Evaluation of Novel Chalcone-Thiosemicarbazones Derivatives as Potential Anti-Leishmania amazonensis Agents and Its HSA Binding Studies
Abstract
:1. Introduction
2. Materials and Methods
2.1. Organic Synthesis
2.1.1. Chemicals and Instruments
2.1.2. (2E)-3-(4-X-phenyl)-1-phenylprop-2-en-1-one (3a–g)
2.1.3. General Procedure for the Preparation of the (1E,2E)-3-(4-X-phenyl)-1-phenylprop-2-en-1-one Thiosemicarbazones (5a–g)
(1E,2E)-3-(phenyl)-1-phenylprop-2-en-1-one thiosemicarbazone (5a)
(1E,2E)-3-(4′-methylphenyl)-1-phenylprop-2-en-1-one thiosemicarbazone (5b)
(1E,2E)-3-(4′-cyanophenyl)-1-phenylprop-2-en-1-one thiosemicarbazone (5c)
(1E,2E)-3-(4′-fluorphenyl)-1-phenylprop-2-en-1-one thiosemicarbazone (5d)
(1E,2E)-3-(4′-chlorophenyl)-1-phenylprop-2-en-1-one thiosemicarbazone (5e)
(1E,2E)-3-(4′-bromophenyl)-1-phenylprop-2-en-1-one thiosemicarbazone (5f)
(1E,2E)-3-(4′-nitrophenyl)-1-phenylprop-2-en-1-one thiosemicarbazone (5g)
2.2. Biologic Assays
2.2.1. Chemicals
2.2.2. Parasite Cultures
2.2.3. Promastigote Assays
2.2.4. Macrophage Cytotoxicity
2.2.5. Intracellular Amastigotes Assays
2.2.6. Axenic Amastigotes Assays
2.2.7. Statistical Analysis
2.3. HSA Binding Studies
2.3.1. Spectroscopic Analysis
2.3.2. Molecular Docking Analysis for the Interaction HSA:5e
3. Results and Discussion
3.1. Synthesis of Chalcone-Thiosemicarbazones
3.2. Anti-Leishmanial Effects
3.3. Evaluation on the Interaction between HSA and 5e
3.4. Evaluation on the Microenvironment and Structure of HSA upon 5e Binding
3.5. Molecular Docking Analysis for HSA:5e
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Compound | Promastigotes IC50 a (µM) | Axenic Amastigotes IC50 (µM) | Intracellular Amastigotes IC50 (µM) | Macrophages LD50 b (µM) | Selectivity Index (SI) |
---|---|---|---|---|---|
5a | 14.68 ± 0.31 | 6.88 ± 1.09 | 3.40 ± 0.28 | 40.98 ± 1.12 | 15.05 |
5b | 14.80 ± 1.92 | 7.08 ± 1.03 | 5.95 ± 0.61 | 56.35 ± 0.78 | 9.47 |
5c | n.a. c | n.d. d | n.d. | n.d. | − |
5d | 13.09 ± 1.85 | 5.57 ± 1.15 | > 3.13 | 35.47 ± 1.38 | − |
5e | 5.22 ± 0.75 | 3.19 ± 1.20 | 4.47 ± 0.42 | 32.48 ± 1.81 | 7.27 |
5f | 12.52 ± 0.99 | 4.24 ± 1.07 | 3.88 ± 0.24 | 44.24 ± 4.21 | 11.40 |
5g | n.a. | n.d. | n.d. | n.d. | − |
Pentamidine | 4.90 ± 0.60 | 12.29 ± 1.17 | 11.12 ± 1.98 | 25.85 ± 4.06 | 2.32 |
Compound | 4-X | σp a | Es b | MR b | π b |
---|---|---|---|---|---|
5a | H | 0.00 | 0.00 | 0.00 | 0.00 |
5b | CH3 | −0.14 | −0.25 | 0.57 | 0.56 |
5c | CN | 0.71 | −0.51 | 0.63 | −0.57 |
5d | F | 0.15 | −0.46 | 0.10 | 0.14 |
5e | Cl | 0.34 | −0.97 | 0.60 | 0.71 |
