Quantitative Structure ‒ Antiprotozoal Activity Relationships of Sesquiterpene Lactones
Abstract
:1. Introduction
2. Results and Discussion
2.1. Biological Activity Data and Activity-Activity Relationships
Compound | T. brucei rhodes. (Tbr) | T. cruzi(Tcr) | L. donovani(Ldon) | P. falciparum(Pfc) | Cytotoxicity (L6) |
---|---|---|---|---|---|
1 | 0.052 | 0.695 | n.t. | n.t. | 0.992 |
2 | 0.063 | 0.538 | 0.446 | 0.329 | 0.809 |
3 | 0.105 | 1.568 | 0.837 | 0.700 | 1.030 |
4 | 0.116 | 2.478 | 0.871 | 0.822 | 1.298 |
5 | 0.686 | 21.477 | 3.848 | 3.047 | 8.902 |
6 | 1.415 | 6.928 | >4* | n.t. | 3.056 |
7 | 0.911 | 3.534 | 1.476 | 1.603 | 4.583 |
8 | 0.319 | 1.870 | >4* | n.t. | 2.443 |
9 | 9.275 | 45.833 | n.t. | n.t. | 12.284 |
10 | 6.705 | 20.422 | 12.240 | 6.461 | 4.392 |
11 | 18.346 | 52.744 | 20.602 | 12.143 | 31.917 |
12 | 10.951 | 49.176 | 17.967 | 10.604 | 16.676 |
13 | 19.242 | 60.165 | 14.505 | 27.473 | 31.758 |
14 | 1.174 | 14.657 | 4.257 | 8.943 | 8.429 |
15 | 3.961 | 16.311 | 8.675 | 5.984 | 7.281 |
16 | 13.607 | 44.891 | 11.831 | 10.656 | 21.557 |
17 | 62.081 | >120* | 23.831 | >20* | 178.790 |
18 | 2.919 | 26.220 | 17.642 | 7.825 | 30.203 |
19 | 0.330 | 11.260 | 0.599 | 6.511 | 22.137 |
20 | 15.887 | 38.992 | 14.597 | 12.702 | 19.839 |
21 | 0.638 | 16.083 | 22.047 | 4.961 | 9.429 |
22 | 1.288 | 95.420 | 26.908 | 6.527 | 13.282 |
23 | 162.200 | >120* | 15.400 | >20* | >365* |
24 | 8.205 | >120* | 27.051 | >20* | 427.350 |
25 | 23.621 | 22.263 | >14* | n.t. | 4.483 |
26 | 7.802 | 24.778 | >4* | n.t. | 0.948 |
27 | 10.724 | 24.345 | 11.759 | 9.207 | 8.914 |
28 | 341.480 | >120* | >120* | >20* | 187.120 |
29 | 2.625 | 8.297 | 3.030 | 6.401 | 5.991 |
30 | 1.602 | 17.256 | 8.699 | 10.691 | 10.183 |
31 | 17.806 | 28.911 | 6.008 | 12.056 | 33.185 |
32 | 1.107 | 26.210 | 7.339 | 13.629 | 25.565 |
33 | 1.303 | 16.799 | 15.212 | 6.323 | 10.212 |
34 | 0.388 | 10.665 | 3.556 | 11.895 | 7.238 |
35 | 49.000 | >120* | 35.560 | >20* | 132.600 |
36 | 14.283 | 25.582 | 2.726 | 9.444 | 13.624 |
37 | 0.478 | 15.786 | 5.190 | 6.333 | 7.750 |
38 | 0.942 | 16.492 | 18.204 | 8.812 | 12.970 |
39 | 0.804 | 17.574 | 30.074 | 8.069 | 10.099 |
40 | 0.698 | 11.833 | 17.095 | 6.643 | 6.667 |
pos. control | 0.008a | 2.000b | 0.270c | 0.248d | 0.012e |
T. b. rhod. | T.cruzi | L. donov. | P. falcip. | L6 cytotox. | |
---|---|---|---|---|---|
T. b. rhod. | 1.000 | ||||
T.cruzi | 0.851 | 1.000 | |||
L. donov. | 0.704 | 0.823 | 1.000 | ||
P. falcip. | 0.808 | 0.912 | 0.753 | 1.000 | |
L6 cytotox. | 0.698 | 0.857 | 0.697 | 0.905 | 1.000 |
2.2. Structure-activity relationships, QSAR
Model | n var.a | n comp.b | n PCsc | R2 | Q2 | ||
---|---|---|---|---|---|---|---|
Tbr | L6 | Tbr | L6 | ||||
1 | 44 | 40 | 7 | 0.83 | 0.91 | 0.52 | 0.41 |
2 | 44 | 39* | 4 | 0.81 | 0.82 | 0.66 | 0.61 |
3 | 20 | 39* | 3 | 0.80 | 0.81 | 0.71 | 0.71 |
3. Conclusions
4. Experimental
4.1. Test compounds
4.2. In vitro assays and IC50 determination
4.3. Computational Methods
1 | ENONCS | accessible surface area of beta carbons in α,β-unsaturated carbonyl structures |
2 | ENONS | accessible surface area of α,β-unsaturated carbonyl structures |
2 | AM1_HOMO | Eigenvalue of highest occupied molecular orbital (MOE/MOPAC/AM1) |
4 | AM1_HOMO1 | Eigenvalue of second highest occupied molecular orbital (MOE/MOPAC/AM1) |
5 | AM1_HOMO2 | Eigenvalue of third highest occupied molecular orbital (MOE/MOPAC/AM1) |
6 | AM1_HOMO3 | Eigenvalue of fourth highest occupied molecular orbital (MOE/MOPAC/AM1) |
7 | AM1_LUMO | Eigenvalue of lowest unoccupied molecular orbital (MOE/MOPAC/AM1) |
8 | AM1_LUMO1 | Eigenvalue of second lowest unoccupied molecular orbital (MOE/MOPAC/AM1) |
9 | AM1_LUMO2 | Eigenvalue of third lowest unoccupied molecular orbital (MOE/MOPAC/AM1) |
10 | AM1_LUMO3 | Eigenvalue of fourth lowest unoccupied molecular orbital (MOE/MOPAC/AM1) |
