Structure–Activity Relationship of Piplartine and Synthetic Analogues against Schistosoma mansoni and Cytotoxicity to Mammalian Cells
Abstract
:1. Introduction
2. Results
2.1. Theoretical Calculations and Ultraviolet–Visible Absorption Spectra
2.2. In Silico Studies Information
2.3. Cytotoxicity Assay
2.4. In Vitro Experiments in Adult Worms of S. mansoni
3. Discussion
4. Materials and Methods
4.1. Piplartine and Synthetic Analogues
4.2. Theoretical Calculations
4.3. UV–Vis Absorption Spectra
4.4. In Silico Physicochemical and Toxicity Studies
4.5. Cytotoxicity Assay
4.5.1. NIH3T3 and J774A.1 Cell Culture
4.5.2. Cell Viability Assays
4.6. Animals and Parasites
4.7. Adult Schistosomes
4.8. In Vitro Experiments with Adult Worms of S. mansoni
4.9. Statistical Analysis
5. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Abbreviations
DMSO | Dimethyl sulfoxide |
THF | Tetrahydrofuran |
DCC | Dicyclohexylcarbodiimide |
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Compounds | Piplartine | 19A | 14B | 6B | 1M | 1G |
---|---|---|---|---|---|---|
Basic properties | ||||||
Atom count | 40 | 51 | 31 | 48 | 56 | 38 |
Mw | 315.32 | 287.31 | 432.48 | 387.39 | 239.27 | 359.42 |
Structural properties | ||||||
Asymmetric atom count | 0 | 0 | 0 | 0 | 0 | 0 |
Rotatable bond count | 5 | 6 | 2 | 5 | 7 | 5 |
Ring count | 2 | 2 | 3 | 3 | 3 | 2 |
Aromatic ring count | 2 | 1 | 2 | 3 | 3 | 2 |
Hetero ring count | 1 | 1 | 2 | 0 | 0 | 1 |
Hydrogen bond donor count | 0 | 0 | 0 | 3 | 1 | 0 |
Hydrogen bond acceptor count | 5 | 5 | 2 | 5 | 5 | 4 |
Formal charge | 0 | 0 | 0 | 0 | 0 | 0 |
Fsp3 (a) | 0.18 | 0.40 | 0.13 | 0.00 | 0.12 | 0.19 |
Topological polar surface area (A2) | 65.07 | 65.07 | 31.23 | 93.11 | 77.10 | 49.69 |
Molar refractivity cm3/mol | 87.42 | 101.15 | 70.63 | 112.82 | 123.64 | 79.89 |
Polarisability (A3) | 32.54 | 38.29 | 26.66 | 41.46 | 46.66 | 30.59 |
Solubility parameters | ||||||
logP | 1.89 | 2.71 | 2.36 | 3.55 | 4.63 | 2.26 |
Milogp(b) | 2.19 | 2.78 | 4.69 | 5.02 | 2.86 | 2.90 |
logD pH range 1.7–8.0 | 1.89 | 2.71 | 2.36 | 3.54 | 4.63 | 2.26 |
Intrinsic solubility | −3.01 | −4.53 | −2.87 | −4.73 | −5.48 | −2.81 |
Solubility category | High | Moderate | High | Low | Low | High |
logS pH range 1.7–8.0 | −3.01 | −4.53 | −2.87 | −4.73 | −5.48 | −2.81 |
Geometry parameters | ||||||
Van der Waals volume (Å3) | 281.06 | 337.61 | 213.99 | 341.62 | 390.54 | 260.80 |
Volume (Å3) (b) | 282.84 | 263.86 | 394.07 | 340.76 | 218.97 | 339.43 |
Van der Waals surface area (Å2) | 425.62 | 543.27 | 333.75 | 515.78 | 620.14 | 423.69 |
Solvent accessible surface area (Å2) | 549.15 | 659.24 | 445.82 | 631.17 | 725.57 | 577.96 |
Topological polar surface area (Å2) | 65.07 | 65.07 | 31.2 | 93.11 | 77.10 | 49.69 |
Absorbance | 322 nm | 329 nm | 321 nm | 312 nm | 306.5 nm | 301.5 nm |
Compounds | Piplartine | 19A | 14B | 6B | 1M | 1G | |||
---|---|---|---|---|---|---|---|---|---|
Toxicity prediction (c) | |||||||||
AMES toxicity | Yes | No | No | No | No | No | |||
Max. tolerated dose (human) (0.505 log mg/kg/day) | 1.006 | 0.677 | 1.043 | 1.095 | 1.051 | 1.114 | |||
hERG I inhibitor | No | No | No | No | No | No | |||
hERG II inhibitor | No | No | No | Yes | Yes | No | |||
Oral Rat Acute Toxicity (LD50) (2.661 mol/kg) | 2.268 | 2.295 | 2.413 | 2.195 | 2.37 | 2.389 | |||
