3-Alkoxy-1-Benzyl-5-Nitroindazole Derivatives Are Potent Antileishmanial Compounds
Abstract
:1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Chemistry
4.2. Parasites
4.3. Growth Curves
4.4. Peritoneal Macrophage Extraction
4.5. In Vitro Assays
4.6. Prediction of ADMET Properties
4.7. Electron Microscopy
4.7.1. Scanning Electron Microscopy
4.7.2. Transmission Electron Microscopy
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Base Structure | Product | Substituent R1 | CC50 ± SD (µM) |
---|---|---|---|
NV4 | (CH2)2-N(CH3)2 | 67.1 ± 8.9 | |
NV6 | (CH2)3-N(CH3)2 | 61 ± 6.9 | |
NV7 | (CH2)2-Piperidine | 24.4 ± 6.7 | |
NV8 | (CH2)3-Piperidine | 23.2 ± 5.0 | |
NV9 | (CH2)3-NH2 | 47.9 ± 10.4 | |
NV10 | (CH2)2-NH2 | 46.7 ± 7.7 | |
NV11 | (CH2)2-Br | 4.5 ± 1.0 | |
NV12 | (CH2)5-Br | 4.1 ± 0.6 | |
NV13 | (CH2)2-NHCH3 | 61.4 ± 9.4 | |
NV14 | (CH2)5-N(CH3)2 | 2.5 ± 0.7 | |
NV15 | (CH2)5-NHCH3 | 5.6 ± 2.5 | |
NV16 | (CH2)5-Piperidine | 21.1 ± 7.1 | |
NV17 | (CH2)5-NH2 | 7.74 ± 3.0 | |
AmB | 5.8 ± 0.5 |
PROMASTIGOTES | ||||||
Species | L. amazonensis | L. infantum | L. mexicana | |||
Products | IC50 ± SD (µM) | SIp | IC50 ± SD (µM) | SIp | IC50 ± SD (µM) | SIp |
NV4 | 0.4 ± 0.1 | 127 | 0.52 ± 0.05 | 127 | 2.3 ± 0.4 | 32 |
NV6 | 0.43 ± 0.007 | 61 | 0.69 ± 0.063 | 45 | 0.28 ± 0.04 | 121 |
NV7 | 0.04 ± 0.01 | 653 | 0.33 ± 0.021 | 74 | 0.2 ± 0.08 | 14 |
NV8 | 0.007 ± 0.001 | 3467 | 0.22 ± 0.003 | 104 | 0.11 ± 0.04 | 208 |
NV9 | 0.81 ± 0.17 | 58 | 0.59 ± 0.16 | 87 | 2.8 ± 0003 | 17 |
NV10 | 0.99 ± 0.14 | 54 | 0.93 ± 0.27 | 51 | 4.5 ± 0.5 | 12 |
NV11 | 20.7 ± 1.38 | 2 | 20.4 ± 1.3 | 0.2 | 9.38 ± 0.13 | 0.5 |
NV12 | 2.88 ± 1.47 | 2 | 32.96 ± 0.25 | 0.1 | 2.8 ± 1.1 | 1 |
NV13 | 0.82 ± 0.27 | 74 | 0.29 ± 0.1 | 223 | 0.3 ± 0.04 | 223 |
NV14 | 0.5 ± 0.22 | 6 | 0.93 ± 0.18 | 3 | 0.05 ± 0.01 | 55 |
NV15 | 1.88 ± 1.34 | 4 | 1.27 ± 0.06 | 4.4 | 0.1 ± 0.01 | 80 |
NV16 | 0.3 ± 0.22 | 49 | 1.41 ± 0.03 | 15 | 0.5 ± 0.1 | 51 |
NV17 | 1.01 ± 0.39 | 8 | 0.20 ± 0.003 | 38 | 2.9 ± 0.1 | 3 |
AmB | 0.03 ± 0.01 | 193 | 0.28 ± 0.01 | 21 | 0.046 ± 0.012 | 126 |
AMASTIGOTES | ||||||
Species | L. amazonensis | L. infantum | L. mexicana | |||
Products | EC50 ± SD (µM) | SIa | EC50 ± SD (µM) | SIa | EC50 ± SD (µM) | SIa |
NV4 | 12.3 ± 0.7 | 5 | 3.42 ± 1.8 | 20 | NE | |
NV6 | 0.43 ± 0.049 | 71 | 3.79 ± 1.46 | 16 | 2.2 ± 0.05 | 14 |
