Synthesis and Acaricidal Activities of Scopoletin Phenolic Ether Derivatives: QSAR, Molecular Docking Study and in Silico ADME Predictions
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Acaricidal Activity
2.3. QSAR Analysis
2.3.1. 2D-QSAR Analysis
2.3.2. 3D-QSAR Analysis
2.4. Molecular Docking
2.5. ADME Study
3. Materials and Methods
3.1. General Information
3.2. Chemistry
3.2.1. Procedure for the Synthesis of Scopoletin (4)
3.2.2. General Procedure for the Synthesis of 8–13 and 18–25
3.2.3. General Procedure for the Synthesis of 14–17
3.2.4. General Procedure for the Synthesis of 26–37
3.3. Acaricidal Activity Assay
3.4. 2D- and 3D-QSAR Study
3.4.1. Data Set
3.4.2. 2D-QSAR (Multiple Linear Regression Model) Method
3.4.3. 3D-QSAR (CoMFA and CoMSIA) Methods
3.5. Molecular Docking
3.6. In Silico ADME Prediction
4. Conclusions
Supplementary Materials
Author Contributions
Acknowledgments
Conflicts of Interest
References
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Sample Availability: Samples of the compounds 4, and 8–37 are available from the authors. |
Compounds | R | LC50 (mmol/L) | pLC50 (mol/L) | χ2 | P |
---|---|---|---|---|---|
8 | methyl | 0.829 ± 0.169 | 3.0813 | 1.678 | 0.642 |
9 | ethyl | 0.840 ± 0.184 | 3.0757 | 4.958 | 0.175 |
10 | n-propyl | 2.326 ± 0.522 | 2.6333 | 2.125 | 0.547 |
11 | isopropyl | 1.767 ± 0.254 | 2.7527 | 1.187 | 0.756 |
12 | n-butyl | 1.253 ± 0.292 | 2.9022 | 4.875 | 0.181 |
13 | isobutyl | 3.021 ± 0.410 | 2.5199 | 1.633 | 0.652 |
14 | methyl cyclopropane | 2.875 ± 0.579 | 2.5414 | 1.929 | 0.587 |
15 | cyclopentyl | 6.588 ± 0.929 | 2.1812 | 0.114 | 0.990 |
16 | cyclohexyl | 2.464 ± 0.549 | 2.6083 | 1.008 | 0.799 |
17 | methyl cyclohexane | 3.586 ± 0.743 | 2.4454 | 2.495 | 0.476 |
18 | benzyl | 2.557 ± 0.363 | 2.5922 | 3.133 | 0.372 |
19 | 4-CH3- benzyl | 3.196 ± 0.808 | 2.4954 | 3.418 | 0.332 |
20 | 4-C(CH3)-benzyl | 0.753 ± 0.105 | 3.1229 | 3.475 | 0.324 |
21 | 4-NO2-benzyl | 1.686 ± 0.412 | 2.7730 | 1.929 | 0.587 |
22 | 3,4-2Cl-benzyl | 1.652 ± 0.222 | 2.7821 | 2.889 | 0.409 |
23 | 4-Cl-benzyl | 4.208 ± 0.872 | 2.3759 | 0.497 | 0.919 |
24 | 4-CF3-benzyl | 1.139 ± 0.218 | 2.9435 | 5.571 | 0.134 |
25 | 4-OCF3-benzyl | 2.853 ± 0.560 | 2.5447 | 0.567 | 0.904 |
26 | methyl | 2.541 ± 0.467 | 2.5950 | 3.990 | 0.263 |
27 | ethyl | 0.815 ± 0.230 | 3.0888 | 5.424 | 0.143 |
28 | n-propyl | 0.762 ± 0.0937 | 3.1180 | 3.764 | 0.288 |
29 | isopropyl | 3.045 ± 0.799 | 2.5165 | 2.416 | 0.491 |
30 | n-butyl | 1.015 ± 0.262 | 2.9935 | 1.689 | 0.639 |
31 | benzyl | 1.134 ± 0.1149 | 2.9452 | 2.428 | 0.297 |
