A SAR and QSAR Study of New Artemisinin Compounds with Antimalarial Activity
Abstract
:1. Introduction
2. Results and Discussion
2.1. Optimization of the Geometry of Artemisinin in Different Methods and Basis Sets
Parameters [a] | Semiempirical | Hartree-Fock/HF | DFT/B3LYP | Experimental [f] | ||||||
---|---|---|---|---|---|---|---|---|---|---|
AM1 [b, c] | PM3 [b, c] | ZINDO [b, c] | 6-31G [b, c] | 6-31G* [b, c] | 6-31G** [d] | 3-21G [e] | 3-21G* [e] | 3-21G**[e] | ||
Bond Length (Å) | ||||||||||
O1O2 | 1.288 | 1.544 | 1.237 | 1.447 | 1.391 | 1.390 | 1.524 | 1.524 | 1.524 | 1.469 |
O2C3 | 1.447 | 1.403 | 1.400 | 1.435 | 1.393 | 1.396 | 1.455 | 1.455 | 1.454 | 1.416 |
C3O13 | 1.427 | 1.428 | 1.396 | 1.435 | 1.388 | 1.408 | 1.473 | 1.473 | 1.472 | 1.445 |
O13C12 | 1.416 | 1.403 | 1.392 | 1.403 | 1.400 | 1.376 | 1.430 | 1.430 | 1.430 | 1.379 |
C12C12a | 1.537 | 1.555 | 1.513 | 1.533 | 1.533 | 1.532 | 1.535 | 1.535 | 1.535 | 1.523 |
C12aO1 | 1.468 | 1.426 | 1.416 | 1.469 | 1.429 | 1.429 | 1.504 | 1.504 | 1.504 | 1.461 |
Bond Angle (°) | ||||||||||
O1O2C3 | 112.530 | 110.340 | 114.310 | 108.800 | 106.100 | 109.460 | 105.590 | 105.590 | 105.480 | 108.100 |
O2C3O13 | 103.600 | 104.810 | 105.370 | 106.760 | 110.800 | 107.800 | 108.220 | 108.220 | 108.250 | 106.600 |
C3O13C12 | 115.480 | 116.010 | 115.843 | 117.300 | 112.800 | 115.300 | 113.200 | 113.200 | 113.200 | 114.200 |
O13C12C12a | 113.510 | 115.200 | 113.270 | 112.280 | 108.700 | 112.300 | 113.300 | 113.300 | 113.230 | 114.500 |
C12C12aO1 | 111.070 | 113.180 | 107.290 | 110.910 | 110.500 | 110.545 | 112.410 | 112.410 | 112.470 | 110.700 |
C12aO1O2 | 113.740 | 112.290 | 118.380 | 113.240 | 112.700 | 112.700 | 109.620 | 109.620 | 109.590 | 111.200 |
Torsion Angle (°) | ||||||||||
O1O2C3O13 | −77.800 | −73.310 | −70.403 | −71.840 | −73.369 | −73.400 | −76.610 | −76.610 | −76.740 | −75.500 |
O2C3O13C12 | 42.070 | 52.700 | 36.370 | 33.390 | 31.034 | 31.100 | 33.750 | 33.750 | 33.720 | 36.000 |
C3O13C12C12a | 11.400 | 2.811 | 17.420 | 25.320 | 27.432 | 27.400 | 29.059 | 29.060 | 29.080 | 25.300 |
O13C12C12aO1 | −41.770 | −40.510 | −46.610 | −49.410 | −50.100 | −50.143 | −52.190 | −52.190 | −52.030 | −51.300 |
C12C12aO1O2 | 12.050 | 19.940 | 18.110 | 12.510 | 10.900 | 10.924 | 9.060 | 9.600 | 9.340 | 12.700 |
C12aO1O2C3 | 47.050 | 35.630 | 40.130 | 46.700 | 48.700 | 48.674 | 51.060 | 51.060 | 51.320 | 47.800 |
Standard Deviation | 4.776 | 8.388 | 4.372 | 1.663 | 2.484 | 1.762 | 1.915 | 1.855 | 1.987 | - |