11 | AM1_dipole | Dipole moment calculated with MOE/MOPAC/AM1 |
12 | ASA | solvent accessible molecular surface area [11] |
13 | ASA+ | solvent accessible molecular surface area due to atoms with positive parial charge [11] |
14 | ASA- | solvent accessible molecular surface area due to atoms with negative parial charge [11] |
15 | ASA_H | solvent accessible molecular surface area due to atoms with hydrophobic properties [11] |
16 | ASA_P | solvent accessible molecular surface area due to atoms with polar properties [11] |
17 | FASA+ | fractional solvent accessible molecular surface area calculated as ASA+/ASA [11] |
18 | FASA- | fractional solvent accessible molecular surface area calculated as ASA-/ASA [11] |
19 | FASA_H | fractional solvent accessible molecular surface area calculated as ASA_H/ASA [11] |
20 | FASA_P | fractional solvent accessible molecular surface area calculated as ASA_P/ASA [11] |
21 | FCASA+ | Positive charge weighted surface area, ASA+ * maximum positive partial charge [11] |
22 | FCASA- | Negative charge weighted surface area, ASA- * maximum negative partial charge [11] |
23 | glob | globularity [11] |
24 | std_dim1 | largest standardized dimension [11] |
25 | std_dim2 | second largest standardized dimension [11] |
26 | std_dim3 | third largest standardized dimension [11] |
27 | logS | log of calculated water solubility [11] |
28 | E_sol | solvation Energy [11] |
29 | logP(o/w) | log of calculated octanol/water partition coefficient [11] |
30 | SlogP | log of calculated octanol/water partition coefficient [11] |
31 | ASAN1 | fractional accessible surface area due to atoms in partial charge interval 0 to -0.05 e [7] |
32 | ASAN2 | fractional accessible surface area due to atoms in partial charge interval -0.05 to -0.1 e [7] |
33 | ASAN3 | fractional accessible surface area due to atoms in partial charge interval -0.1 to -0.15 e [7] |
34 | ASAN4 | fractional accessible surface area due to atoms in partial charge interval -0.15 to -0.2 e [7] |
35 | ASAN5 | fractional accessible surface area due to atoms in partial charge interval -0.2 to -0.25 e [7] |
36 | ASAN6 | fractional accessible surface area due to atoms in partial charge interval -0.25 to -0.3 e [7] |
37 | ASAN7 | fractional accessible surface area due to atoms in partial charge interval <-0.30 e [7] |
38 | ASAP1 | fractional accessible surface area due to atoms in partial charge interval 0 to 0.05 e [7] |
39 | ASAP2 | fractional accessible surface area due to atoms in partial charge interval 0.05 to 0.1 e [7] |
40 | ASAP3 | fractional accessible surface area due to atoms in partial charge interval 0.1 to 0.15 e [7] |
41 | ASAP4 | fractional accessible surface area due to atoms in partial charge interval 0.15 to 0.2 e [7] |
42 | ASAP5 | fractional accessible surface area due to atoms in partial charge interval 0.2 to 0.25 e [7] |
43 | ASAP6 | fractional accessible surface area due to atoms in partial charge interval 0.25 to 0.3 e [7] |
44 | ASAP7 | fractional accessible surface area due to atoms in partial charge interval >0.3 e [7] |
Acknowledgements
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Schmidt, T.J.; Nour, A.M.M.; Khalid, S.A.; Kaiser, M.; Brun, R. Quantitative Structure ‒ Antiprotozoal Activity Relationships of Sesquiterpene Lactones. Molecules 2009, 14, 2062-2076. https://doi.org/10.3390/molecules14062062
Schmidt TJ, Nour AMM, Khalid SA, Kaiser M, Brun R. Quantitative Structure ‒ Antiprotozoal Activity Relationships of Sesquiterpene Lactones. Molecules. 2009; 14(6):2062-2076. https://doi.org/10.3390/molecules14062062
Chicago/Turabian StyleSchmidt, Thomas J., Amal M. M. Nour, Sami A. Khalid, Marcel Kaiser, and Reto Brun. 2009. "Quantitative Structure ‒ Antiprotozoal Activity Relationships of Sesquiterpene Lactones" Molecules 14, no. 6: 2062-2076. https://doi.org/10.3390/molecules14062062