Multi-Anti-Parasitic Activity of Arylidene Ketones and Thiazolidene Hydrazines against Trypanosoma cruzi and Leishmania spp.
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis of HIT1 and HIT2 Derivatives
In Vitro Biological Studies
2.2. In Vitro Molecular Stripping for T. cruzi
2.3. Exploring the Mechanism of Action
2.3.1. Inhibition of Triosephosphate Isomerase and Cruzipain
2.3.2. Selective Inhibitors
2.4. Toxicology In Vivo
2.4.1. LD50 in Zebrafish Embryos and Developmental Toxicity
2.4.2. Biodistribution of the Compound in a Zebrafish Model
3. Experimental Section
3.1. General
3.1.1. General Synthetic-Procedure for Thiazolylidene Hydrazines GAT0113A, GAT0513, GAT2015, GATA2 and GAT2212b
3.1.2. Synthetic Procedure for 4(4-Chlorophenyl)-thiazol-2(3H)-ylidene-2-amine (GAT2012)
3.1.3. Synthetic Procedure of (E)-4-(4-Chlorophenyl)-N-((E)-3-(furan-2-yl)allylidene)thiazol-2-amine (GAT2112)
3.1.4. General Synthetic Procedure for Piperazine-Hydrazine Derivatives
3.1.5. Synthetic Procedure for Thiazolylidene Hydrazides GATk1, GATk2, GATk4, GATk5, GATk6 and GAT0613
3.1.6. General Synthetic Procedure for Compounds GAT1113, GAT0413, GAT0913b and GAT1912
3.1.7. Synthetic Procedure for Compound (3E,5E)-3,5-Bis((E)-3-(furan-2-yl)allylidene)-1-methylpiperidin-4-one (Pg150) [12]
3.2. Anti-Parasitic Test In Vitro [15,37]
3.3. Nonspecific In Vitro Cytotoxicity of Mammalian Cells [15,38]
3.4. Inhibition of Triosephosphate Isomerase [12]
3.5. Inhibition of T. cruzi Cruzipain [12]
3.6. Nucleophile Challenge [41]
3.7. Adapting the Zebrafish Embryo Toxicity Test (FET) to Lipophilic Drugs
3.7.1. Embryo Toxicity Test [42,43]
3.7.2. Determination of Drug Bioconcentration [33]
3.7.3. Fluorescence Measurements Using Laser Scanning Confocal Microscopy
4. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Sample Availability: Samples of the studied compounds are available from the authors. |
A | ||||
Structure | Compound | IC50 ± SD a (µM) Epimastigotes T. cruzi | IC50 ± SD (µM) Promastigotes L. braziliensis | IC50 ± SD (µM) Promastigotes L. infantum |
GAT1033 b | 1.6 ± 0.5 c | 7 ± 1 | 2.0 ± 0.2 | |
GAT0113A | 3.0 ± 0.5 | 10 ± 1 | 8 ± 2 | |
GAT0513 | 0.09 ± 0.02 | 33 ± 11 | 58 ± 12 | |
HIT1 | 3.1 ± 0.2 d | 12 ± 5 | 4 ± 1 | |
GAT1113 | 1.6 ± 0.3 | 16 ± 4 | 14 ± 2 | |
GAT0913b | 25 ± 8 | 18 ± 5 | 21 ± 2 | |
Glucantime | - | 18 ± 2 | 26 ± 9 | |
Miltefosine | 8 ± 1 | - | 0.9 ± 0.2 | |
Benznidazole | 7 ± 1 | - | - | |
B | ||||
Curcumin | 5.6 ± 1 e | - | 5.9 ± 0.3 b | |
Comp13 f | 31 ± 2 f | 0.9 ± 0.2 c | - | |
EA142 g | 5.1 ± 0.3 h | 4.2 ± 0.7 | 9.6 ± 0.9 | |
EA134 | 24 ± 2 h | 10 ± 6 | 6 ± 2 | |
EA128 | 5.0 ± 0.7 h | 36 ± 9 | 31 ± 9 | |
EA155 | 8.2 ± 2.0 h | 16 ± 2 | 6 ± 1 | |
EA161 | 5.4 ± 1.6 h | 18 ± 4 | 16 ± 4 | |
HIT2 | 0.6 ± 0.2 h | 7 ± 1 | 13 ± 7 | |
EA138 | 5.0 ± 0.8 h | 8 ± 2 | 4.0 ± 0.5 | |