2.2. Molecular Docking
Compounds | EComplex (Kcal mol−1) | Fe–O1 Distance (Å) | Fe–O2 Distance (Å) | Fe–O13 Distance (Å) | Fe–O11 Distance (Å) | logRA |
---|---|---|---|---|---|---|
1 | −6.06 | 2.542 | 3.684 | 5.153 | 5.525 | 0.00000 |
3 | −5.09 | 2.457 | 2.778 | 4.811 | 5.202 | 0.55376 |
4 | −6.54 | 2.555 | 3.201 | 4.982 | 5.448 | 0.34115 |
10 | −5.27 | 2.562 | 3.510 | 5.184 | 5.404 | 0.41754 |
11 | −5.37 | 2.616 | 3.684 | 5.300 | 5.364 | 0.02633 |
15 | −4.70 | 2.500 | 3.415 | 5.127 | 5.351 | 0.86031 |
16 | −5.53 | 2.310 | 2.760 | 4.874 | 4.897 | 0.30707 |
19 | −5.99 | 2.523 | 3.490 | 5.158 | 5.357 | 0.35423 |
20 | −5.03 | 2.727 | 3.808 | 5.434 | 5.475 | 0.02174 |
EComplex | 0.06551 | 0.01761 | 0.19250 | −0.20162 | 0.38917 | |
Fe–O1 | 0.84202 | 0.85273 | 0.83598 | −0.44984 | ||
Fe–O2 | 0.94792 | 0.81259 | −0.48039 | |||
Fe–O13 | 0.65135 | −0.48864 | ||||
Fe–O11 | −0.27755 |
2.3. Molecular Electrostatic Potential Maps
2.4. PCA Results
Compounds | HE | QO11 | RTe+ | D2 | logRA | RA | IC50 (ng/mL) |
---|---|---|---|---|---|---|---|
1+ | −2.820 | −0.605 | 0.105 | 120.868 | 0.00000 | 1.000000 | 0.6800 |
2− | −13.330 | −0.516 | 0.127 | 27.480 | −0.08130 | 0.829268 | 0.8200 |
3+ | −4.190 | −0.567 | 0.066 | −62.834 | 0.55376 | 3.578947 | 0.1900 |
4+ | −2.970 | −0.558 | 0.069 | 94.272 | 0.34115 | 2.193548 | 0.3100 |
5− | −26.220 | −0.558 | 0.079 | −143.766 | −2.40049 | 0.003977 | 171.0000 |
6− | −16.200 | −0.547 | 0.123 | −163.237 | −1.72137 | 0.018994 | 35.6000 |
7− | −16.640 | −0.517 | 0.135 | −158.396 | −1.69986 | 0.019959 | 34.0700 |
8− | −3.690 | −0.631 | 0.187 | 111.395 | −0.00634 | 0.985507 | 0.6900 |
9− | −5.670 | −0.676 | 0.126 | 113.465 | −0.00634 | 0.985507 | 0.6900 |
10+ | −1.680 | −0.599 | 0.100 | 13.716 | 0.41754 | 2.615385 | 0.2600 |
11+ | −3.330 | −0.662 | 0.080 | 124.375 | 0.02633 | 1.062500 | 0.6400 |
12− | −8.530 | −0.666 | 0.131 | 105.696 | −1.71943 | 0.019080 | 35.6400 |
13− | −8.210 | −0.648 | 0.132 | 138.353 | −1.07275 | 0.084577 | 8.0400 |
14− | −7.420 | −0.651 | 0.131 | 127.415 | −0.30737 | 0.492754 | 1.3800 |
15+ | −2.930 | −0.675 | 0.068 | −17.600 | 0.86031 | 7.249467 | 0.0938 |
16+ | −2.540 | −0.637 | 0.081 | 100.819 | 0.30707 | 2.028035 | 0.3353 |
17− | −6.900 | −0.754 | 0.150 | 95.974 | −0.57147 | 0.268245 | 2.5350 |
18− | −6.980 | −0.645 | 0.118 | 107.153 | −0.25768 | 0.552486 | 1.2308 |
19+ | −1.870 | −0.501 | 0.105 | 114.392 | 0.35423 | 2.260638 | 0.3008 |
20+ | −5.560 | −0.641 | 0.082 | 153.908 | 0.02174 | 1.051330 | 0.6468 |