5f | Br | 0.26 | −1.16 | 0.89 | 0.86 |
5g | NO2 | 0.81 | −1.01 | 0.74 | −0.28 |
T (K) | KSV (×104) (M−1) a | kq (×1012) (M−1s−1) a | Ka (×104) (M−1) b | nb | ΔH° (kJmol−1) c | ΔS° (×10−2) (kJmol−1K−1) c | ΔG° (kJmol−1) c |
---|---|---|---|---|---|---|---|
289 | 2.48 ± 0.52 | 4.15 | 5.16 ± 0.04 | 1.05 ± 0.01 | −5.79 ± 0.27 | 7.02 ± 0.09 | −26.1 |
296 | 2.49 ± 0.50 | 4.16 | 4.85 ± 0.06 | 1.07 ± 0.01 | −26.6 | ||
303 | 2.59 ± 0.51 | 4.34 | 4.57 ± 0.06 | 1.06 ± 0.01 | −27.1 | ||
310 | 2.75 ± 0.33 | 4.60 | 4.39 ± 0.04 | 1.05 ± 0.01 | −27.6 |
Sites | Amino Acid Residues | Interaction | Distance (Å) |
---|---|---|---|
Phe-210 | Van der Waals | 2.60 | |
Trp-214 | Van der Waals | 3.00 | |
Ser-201 | Hydrogen bonding | 2.80 | |
I | His-241 | Van der Waals | 3.60 |
Val-343 | Van der Waals | 3.50 | |
Leu-346 | Van der Waals | 2.40 | |
Leu-480 | Van der Waals | 2.70 | |
Val-481 | Van der Waals | 2.70 | |
Leu-386 | Van der Waals | 3.20 | |
Lys-413 | Van der Waals | 3.10 | |
Val-414 | Van der Waals | 2.90 | |
II | Val-425 | Van der Waals | 2.20 |
Leu-429 | Van der Waals | 2.90 | |
Leu-452 | Van der Waals | 3.60 | |
Ser-488 | Hydrogen bonding | 1.80 | |
Arg-113 | Hydrogen bonding | 3.30 | |
Leu-114 | Van der Waals | 2.40 | |
Arg-116 | Van der Waals | 2.40 | |
III | Tyr-137 | Van der Waals | 2.40 |
Ile-141 | Van der Waals | 2.70 | |
Phe-156 | Van der Waals | 3.70 | |
Arg-185 | Hydrogen bonding | 3.80 |
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Mendes, E.P.; Goulart, C.M.; Chaves, O.A.; Faiões, V.d.S.; Canto-Carvalho, M.M.; Machado, G.C.; Torres-Santos, E.C.; Echevarria, A. Evaluation of Novel Chalcone-Thiosemicarbazones Derivatives as Potential Anti-Leishmania amazonensis Agents and Its HSA Binding Studies. Biomolecules 2019, 9, 643. https://doi.org/10.3390/biom9110643
Mendes EP, Goulart CM, Chaves OA, Faiões VdS, Canto-Carvalho MM, Machado GC, Torres-Santos EC, Echevarria A. Evaluation of Novel Chalcone-Thiosemicarbazones Derivatives as Potential Anti-Leishmania amazonensis Agents and Its HSA Binding Studies. Biomolecules. 2019; 9(11):643. https://doi.org/10.3390/biom9110643
Chicago/Turabian StyleMendes, Edinéia Pastro, Carla Marins Goulart, Otávio Augusto Chaves, Viviane dos S. Faiões, Marilene M. Canto-Carvalho, Gerzia C. Machado, Eduardo Caio Torres-Santos, and Aurea Echevarria. 2019. "Evaluation of Novel Chalcone-Thiosemicarbazones Derivatives as Potential Anti-Leishmania amazonensis Agents and Its HSA Binding Studies" Biomolecules 9, no. 11: 643. https://doi.org/10.3390/biom9110643