EA141 | 12.6 ± 1.4 h | 36 ± 3 | 19 ± 5 | |
EA160 | 0.04 ± 0.01 h | >100 | 11 ± 3 | |
EA156 | 0.6 ± 0.2 h | >100 | 16 ± 3 | |
Glucantime | - | 18 ± 2 | 26 ± 9 | |
Miltefosine | 8 ± 3 | 0.9 ± 0.2 | - | |
Benznidazole | 7 ± 1 | - | - |
Compound | IC50 ± SD (µM) Fibroblast NCTC929 | IC50 ± SD (µM) Murine Macrophages | SI e NCTC/ L. braziliensis | SI NCTC/ L. infantum | SI J774.1/ T. cruzi |
---|---|---|---|---|---|
GAT1033 | 405 ± 10 | 60 ± 6 a | 58 | 203 | 37 a |
GAT0113A | 319 ± 16 | 66 ± 7 | 32 | 40 | 22 |
GAT0513 | 1443 ± 30 | 55 ± 5 | 44 | 25 | 611 |
HIT1 | 346 ± 9 | 30 ± 5 b | 29 | 87 | 10 |
GAT1113 | 165 ± 5 | 45 ± 5 | 10 | 12 | 28 |
GAT0913b | 160 ± 7 | 25 ± 3 | 9 | 8 | 1 |
Curcumin | - | 10 ± 2 d | 2 | - | 2 |
Comp13 | - | 21± 5 d | 23 | - | 1 |
EA134 | 114 ± 2 | 115 ± 6 c | 11 | 19 | 5 c |
EA128 | 494 ± 25 | 60 ± 3 c | 14 | 16 | 12 c |
EA155 | 543 ± 15 | 33 ± 8 c | 34 | 91 | 4 c |
EA161 | 756 ± 17 | 19 ± 2 c | 42 | 47 | 4 c |
HIT2 | 160 ± 9 | 10 ± 2 c | 23 | 12 | 17 c |
EA138 | 158 ± 5 | 38 ±7 c | 20 | 40 | 8 c |
EA141 | 1704 ± 40 | 10 ± 2 c | 47 | 90 | 1 c |
EA160 | 4909 ± 36 | 15 ± 1 c | nc | 446 | 375 c |
EA156 | 1985 ± 20 | 20 ± 1 c | nc | 124 | 33 c |
Glucantime | - | 15 ± 1 | 1 | 0.5 | - |
Miltefosine | - | 50 ± 7 | - | 56 | 6 |
Benznidazole | - | 400 ± 4 | - | - | 57 |
Compound | Percentage of Inhibition a,b/IC50 ± SD (µM) TcTIM | Percentage of Inhibition a,b/IC50 ± SD (µM) LmTIM c | Percentage of Inhibition a,b/IC50 ± SD (µM) Cruzipain |
---|---|---|---|
GAT1033 | 0/- | 0/- | 0/- |
HIT1 | 0/- | 0/- | 100/4.3 ± 0.4 |
EA128 | 100/3.0 ± 0.7 d | 0/- | 48/- d |
EA155 | 100/3.3 ± 0.5 d | 100/˂25 e | 0/- d |
HIT2 | 100/0.086 ± 0.007 d | 100/˂25 e | 80/37.0 ± 1.1 d |
EA138 | 0/- d | 100/˂25 e | 50/- d |
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Share and Cite
Álvarez, G.; Perdomo, C.; Coronel, C.; Aguilera, E.; Varela, J.; Aparicio, G.; Zolessi, F.R.; Cabrera, N.; Vega, C.; Rolón, M.; et al. Multi-Anti-Parasitic Activity of Arylidene Ketones and Thiazolidene Hydrazines against Trypanosoma cruzi and Leishmania spp. Molecules 2017, 22, 709. https://doi.org/10.3390/molecules22050709
Álvarez G, Perdomo C, Coronel C, Aguilera E, Varela J, Aparicio G, Zolessi FR, Cabrera N, Vega C, Rolón M, et al. Multi-Anti-Parasitic Activity of Arylidene Ketones and Thiazolidene Hydrazines against Trypanosoma cruzi and Leishmania spp. Molecules. 2017; 22(5):709. https://doi.org/10.3390/molecules22050709
Chicago/Turabian StyleÁlvarez, Guzmán, Cintya Perdomo, Cathia Coronel, Elena Aguilera, Javier Varela, Gonzalo Aparicio, Flavio R. Zolessi, Nallely Cabrera, Celeste Vega, Miriam Rolón, and et al. 2017. "Multi-Anti-Parasitic Activity of Arylidene Ketones and Thiazolidene Hydrazines against Trypanosoma cruzi and Leishmania spp." Molecules 22, no. 5: 709. https://doi.org/10.3390/molecules22050709