21− | −11.120 | −0.651 | 0.141 | 10.910 | −0.70556 | 0.196987 | 3.4520 |
EH | −0.329 | −0.156 | 0.694 | 0.860 | - | - | |
QO11 | −0.203 | −0.509 | −0.127 | - | - | ||
RTe+ | 0.128 | −0.333 | - | - | |||
D2 | 0.485 | - | - |
Parameters | Main Component | ||
---|---|---|---|
PC1 | PC2 | PC3 | |
Variance (%) | 40.8865 | 22.7045 | 11.5660 |
Cumulative Variance (%) | 51.1081 | 79.4887 | 93.9461 |
Molecular Descriptors | Contribution | ||
PC1 | PC2 | ||
EH | 0.5705 | −0.3847 | |
QO11 | −0.5088 | −0.2987 | |
RTe+ | 0.0925 | 0.8731 | |
D2 | 0.6381 | −0.0207 |
2.5. HCA Results
2.6. Partial Least Squares (PLS) and Principal Component Regression (PCR) Results
Compounds | Predicted | Validation Error | Experimental | ||
---|---|---|---|---|---|
PLS | PCR | PLS | PCR | logRA | |
1+ | 0.2548 | 0.0902 | 0.2548 | 0.0902 | 0.0000 |
2− [a] | −1.0163 | −0.8805 | −0.935 | −0.7992 | −0.0813 |
3+ | −0.2855 | −0.6548 | −0.8392 | −1.2085 | 0.5537 |
4+ | 0.2199 | −0.1981 | −0.1212 | −0.5392 | 0.3411 |
5− | −2.1192 | −1.7899 | 0.2812 | 0.6105 | −2.4004 |
6− | −1.6837 | −1.4214 | 0.0376 | 0.2999 | −1.7213 |
7− | −1.8113 | −1.5164 | −0.1115 | 0.1834 | −1.6998 |
8− | −0.1174 | 0.2199 | −0.1111 | 0.2262 | −0.0063 |
9− | 0.0948 | 0.2284 | 0.1011 | 0.2347 | −0.0063 |
10+ | 0.0342 | −0.1872 | −0.3833 | −0.6047 | 0.4175 |
11+ | 0.4495 | 0.2485 | 0.4232 | 0.2222 | 0.0263 |
12− [a] | −0.1670 | 0.1032 | 1.5524 | 1.8226 | −1.7194 |
13− [a] | −0.0920 | 0.1144 | 0.9807 | 1.1871 | −1.0727 |
14− | −0.0583 | 0.1144 | 0.249 | 0.4217 | −0.3073 |
15+ | 0.1452 | −0.0974 | −0.7151 | −0.9577 | 0.8603 |
16+ | 0.3812 | 0.1289 | 0.0742 | −0.1781 | 0.3070 |
17− | 0.0203 | 0.4326 | 0.5917 | 1.004 | −0.5714 |
18− | −0.0448 | 0.0392 | 0.2128 | 0.2968 | −0.2576 |
19+ | 0.0888 | −0.2535 | −0.2654 | −0.6077 | 0.3542 |
20+ | 0.3283 | 0.1684 | 0.3066 | 0.1467 | 0.0217 |
21− | −0.6913 | −0.3463 | 0.0142 | 0.3592 | −0.7055 |
Test Set | EH | QO11 | RTe+ | D2 |
---|---|---|---|---|
22 | −3.460 | −0.663 | 0.076 | 7.585 |
23 | −3.370 | −0.664 | 0.077 | 141.065 |
24 | −4.790 | −0.556 | 0.069 | 130.453 |
25 | −5.780 | −0.675 | 0.077 | 98.153 |
26 | −8.070 | −0.603 | 0.076 | −76.018 |
27 | −4.650 | −0.602 | 0.073 | −4.170 |
28 | −7.440 | −0.575 | 0.066 | −9.051 |
29 | −15.920 | −0.482 | 0.100 | 73.480 |
30 | −4.470 | −0.594 | 0.070 | 125.875 |
31 | −15.240 | −0.601 | 0.106 | 9.276 |
32 | −4.500 | −0.532 | 0.063 | −37.529 |
33 | −13.680 | −0.578 | 0.126 | −83.125 |
34 | −4.550 | −0.572 | 0.071 | 8.222 |
35 | −13.620 | −0.523 | 0.121 | 32.018 |