32 | 3-Cl-benzyl | 0.655 ± 0.2539 | 3.1835 | 2.280 | 0.516 |
33 | 4-Cl-benzyl | 0.848 ± 0.1359 | 3.0716 | 2.642 | 0.45 |
34 | 3,4-2Cl-benzyl | 0.963 ± 0.2437 | 3. 0165 | 1.208 | 0.598 |
35 | 4-CH3-benzyl | 1.774 ± 0.3783 | 2.7510 | 1.330 | 0.722 |
36 | 4-OCH3-benzyl | 1.516 ± 0.2618 | 2.8193 | 0.062 | 0.996 |
37 | 4-C(CH3)-benzyl | 3.601 ± 0.4786 | 2.4436 | 3.129 | 0.209 |
Scopoletin | — | 5.510 ± 1.553 | 2.2588 | 0.416 | 0.937 |
Propargite | — | 0.953 ± 0.1093 | 3.0209 | 4.034 | 0.258 |
Stages of T. cinnabarinus | LC50 (mmol/L) | pLC50 (mol/L) | χ2 | P |
---|---|---|---|---|
Eggs | Non-ovicidal | — | — | — |
Larva | 0.679 ± 0.2066 | 3.1682 | 3.268 | 0.195 |
Nymph | 3.889 ± 1.059 | 2.4101 | 5.177 | 0.075 |
Descriptor | Chemical Meaning | Type | Sig. | t | VIF |
---|---|---|---|---|---|
constant | Intercept | 0.000 | 6.026 | ||
R8e | R autocorrelation of lag 8/weighted by Sanderson electronegativity | GETAWAY descriptor | 0.000 | −4.787 | 1.314 |
HATS5p | Leverage-weighted autocorrelation of lag5/weighted by polarizability | GETAWAY descriptor | 0.000 | 6.725 | 1.479 |
Depressant-80 | Ghose-Viswanadhan-Wendoloski antidepressant-like index at 80% | Drug-like indices | 0.000 | 5.061 | 1.605 |
MATS6e | Moran autocorrelation of lag 6 weighted by Sanderson electonegativity | 2D autocorrelations | 0.002 | −3.514 | 1.032 |
HNar | Narumi harmonic topological index | Topological indices | 0.005 | −3.178 | 1.439 |
R8e | HATS5p | Depressant-80 | MATS6e | HNar | |
---|---|---|---|---|---|
R8e | 1 | −0.314 | 0.165 | −0.023 | 0.391 |
HATS5p | −0.314 | 1 | −0.494 | −0.080 | −0.141 |
Depressant-80 | 0.165 | −0.494 | 1 | 0.099 | 0.398 |
MATS6e | −0.023 | −0.080 | 0.099 | 1 | −0.092 |
HNar | 0.391 | −0.141 | 0.398 | −0.092 | 1 |
Compounds | R8e | HATS-5p | Depressant-80 | MATS-6e | HNar | Experimental Activity | Prediced Activity | Residual |
---|---|---|---|---|---|---|---|---|
8 | 0.384 | 0.118 | 0 | −0.02 | 1.837 | 3.0813 | 3.0281 | 0.0532 |
9 | 0.706 | 0.146 | 0 | −0.03 | 1.846 | 3.0757 | 3.0818 | −0.0061 |
10 | 0.749 | 0.116 | 0 | −0.043 | 1.855 | 2.6333 | 2.6575 | −0.0242 |
11 | 0.919 | 0.117 | 0 | −0.043 | 1.789 | 2.7527 | 2.5732 | 0.1795 |
12 | 0.81 | 0.117 | 1 | 0.004 | 1.862 | 2.9022 | 2.8258 | 0.0764 |
13 | 0.821 | 0.075 | 1 | −0.055 | 1.8 | 2.5199 | 2.3743 | 0.1456 |
14 | 0.807 | 0.098 | 1 | −0.055 | 2 | 2.5414 | 2.4945 | 0.0469 |
15 | 0.955 | 0.099 | 1 | −0.066 | 2 | 2.1812 | 2.4751 | −0.2939 |
16 | 0.99 | 0.097 | 1 | −0.034 | 2 | 2.6083 | 2.2726 | 0.3357 |
17 | 0.83 | 0.103 | 1 | 0.025 | 2 | 2.4454 | 2.4343 | 0.0111 |
18 | 0.747 | 0.097 | 1 | 0.025 | 2 | 2.5922 | 2.4056 | 0.1866 |