NV7 | 5.61 ± 0.69 | 5 | 12.8 ± 0.13 | 2 | 3.1 ± 1.05 | 8 |
NV8 | 1.00 ± 0.48 | 23 | 1.26 ± 0.5 | 18 | 1.0 ± 0.1 | 23 |
NV9 | 1.13 ± 0.98 | 42 | 9.71 ± 0.4 | 5 | NE | |
NV10 | 4.35 ± 0.9 | 11 | 2.4 ± 0.34 | 194 | NE | |
NV11 | NE | NE | NE | |||
NV12 | NE | NE | NE | |||
NV13 | 5.66 ± 0.53 | 11 | 16.2± 0.54 | 4 | 11.6 ± 0.7 | 5 |
NV14 | NE | NE | 8.2 ± 0.2 | 0.3 | ||
NV15 | NE | NE | 1.53 ± 0.13 | 4 | ||
NV16 | 0.17 ± 0.042 | 129 | NE | 4.29 ± 0.48 | 5 | |
NV17 | NE | 11.8 ± 1.04 | 1 | NE | ||
AmB | 0.034 ± 0.006 | 170 | 0.6 ± 0.21 | 10 | 0.036 ± 0.008 | 725 |
Molecule Property | Unit | NV4 | NV6 | NV8 | NV9 | NV10 | NV16 | AmB |
Molecular Weight | kg/mol | 340.15 | 354.17 | 394.2 | 326.14 | 312.12 | 422.23 | 901.56 |
Number of Heteroatoms | 7 | 7 | 7 | 7 | 7 | 7 | 14 | |
Number of Rotatable Bonds | 7 | 8 | 8 | 7 | 6 | 10 | 3 | |
Number of Rings | 3 | 3 | 4 | 3 | 3 | 4 | 3 | |
Number of HA | 6 | 6 | 6 | 6 | 6 | 6 | 14 | |
Number of HD | 0 | 0 | 0 | 1 | 1 | 0 | 9 | |
log KOW | log-ratio | 2.93 | 3.32 | 4.25 | 2.72 | 2.33 | 5.03 | 4.51 |
Absorption | Unit | NV4 | NV6 | NV8 | NV9 | NV10 | NV16 | AmB |
Caco-2 Permeability | log(cm/s) | −5.05 | −5.04 | −5.09 | −5.35 | −5.36 | −5.2 | −5.45 |
HIA | % | 75.42 | 73.4 | 75.73 | 75.39 | 76.06 | 75.7 | 66.16 |
Pgp Inhibition | % | 46.26 | 50.9 | 52.58 | 48.08 | 46.75 | 51.01 | 41.51 |
log D7.4 | log-ratio | 1.99 | 2 | 1.92 | 1.68 | 1.74 | 1.91 | 1.65 |
Aqueous Solubility | log(mol/L) | −4.25 | −4.4 | −4.41 | −4.1 | −4.03 | −4.41 | −4.16 |
Oral Bioavailability | % | 50.3 | 48.42 | 41.73 | 49.73 | 50.45 | 35.75 | 38.02 |
Distribution | Unit | NV4 | NV6 | NV8 | NV9 | NV10 | NV16 | AmB |
BBB | % | 39.3 | 40.39 | 39.87 | 38.68 | 38.44 | 38.8 | 26.41 |
PPBR | % | 49.51 | 50.1 | 50.93 | 49.34 | 48.56 | 50.92 | 41.18 |
VDss | L/kg | 3.64 | 3.64 | 4.15 | 3.33 | 3.36 | 4.14 | 3.85 |
Metabolism | Unit | NV4 | NV6 | NV8 | NV9 | NV10 | NV16 | AmB |
CYP2C9 Inhibition | % | 78.25 | 80 | 67.88 | 78.18 | 70.38 | 74.12 | 50.16 |
CYP2D6 Inhibition | % | 95.53 | 97.23 | 97.64 | 89.45 | 91.47 | 96.98 | 96.33 |
CYP3A4 Inhibition | % | 31.87 | 33.97 | 29.14 | 33.95 | 32.39 | 31.28 | 30.95 |
CYP2C9 Substrate | % | 31.29 | 32.76 | 30.06 | 29.4 | 29.32 | 30.68 | 31.7 |
CYP2D6 Substrate | % | 59.39 | 64.41 | 53.41 | 60.29 | 62.1 | 52.28 | 57.32 |
