1.47 | 3.3 ± 0.3 × 103 |
5 | 3,5-Dinitrobenzoic acid | −0.350 | 390 ± 17 | −1.79 | 3.9 ± 0.3 × 103 |
6 | 1,3-Dinitrobenzene | −0.345 | 50.5 ± 2.4 | 1.85 | 2.7 ± 0.3 × 103 |
7 | 4-Nitrobenzaldehyde | −0.325 | 79 ± 28 | 1.63 | 4.0 ± 0.3 × 103 |
8 | 3,5-Dinitrobenzamide | −0.311 | 30.3 ± 3.1; 26.5 ± 6.4 b | 0.7 | 4.9 ± 0.4 × 103 |
9 | 1,2-Dinitrobenzene | −0.287 | 11.7 ± 1.1 | 1.85 | 1.1 ± 0.2 × 104 |
10 | Nitrofurantoin | −0.255 | 12.9 ± 1.3 | −0.25 | 6.8 ± 0.7 × 104 |
11 | Nifuroxime | −0.255 | 14.7 ± 0.8 | −0.34 | 3.3 ± 0.4 × 104 |
12 | 1,4-Dinitrobenzene | −0.255 | 0.26 ± 0.03 | 1.85 | 9.3 ± 0.8 × 104 |
13 | 2,4,6-Trinitrotoluene | −0.253 | 9.4 ± 7.8 b | 2.31 | 1.3 ± 0.1 × 104 |
14 | N-Methylpicramide | −0.247 | 7.3 ± 1.1 b | 1.92 | 6.8 ± 0.5 × 104 |
15 | Nitrofuran IIIa | −0.225 a | 17.1 ± 1.5 | 0.27 | 4.8 ± 0.5 × 104 |
16 | Nitrofuran IIIb | −0.225 a | 4.5 ± 0.3 | 2.64 | 1.6 ± 0.2 × 105 |
17 | Nitrofuran IIIc | −0.225 a | 7.4 ± 0.3 | 2.87 | n.d. |
18 | Nitrofuran IIId | −0.225 a | 7.4 ± 0.3 | 3.23 | n.d. |
19 | Nitrofuran IIIe | −0.225 a | 9.2 ± 0.3 | 2.24 | n.d. |
20 | Nitrofuran IIIf | −0.225 a | 11.1 ± 0.4 | 2.62 | n.d. |
21 | Nitrofuran IIIg | −0.225 a | 6.4 ± 0.4 | 2.45 | 8.3 ± 0.7 × 104 |
22 | Nitrofuran IIIh | −0.225 a | 4.3 ± 0.3 | 2.62 | n.d. |
23 | Tetryl | −0.191 | 4.1 ± 0.8 b | 1.38 | 2.0 ± 0.3 × 105 |
No. | Compound | Ki (μM) | |
---|---|---|---|
PfGR a | HGR b | ||
1 | Nitrobenzene | ≥6000 | ≥2000 |
2 | 4-Nitrobenzoic acid | 1200 ± 180 | 800 |
3 | CB-1954 | 350 ± 40 | ≥1000 |
4 | 4-Nitroacetophenone | 70 ± 11 | 400 |
5 | 3,5-Dinitrobenzoic acid | 220 ± 29 | 350 |
6 | 1,3-Dinitrobenzene | 40 ± 5.0 | 320; 350 ± 30a |
7 | 4-Nitrobenzaldehyde | 25 ± 4.0 | 290 |
8 | 3,5-Dinitrobenzamide | 75 ± 9.0 | ≥1000 |
9 | 1,2-Dinitrobenzene | 30 ± 4.0 | ≥1000 |
10 | Nitrofurantoin | 9.0 ± 1.0 | 200 |
11 | Nifuroxime | 32 ± 5.0 | 200 |
12 | 1,4-Dinitrobenzene | 0.85 ± 0.13 | 71 |
13 | 2,4,6-Trinitrotoluene | 8.0 ± 2.0 | 6.0 c; 5.2 ± 0.6 a |
14 | N-Methylpicramide | 5.9 ± 0.6 | 10 c |
15 | Nitrofuran IIIa | 9.0 ± 1.0 | 3.0; 3.5 ± 0.2 a |
16 | Nitrofuran IIIb | 25 ± 3.0 | 2.5 |
17 | Nitrofuran IIIc | 115 ± 17 | 25 |
18 | Nitrofuran IIId | 50 ± 6.0 | ≥300 |
19 | Nitrofuran IIIe | 5.0 ± 1.0 | 2.5 |
20 | Nitrofuran IIIf | 75 ± 10 | 42.5 |
21 | Nitrofuran IIIg | 35 ± 5.0 | 25 |
22 | Nitrofuran IIIh | 100 ± 12 | 45 |
23 | Tetryl | 2.3 ± 0.5 | 14 c |
Enzyme | Oxidants | |
---|---|---|
Nitrofurans, Nitrobenzenes | Menadione | |
E17 = −0.25–−0.19 V | ||
PfFNR | kcat > 20 s−1, kcat/Km = 4.8 × 104 – 1.6×105 M−1·s−1, this work | kcat = 14 s−1, kcat/Km = 1.0 ×106 M−1·s−1 [30] |
PfGR | kcat = 0.06–5.9 s−1, kcat/Km = 7.6 × 103 – 110 M−1·s−1, this work | kcat = 0.16 s−1, kcat/Km = 2.0 × 103 M−1·s−1 [54] |
P. falciparum thioredoxin reductase | kcat = 31 s−1, kcat/Km = 1.6 × 105 M−1·s−1 [54] | |
P. falciparum type II NADH dehydrogenase | kcat = 0.1 s−1 [55] |
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Marozienė, A.; Lesanavičius, M.; Davioud-Charvet, E.; Aliverti, A.; Grellier, P.; Šarlauskas, J.; Čėnas, N. Antiplasmodial Activity of Nitroaromatic Compounds: Correlation with Their Reduction Potential and Inhibitory Action on Plasmodium falciparum Glutathione Reductase. Molecules 2019, 24, 4509. https://doi.org/10.3390/molecules24244509
Marozienė A, Lesanavičius M, Davioud-Charvet E, Aliverti A, Grellier P, Šarlauskas J, Čėnas N. Antiplasmodial Activity of Nitroaromatic Compounds: Correlation with Their Reduction Potential and Inhibitory Action on Plasmodium falciparum Glutathione Reductase. Molecules. 2019; 24(24):4509. https://doi.org/10.3390/molecules24244509
Chicago/Turabian StyleMarozienė, Audronė, Mindaugas Lesanavičius, Elisabeth Davioud-Charvet, Alessandro Aliverti, Philippe Grellier, Jonas Šarlauskas, and Narimantas Čėnas. 2019. "Antiplasmodial Activity of Nitroaromatic Compounds: Correlation with Their Reduction Potential and Inhibitory Action on Plasmodium falciparum Glutathione Reductase" Molecules 24, no. 24: 4509. https://doi.org/10.3390/molecules24244509