In Vitro Evaluation of New 5-Nitroindazolin-3-one Derivatives as Promising Agents against Trypanosoma cruzi
Abstract
1. Introduction
2. Results and Discussion
2.1. Synthesis of 1,2-Disubstituted 5-nitroindazolin-3-ones
2.2. Cyclic Voltammetry
Characterization of Radicals by ESR
2.3. Determination of Cytotoxic Activity against T. cruzi (Dm28c) Epimastigotes and Trypomastigote Forms
2.4. Action Mechanism
2.4.1. Plasma Membrane Permeability
2.4.2. Mitochondrial Membrane Potential (ψm)
2.4.3. Analysis of ATP Levels
2.4.4. Intracellular ROS Generation
2.4.5. Study of the Generation of Radical Species by Spin Trapping
2.4.6. Interaction of Nitroreductase Receptor on T. cruzi and Compounds
2.4.7. General Discussion
3. Materials and Methods
3.1. Chemistry
3.1.1. General Methods
3.1.2. Preparation of 1,2-Disubstituted Indazolinones
3.1.3. Preparation of 5-Nitroindazole
3.2. Cyclic Voltammetry (CV)
3.3. ESR Spectroscopy
3.4. Biologic Assays
3.4.1. Cytotoxicity Assay
3.4.2. Epimastigotes Viability Study
3.4.3. Trypomastigote Viability Study
3.4.4. Plasmatic Membrane Permeability Assay
3.4.5. Analysis of ATP Levels
3.4.6. Intracellular Generation of Reactive Oxygen Species (ROS)
3.4.7. Determination of the Effect on Mitochondrial Membrane Potential (Δψm) in Dm28c Trypomastigote of T. cruzi
3.4.8. ESR Studies in Parasite Media
3.4.9. Interaction of Nitro Compounds with TcNTR through Docking Calculations
3.5. Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Compound | −EpcIII (V) | −EpaIII (V) | −E1/2 (V) | Ipa/Ipc | Compound | −EpcIII (V) | −EpaIII (V) | −E1/2 (V) | Ipa/Ipc |
---|---|---|---|---|---|---|---|---|---|
1 | 1.12 | 1.02 | 1.07 | 0.94 | 13 | 1.13 | 0.99 | 1.06 | 0.97 |
3a | 1.13 | 0.95 | 1.04 | 0.99 | 14 | 1.20 | 0.99 | 1.10 | 0.94 |
3b | 1.13 | 1.03 | 1.08 | 1.00 | 15 | 1.16 | 1.04 | 1.10 | 0.96 |
4 | 1.37 | 1.27 | 1.32 | 0.63 | 16 | 1.15 | 1.03 | 1.09 | 0.91 |
5a | 1.36 | 1.32 | 1.34 | 0.62 | 17 | 1.37 | 0.82 | 1.10 | 0.96 |
5b | 1.12 | 1.04 | 1.08 | 0.97 | 18 | 1.12 | 1.02 | 1.07 | 0.91 |
6 | 1.22 | 0.94 | 1.08 | 0.99 | 19 | 1.35 | 1.28 | 1.32 | 0.65 |
7 | 1.20 | 0.98 | 1.09 | 1.00 | 20 | 1.38 | 1.28 | 1.33 | 0.67 |
8 | 1.14 | 0.99 | 1.07 | 1.00 | 21 | 1.37 | 1.27 | 1.32 | 0.56 |
9 | 1.10 | 1.02 | 1.06 | 0.96 | 22 | 1.38 | 1.26 | 1.33 | 0.59 |
10 | 1.17 | 0.96 | 1.07 | 0.93 | 23 | 1.37 | 1.25 | 1.31 | 0.78 |