36 | −4.280 | −0.584 | 0.071 | −27.718 |
37 | −2.740 | −0.650 | 0.105 | 152.098 |
38 | −2.850 | −0.673 | 0.081 | 101.819 |
39 | −2.680 | −0.603 | 0.068 | −13.617 |
40 | −3.290 | −0.577 | 0.064 | −65.438 |
41 | −10.210 | −0.615 | 0.122 | 10.190 |
42 | −7.044 | −0.557 | 0.062 | −13.671 |
43 | −7.841 | −0.654 | 0.131 | 127.514 |
44 | −2.910 | −0.657 | 0.072 | −25.670 |
45 | −2.870 | −0.670 | 0.069 | −19.115 |
46 | −7.020 | −0.745 | 0.155 | 95.479 |
47 | −4.240 | −0.600 | 0.066 | 122.578 |
48 | −8.120 | −0.684 | 0.123 | 131.353 |
49 | −8.350 | −0.665 | 0.134 | 105.669 |
50 | −5.676 | −0.667 | 0.126 | 113.564 |
51 | −3.640 | −0.636 | 0.067 | 7.855 |
Test Set Compounds | Predicted (logRA) | Residues of Prediction (PLS−PCR) | |
---|---|---|---|
PLS | PCR | ||
22 | 0.28515 | −0.08153 | 0.36669 |
23 | 0.16134 | 0.29643 | −0.13510 |
24 | −0.02669 | −0.17894 | 0.15225 |
25 | −0.13236 | 0.11823 | −0.25059 |
26 | −0.27509 | −0.71065 | 0.43556 |
27 | 0.13050 | −0.37989 | 0.51040 |
28 | −0.25528 | −0.60997 | 0.35469 |
29 | −1.52738 | −1.01052 | −0.51686 |
30 | 0.02281 | −0.04421 | 0.06701 |
31 | −1.36654 | −0.73626 | −0.63028 |
32 | 0.18562 | −0.72371 | 0.90933 |
33 | −1.05361 | −0.98490 | −0.06871 |
34 | 0.13185 | −0.44910 | 0.58095 |
35 | −1.16288 | −0.86252 | −0.30036 |
36 | 0.20640 | −0.49559 | 0.70198 |
37 | 0.23829 | 0.33770 | −0.09941 |
38 | 0.27428 | 0.24533 | 0.02895 |
39 | 0.41609 | −0.32859 | 0.74468 |
40 | 0.38362 | −0.59287 | 0.97649 |
41 | −0.66296 | −0.46071 | −0.20225 |
42 | −0.19509 | −0.67464 | 0.47955 |
43 | −0.45107 | 0.10809 | −0.55916 |
44 | 0.39618 | −0.17717 | 0.57335 |
45 | 0.39508 | −0.11549 | 0.51058 |
46 | −0.30336 | 0.40099 | −0.70434 |
47 | 0.05839 | −0.02784 | 0.08623 |
48 | −0.49407 | 0.20276 | −0.69682 |
49 | −0.50004 | 0.06913 | −0.56917 |
50 | −0.13357 | 0.19691 | −0.33048 |
51 | 0.25967 | −0.19372 | 0.45339 |
3. Experimental
3.1. Compounds Studied
3.2. Geometric Optimization and Descriptor Calculations
- (a)
- MOLECULAR DOCKING descriptors: These were calculated to better represent the interaction between the drug and receptor with the aid of the AutoDock 4.0 program. The following 17 molecular docking descriptors were included in the data matrix: binding energy (BE); partition function (Q), Gibbs free energy (G), internal energy (U), electrostatic energy (EE); bond length (Fe–O1, Fe–O2, Fe–O13 and Fe–O11), bond angle (O2–O1–Fe, O1–O2–Fe, C4–O1–Fe and C5a–O1–Fe); and dihedral angle (O2–O1–Fe–N1, O2–O1–Fe–N2, O2–O1–Fe–N3 and O2–O1–Fe–N4).