CYP3A4 Substrate | % | 38.43 | 39.3 | 36.13 | 35.46 | 35.79 | 36.86 | 33.09 |
Excretion | Unit | NV4 | NV6 | NV8 | NV9 | NV10 | NV16 | AmB |
Half Life | h | 78.88 | 92.59 | 79.39 | 80.43 | 81.42 | 79.75 | 118.71 |
CL-Hepa | uL∙min−1(106 cells)−1 | 44.17 | 48.83 | 45.61 | 57.02 | 52.74 | 44.73 | 41.66 |
CL-Micro | mL∙min−1 g−1 | 42.42 | 43.52 | 39.64 | 43.65 | 41.2 | 41.8 | 46.05 |
Toxicity | Unit | NV4 | NV6 | NV8 | NV9 | NV10 | NV16 | AmB |
hERG Blockers | % | 42.2 | 44.89 | 46.81 | 43.1 | 42.02 | 47.91 | 42.12 |
DILI | % | 52.83 | 51.13 | 47.9 | 53.34 | 53.44 | 49.41 | 52.26 |
LD50 | −log(mol/kg) | 2.35 | 2.28 | 2.21 | 2.24 | 2.37 | 2.11 | 2.75 |
OSIRIS Property Explorer | Unit | NV4 | NV6 | NV8 | NV9 | NV10 | NV16 | AmB |
Mutagenic | No | No | No | No | No | No | No | |
Tumorigenic | No | No | No | No | No | No | No | |
Irritant | No | No | No | No | No | No | No | |
Reproductive effects | No | No | No | No | No | No | No | |
Drug score | 0.68 | 0.56 | 0.37 | 0.42 | 0.43 | 0.31 | 0.09 |
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Mollineda-Diogo, N.; Sifontes-Rodríguez, S.; Aguirre-García, M.M.; Escalona-Montaño, A.R.; Espinosa-Buitrago, T.; Mondragón-Flores, R.; Mondragón-Castelán, M.E.; Meneses-Marcel, A.; Pérez-Olvera, O.; Sánchez-Almaraz, D.A.; et al. 3-Alkoxy-1-Benzyl-5-Nitroindazole Derivatives Are Potent Antileishmanial Compounds. Int. J. Mol. Sci. 2024, 25, 10582. https://doi.org/10.3390/ijms251910582
Mollineda-Diogo N, Sifontes-Rodríguez S, Aguirre-García MM, Escalona-Montaño AR, Espinosa-Buitrago T, Mondragón-Flores R, Mondragón-Castelán ME, Meneses-Marcel A, Pérez-Olvera O, Sánchez-Almaraz DA, et al. 3-Alkoxy-1-Benzyl-5-Nitroindazole Derivatives Are Potent Antileishmanial Compounds. International Journal of Molecular Sciences. 2024; 25(19):10582. https://doi.org/10.3390/ijms251910582
Chicago/Turabian StyleMollineda-Diogo, Niurka, Sergio Sifontes-Rodríguez, María Magdalena Aguirre-García, Alma Reyna Escalona-Montaño, Teresa Espinosa-Buitrago, Ricardo Mondragón-Flores, Mónica Edith Mondragón-Castelán, Alfredo Meneses-Marcel, Ofelia Pérez-Olvera, Daniel Andrés Sánchez-Almaraz, and et al. 2024. "3-Alkoxy-1-Benzyl-5-Nitroindazole Derivatives Are Potent Antileishmanial Compounds" International Journal of Molecular Sciences 25, no. 19: 10582. https://doi.org/10.3390/ijms251910582