11 | 1.21 | 0.99 | 1.10 | 0.89 | NFX | 0.91 | 0.85 | 0.88 | 1.01 |
12 | 1.17 | 0.96 | 1.07 | 1.00 | BNZ | 1.08 | 0.93 | 1.00 | 0.98 |
Compounds | aN1 | aN2 | aH1 | aH2 | aH3 |
---|---|---|---|---|---|
1 | 10.28 | 1.42 | 4.57 | 2.42 | 0.97 |
3a | 10.42 | 1.39 | 4.60 | 2.39 | 1.05 |
3b | 11.01 | 1.26 | 5.30 | 2.31 | 1.01 |
4 | 11.04 | 1.28 | 5.30 | 2.29 | 0.95 |
5a | 11.67 | 1.20 | 5.25 | 2.37 | 1.01 |
5b | 11.51 | 1.21 | 5.01 | 2.31 | 1.06 |
6 | 10.95 | 1.23 | 4.97 | 2.28 | 1.05 |
7 | 11.09 | 1.20 | 5.31 | 2.27 | 0.98 |
8 | 11.15 | 1.17 | 5.19 | 2.41 | 0.95 |
9 | 11.27 | 1.28 | 5.21 | 2.38 | 0.86 |
10 | 10.11 | 1.25 | 5.18 | 2.43 | 1.96 |
11 | 11.04 | 1.27 | 5.24 | 2.28 | 1.05 |
12 | 11.17 | 1.21 | 5.19 | 2.40 | 1.11 |
13 | 11.32 | 1.24 | 5.20 | 2.37 | 1.04 |
14 | 11.41 | 1.18 | 5.17 | 2.29 | 0.94 |
15 | 11.36 | 1.21 | 5.15 | 2.37 | 1.01 |
16 | 11.06 | 1.23 | 5.20 | 2.41 | 1.04 |
17 | 11.12 | 1.18 | 5.26 | 2.39 | 1.01 |
18 | 11.09 | 1.21 | 5.21 | 2.41 | 1.10 |
19 | 12.29 | 4.55 | 2.03 | 2.03 | |
20 | 12.43 | 4.69 | 2.08 | 2.08 | |
21 | 12.36 | 4.77 | 1.77 | 1.77 | |
22 | 12.31 | 4.62 | 2.09 | 2.09 | |
23 | 12.33 | 4.70 | 2.05 | 2.05 |
IC50 (µM) | ||||||
---|---|---|---|---|---|---|
RAW 264.7 | Epimastigote | Trypomastigote | SI * Epimastigote | SI * Trypomastigote | iLogP ** | |
1 | 37.8 ± 1.2 | 10.1 ± 0.6 | >100 | 3.7 | - | 2.14 |
3a | 26.1 ± 0.8 | 8.9 ± 1.3 | 18.5 ± 0.9 | 2.9 | 1.4 | 1.05 |
3b | >200 | 28.6 ± 2.1 | 41.8 ± 1.1 | >22.5 | >4.8 | 1.49 |
4 | 97.5 ± 1.2 | 46.9 ± 3.4 | 63.4 ± 1.4 | 2.1 | 1.5 | 1.73 |
5a | 68.9 ± 0.7 | 1.1 ± 0.3 | 5.4 ± 0.7 | 62.6 | 12.8 | 1.78 |
5b | 76.5 ± 1.2 | 52.2 ± 1.3 | 86.5 ± 1.2 | 1.5 | 0.9 | 2.03 |
6 | 83.9 ± 0.9 | 32.9 ± 0.7 | 56.4 ± 1.5 | 2.6 | 1.5 | 2.09 |
7 | 95.1 ± 1.1 | 29.5 ± 1.5 | 41.2 ± 0.8 | 3.2 | 2.3 | 2.30 |
8 | 116.4 ± 1.7 | 36.4 ± 0.8 | 57.8 ± 1.3 | 3.2 | 2.0 | 2.21 |
9 | 175.5 ± 2.3 | 43.7 ± 2.0 | 61.6 ± 1.4 | 4.0 | 2.8 | 2.10 |
10 | >200 | 40.3 ± 2.0 | 54.2 ± 1.1 | >5.0 | >3.7 | 2.41 |
11 | 68.8 ± 1.2 | 70.1 ± 2.1 | 67.8 ± 1.7 | 1.0 | 1.0 | 2.39 |
12 | 72.4 ± 1.6 | 30.3 ± 1.1 | 52.5 ± 1.3 | 2.4 | 1.4 | 2.23 |
13 | >200 | 79.8 ± 2.3 | 43.6 ± 1.1 | >2.5 | >4.6 | 2.47 |
14 | 172.2 ± 2.3 | 83.9 ± 1.9 | 48.6 ± 1.2 | 2.1 | 3.5 | 2.44 |
15 | 36.3 ± 1.1 | >100 | >100 | - | - | 2.23 |
16 | >200 | >100 | >100 | - | - | 2.35 |