19 | 0.678 | 0.1 | 1 | −0.017 | 1.941 | 2.4954 | 2.6896 | −0.1942 |
20 | 0.66 | 0.112 | 1 | 0.019 | 1.84 | 3.1229 | 2.9197 | 0.2032 |
21 | 0.695 | 0.102 | 1 | −0.013 | 1.895 | 2.7730 | 2.7490 | 0.024 |
22 | 0.755 | 0.117 | 1 | 0.098 | 1.89 | 2.7821 | 2.7227 | 0.0594 |
23 | 0.747 | 0.098 | 1 | 0.145 | 1.941 | 2.3759 | 2.3697 | 0.0062 |
24 | 0.674 | 0.097 | 1 | −0.115 | 1.84 | 2.9435 | 2.9037 | 0.0398 |
25 | 0.74 | 0.114 | 0 | 0.001 | 1.846 | 2.5447 | 2.5984 | −0.0537 |
26 | 0.761 | 0.118 | 0 | 0.05 | 1.81 | 2.5950 | 2.5985 | −0.0035 |
27 | 0.668 | 0.117 | 1 | 0.08 | 1.818 | 3.0888 | 2.9454 | 0.1434 |
28 | 0.609 | 0.115 | 1 | 0.037 | 1.826 | 3.1180 | 3.0118 | 0.1062 |
29 | 0.59 | 0.092 | 1 | 0.106 | 1.775 | 2.5165 | 2.8367 | −0.3202 |
30 | 0.604 | 0.109 | 1 | 0.015 | 1.833 | 2.9935 | 2.9747 | 0.0188 |
31 | 0.586 | 0.108 | 1 | −0.01 | 1.948 | 2.9452 | 2.8549 | 0.0903 |
32 | 0.567 | 0.133 | 1 | −0.063 | 1.902 | 3.1835 | 3.4251 | −0.2416 |
33 | 0.589 | 0.113 | 1 | −0.004 | 1.902 | 3.0716 | 2.9827 | 0.0889 |
34 | 0.591 | 0.124 | 0 | −0.052 | 1.862 | 3.0165 | 2.9033 | 0.1132 |
35 | 0.568 | 0.103 | 1 | −0.012 | 1.902 | 2.7510 | 2.9068 | −0.1558 |
36 | 0.625 | 0.113 | 1 | 0.019 | 1.906 | 2.8193 | 2.9159 | −0.0966 |
37 | 0.693 | 0.105 | 0 | 0.045 | 1.822 | 2.4436 | 2.5076 | −0.064 |
Parameter | CoMFA | CoMSIA |
---|---|---|
R2 (correlation coefficient squared) | 0.993 | 0.965 |
ONC (the optimal number of components) | 6 | 6 |
q2LOO (leave-one-out cross validation correlation coefficient squared) | 0.802 | 0.735 |
F value | 422.047 | 83.553 |
SEE | 0.029 | 0.059 |
Fields | SE | SEHDA |
Field distribution (%) | ||
Steric | 70.8 | 21.5 |
Electrostatic | 29.2 | 28.5 |
Hydrophobic | – | 44.9 |
Donor | – | 0 |
Acceptor | – | 5.0 |
Testing set | ||
R2pred | 0.999 | 0.787 |
Compounds | Experimental pLC50 | CoMFA | CoMSIA | ||
---|---|---|---|---|---|
Prediced pLC50 | Residual | Prediced pLC50 | Residual | ||
8 | 3.0813 | 3.0973 | −0.016 | 3.0924 | −0.0111 |
9 | 3.0757 | 3.0725 | 0.0032 | 3.0575 | 0.0182 |
10 | 2.6333 | 2.6274 | 0.0059 | 2.5286 | 0.1047 |
11 | 2.7527 | 2.7598 | −0.0071 | 2.7593 | −0.0066 |
12 | 2.9022 | 2.9078 | −0.0056 | 2.9684 | −0.0662 |
13 | 2.5199 | 2.4480 | 0.0719 | 2.4733 | 0.0466 |
14 | 2.5414 | 2.5493 | −0.0079 | 2.5388 | 0.0026 |
15 | 2.1812 | 2.2194 | −0.0382 | 2.2796 | −0.0984 |
16 | 2.6083 | 2.6112 | −0.0029 | 2.8778 | −0.2695 |
17 | 2.4454 | 2.4623 | −0.0169 | 2.4475 | −0.0021 |
18 | 2.5922 | 2.6016 | −0.0094 | 2.5501 | 0.0421 |
19 | 2.4954 | 2.4951 | 0.0003 | 2.5121 | −0.0167 |
20 | 3.1229 | 3.1170 | 0.0059 | 3.1055 | 0.0174 |