- (b)
- QUANTUM CHEMICAL descriptors: In our study, we calculated the following 25 quantum-chemical descriptors: total energy (ET), energy of the highest occupied molecular orbital (HOMO), a level below the energy of the highest occupied molecular orbital (HOMO-1), lowest unoccupied molecular orbital energy (LUMO), a level above the energy of the lowest unoccupied molecular orbital (LUMO + 1), difference in energy between HOMO and LUMO (GAP = HOMO-LUMO), Mulliken electronegativity (χ), molecular hardness (η), molecular softness (1/η), and charge on the atom n (where n = 1, 2, 3, 4, 5, 5a, 6, 7, 8, 8a, 9, 10, 11, 12, 12a, 13). The atomic charges used in this study were obtained with the key word POP = CHELPG using the electrostatic potential [68]. With this strategy, it was possible to obtain the best potential quantum molecular series of points defined around the molecule, and atomic charges offer the general advantage of being physically more satisfactory than Mulliken charges [69].
- (c)
- Descriptors related to quantitative properties of chemical structure and biological activity: In our data matrix, QSAR descriptors were included, i.e., total surface area (TSA), molecular volume (MV), molar refractivity (MR), molar polarizability (MP), coefficient of lipophilicity (logP), molecular mass (MM) and hydration energy (HE) according to the HyperChem 6.02 program. The molecular descriptors were selected to provide valuable information about the influence of electronic, steric, hydrophilic and hydrophobic features on the antimalarial activity of artemisinins.
3.3. Interaction between Artemisinins and Heme
3.4. Molecular Electrostatic Potential Maps
3.5. Variable Selection and Model Building
4. Conclusions
Acknowledgments
Conflicts of Interest
References
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Santos, C.B.R.; Vieira, J.B.; Lobato, C.C.; Hage-Melim, L.I.S.; Souto, R.N.P.; Lima, C.S.; Costa, E.V.M.; Brasil, D.S.B.; Macêdo, W.J.C.; Carvalho, J.C.T. A SAR and QSAR Study of New Artemisinin Compounds with Antimalarial Activity. Molecules 2014, 19, 367-399. https://doi.org/10.3390/molecules19010367
Santos CBR, Vieira JB, Lobato CC, Hage-Melim LIS, Souto RNP, Lima CS, Costa EVM, Brasil DSB, Macêdo WJC, Carvalho JCT. A SAR and QSAR Study of New Artemisinin Compounds with Antimalarial Activity. Molecules. 2014; 19(1):367-399. https://doi.org/10.3390/molecules19010367
Chicago/Turabian StyleSantos, Cleydson Breno R., Josinete B. Vieira, Cleison C. Lobato, Lorane I. S. Hage-Melim, Raimundo N. P. Souto, Clarissa S. Lima, Elizabeth V. M. Costa, Davi S. B. Brasil, Williams Jorge C. Macêdo, and José Carlos T. Carvalho. 2014. "A SAR and QSAR Study of New Artemisinin Compounds with Antimalarial Activity" Molecules 19, no. 1: 367-399. https://doi.org/10.3390/molecules19010367