17 | 165.7 ± 2.3 | 35.4 ± 1.1 | 89.3 ± 1.0 | 4.7 | 1.9 | 2.19 |
18 | >200 | 68.7 ± 1.7 | >100 | >2.9 | - | 2.39 |
19 | >200 | >100 | >100 | - | - | 1.29 |
20 | >200 | >100 | >100 | - | - | 1.72 |
21 | >200 | 84.3 ± 2.1 | 91.2 ± 2.2 | >2.4 | >2.1 | 2.33 |
22 | >200 | 6.2 ± 0.9 | 15.3 ± 1.2 | >32.3 | >13.1 | 1.93 |
23 | >200 | >100 | >100 | - | - | 1.38 |
NFX | 263.4 ± 2.2 | 17.4 ± 1.3 | 21.5 ± 1.4 | 15.1 | 12.3 | 0.71 |
Compounds | Docking Score (kcal/mol) | Compounds | Docking Score (kcal/mol) |
---|---|---|---|
1 | −6.6 | 12 | −5.9 |
2a | −7.4 | 13 | −6.0 |
2b | −6.9 | 14 | −6.5 |
3a | −5.3 | 15 | −5.2 |
3b | −5.2 | 16 | −5.5 |
4 | −6.4 | 17 | −6.1 |
5a | −7.3 | 18 | −4.6 |
5b | −6.6 | 19 | −5.8 |
6 | −6.3 | 20 | −5.6 |
7 | −6.8 | 21 | −6.0 |
8 | −4.5 | 22 | −6.4 |
9 | −5.9 | 23 | −5.0 |
10 | −5.9 | NFX | −6.5 |
11 | −6.2 |
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Pozo-Martínez, J.; Arán, V.J.; Zúñiga-Bustos, M.; Parra-Magna, S.; Rocha-Valderrama, E.; Liempi, A.; Castillo, C.; Olea-Azar, C.; Moncada-Basualto, M. In Vitro Evaluation of New 5-Nitroindazolin-3-one Derivatives as Promising Agents against Trypanosoma cruzi. Int. J. Mol. Sci. 2024, 25, 11107. https://doi.org/10.3390/ijms252011107
Pozo-Martínez J, Arán VJ, Zúñiga-Bustos M, Parra-Magna S, Rocha-Valderrama E, Liempi A, Castillo C, Olea-Azar C, Moncada-Basualto M. In Vitro Evaluation of New 5-Nitroindazolin-3-one Derivatives as Promising Agents against Trypanosoma cruzi. International Journal of Molecular Sciences. 2024; 25(20):11107. https://doi.org/10.3390/ijms252011107
Chicago/Turabian StylePozo-Martínez, Josué, Vicente J. Arán, Matías Zúñiga-Bustos, Sebastián Parra-Magna, Esteban Rocha-Valderrama, Ana Liempi, Christian Castillo, Claudio Olea-Azar, and Mauricio Moncada-Basualto. 2024. "In Vitro Evaluation of New 5-Nitroindazolin-3-one Derivatives as Promising Agents against Trypanosoma cruzi" International Journal of Molecular Sciences 25, no. 20: 11107. https://doi.org/10.3390/ijms252011107
APA StylePozo-Martínez, J., Arán, V. J., Zúñiga-Bustos, M., Parra-Magna, S., Rocha-Valderrama, E., Liempi, A., Castillo, C., Olea-Azar, C., & Moncada-Basualto, M. (2024). In Vitro Evaluation of New 5-Nitroindazolin-3-one Derivatives as Promising Agents against Trypanosoma cruzi. International Journal of Molecular Sciences, 25(20), 11107. https://doi.org/10.3390/ijms252011107