Oral Rat Chronic Toxicity (LOAEL) (3.402 log mg/kg bw/day) | 1.64 | 1.787 | 1.812 | 2.455 | 2.388 | 1.592 | |||
Hepatotoxicity | No | Yes | No | Yes | Yes | No | |||
Skin sensitisation | No | No | No | No | No | No | |||
T. pyriformis toxicity (0.285 × log µg/L) | 1.138 | 1.359 | 2.004 | 0.437 | 0.658 | 1.591 | |||
Minnow toxicity (5.577 × log mM) | 1.293 | 0.446 | 1.179 | −0.172 | −0.914 | 1.027 | |||
Predictive bioactivity (b) | |||||||||
GPCR ligand | 0.13 | 0.17 | 0.07 | −0.11 | −0.04 | −0.15 | |||
Ion channel modulator | −0.51 | −0.16 | −0.53 | −0.27 | −0.29 | −0.54 | |||
Kinase inhibitor | −0.13 | −0.12 | −0.13 | −0.20 | −0.09 | −0.14 | |||
Nuclear receptor ligand | −0.32 | −0.07 | −0.12 | −0.31 | −0.30 | −0.31 | |||
Protease inhibitor | −0.40 | 0.02 | −0.39 | −0.38 | −0.33 | −0.48 | |||
Enzyme inhibitor | −0.02 | 0.05 | 0.24 | −0.17 | −0.12 | −0.00 |
Compounds | pD2 (−logIC50) a | Emax (%) b |
---|---|---|
19A | −3.06 ± 0.15 | 37.93 ± 2.85 |
1G | −2.00 ± 0.03 | 95.69 ± 0.79 |
1M | −2.31 ± 0.04 | 70.94 ± 1.20 |
14B | −1.95 ± 0.04 | 83.64 ± 0.47 |
6B | −2.80 ± 0.08 | 47.93 ± 2.52 |
Piplartine | 5.68 ± 2.95 | 96.94 ± 0.12 |
Group | Period of Incubation (h) | Dead Worms (%) a | Motor Activity Reduction (%) a | ||||
---|---|---|---|---|---|---|---|
Slight | Significant | ||||||
M | F | M | F | M | F | ||
Control b | 24 | 0 | 0 | 0 | 0 | 0 | 0 |
48 | 0 | 0 | 0 | 0 | 0 | 0 | |
72 | 0 | 0 | 0 | 0 | 0 | 0 | |
96 | 0 | 0 | 0 | 0 | 0 | 0 | |
0.5% DMSO | 24 | 0 | 0 | 0 | 0 | 0 | 0 |
48 | 0 | 0 | 0 | 0 | 0 | 0 | |
72 | 0 | 0 | 0 | 0 | 0 | 0 | |
96 | 0 | 0 | 0 | 0 | 0 | 0 | |
Praziquantel | 24 | 100 | 100 | 0 | 0 | 100 | 100 |
2 µM | 48 | 100 | 100 | 0 | 0 | 100 | 100 |
72 | 100 | 100 | 0 | 0 | 100 | 100 | |
96 | 100 | 100 | 0 | 0 | 100 | 100 | |
Amide piplartine | 24 | 100 | 100 | 0 | 0 | 100 | 100 |
10 µM | 48 | 100 | 100 | 0 | 0 | 100 | 100 |
5 µM | 72 | 100 | 100 | 0 | 0 | 100 | 100 |
96 | 100 | 100 | 0 | 0 | 100 | 100 | |
24 | 0 | 0 | 100 | 100 | 0 | 0 | |
48 | 0 | 0 | 100 | 100 | 0 | 0 | |
72 | 0 | 0 | 100 | 100 | 0 | 0 | |
96 | 60 | 60 | 0 | 0 | 60 | 60 |
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Campelo, Y.; Ombredane, A.; Vasconcelos, A.G.; Albuquerque, L.; Moreira, D.C.; Plácido, A.; Rocha, J.; Hilarion Fokoue, H.; Yamaguchi, L.; Mafud, A.; et al. Structure–Activity Relationship of Piplartine and Synthetic Analogues against Schistosoma mansoni and Cytotoxicity to Mammalian Cells. Int. J. Mol. Sci. 2018, 19, 1802. https://doi.org/10.3390/ijms19061802
Campelo Y, Ombredane A, Vasconcelos AG, Albuquerque L, Moreira DC, Plácido A, Rocha J, Hilarion Fokoue H, Yamaguchi L, Mafud A, et al. Structure–Activity Relationship of Piplartine and Synthetic Analogues against Schistosoma mansoni and Cytotoxicity to Mammalian Cells. International Journal of Molecular Sciences. 2018; 19(6):1802. https://doi.org/10.3390/ijms19061802
Chicago/Turabian StyleCampelo, Yuri, Alicia Ombredane, Andreanne G. Vasconcelos, Lucas Albuquerque, Daniel C. Moreira, Alexandra Plácido, Jefferson Rocha, Harold Hilarion Fokoue, Lydia Yamaguchi, Ana Mafud, and et al. 2018. "Structure–Activity Relationship of Piplartine and Synthetic Analogues against Schistosoma mansoni and Cytotoxicity to Mammalian Cells" International Journal of Molecular Sciences 19, no. 6: 1802. https://doi.org/10.3390/ijms19061802