21 | 2.773 | 2.7801 | −0.0071 | 2.7715 | 0.0015 |
22 | 2.7821 | 2.7970 | −0.0149 | 2.8082 | −0.0261 |
23 | 2.3759 | 2.3723 | 0.0036 | 2.3906 | −0.0147 |
24 | 2.9435 | 2.9283 | 0.0152 | 2.9396 | 0.0039 |
25 | 2.5447 | 2.5653 | −0.0206 | 2.5621 | −0.0174 |
26 | 2.595 | 2.5766 | 0.0184 | 2.5922 | 0.0029 |
27 | 3.0888 | 3.0794 | 0.0094 | 3.0367 | 0.0521 |
28 | 3.118 | 3.1368 | −0.0188 | 3.0989 | 0.0191 |
29 | 2.5165 | 2.5110 | 0.0055 | 2.5584 | −0.0419 |
30 | 2.9935 | 2.9990 | −0.0055 | 2.9795 | 0.0140 |
31 | 2.9452 | 2.9766 | −0.0314 | 2.9259 | 0.0193 |
32 | 3.1835 | 3.1459 | 0.0376 | 3.0742 | 0.1093 |
33 | 3.0716 | 3.0717 | −0.00005 | 3.1080 | −0.0364 |
34 | 3.0165 | 3.0186 | −0.0021 | 3.0850 | −0.0685 |
35 | 2.751 | 2.7630 | −0.012 | 2.8301 | −0.0791 |
36 | 2.8193 | 2.7858 | 0.0335 | 2.8629 | −0.0436 |
37 | 2.4436 | 2.4378 | 0.0058 | 2.3760 | 0.0676 |
Compounds | Binding Energy | Van der Waals | H-Bond | Hydrophobic Interaction (Pi–Alkyl and Alkyl) | Electrostatic Interaction (Pi–Anion and Pi–Cation) | |||
---|---|---|---|---|---|---|---|---|
Amino Acid-Ligand Atom | Distance (Å) | Amino Acid-Ligand Atom | Distance (Å) | Amino Acid-Ligand Atom | Distance (Å) | |||
4 | −5.25 | GLU214, SER215, HIS223, SER221, ARG781 | ASP222 [C-O…H] ASP213 [C-O…H] * GLU220 [C-O…H] * | 2.05 2.81 3.33 | VAL224 [Alkyl–Pi] THR218 [Sigma–Pi] | 4.07, 4.88 2.23 | ||
8 | −5.15 | SER215, HIS223, THR218, ARG781, ASN725, GLU220, SER221 | GLU214 [N-H…O] ASP222 [N-H…O] ASP213 [C-H…O] * GLY723 [C-O…H] * ASP724 [C-O…H] * | 2.15 1.97 2.75 3.31 3.11 | VAL224 [Alkyl–Pi] | 4.53, 5.47 | ||
9 | −5.38 | SER215, THR218, ASN725, MET490, GLU220, SER 221, HIS223 | GLU214 [N-H…O] ASP222 [N-H…O] ASP213 [C-H…O] * GLY723 [C-O…H] * ASP724 [C-O…H] * | 2.12 1.97 2.76 3.66 3.25 | VAL224 [Alkyl–Pi] | 4.50, 5.39 | ||
12 | −5.40 | SER215, HIS223, THR218, ASN725, GLY723, LYS481, LYS549, GLU220, SER221 | GLU214 [N-H…O] ASP222 [N-H…O] ASP213 [C-H…O] *ASP724 [C-O…H] * | 2.03 2.03 2.55 3.19 | VAL224 [Alkyl–Pi] MET490 [Alkyl–Alkyl] | 4.17, 5.20 5.08 | ||
20 | −7.41 | SER215, SER221, GLU220, MET490, ILE732, ASP698, THR728, GLU697, GLY648, LEU649, ARG781, ASN725, THR218, HIS223 | GLU214 [N-H…O] ASP222 [N-H…O] ASP213 [C-H…O] * GLY723 [C-O…H] * | 1.98 2.05 2.48 3.16 | VAL224 [Alkyl–Pi] | 4.27, 5.47 | LYS481[Cation–Pi] ASP724[Anion–Pi] | 4.54 4.45 |
28 | −6.22 | ILE212, HIS223, ASP222, GLU220, ASN725, ASP724, PRO784, SER783, SER782 | GLU214 [N-H…O] VAL224 [N-H…O] THR218 [C-O…H] ASP213 [C-H…O] * GLY723 [C-O…H] * ARG781 [C-H…O] * GLU214 [C-O…H] * | 1.77 2.96 2.15 2.53 3.16 2.21 3.53 | VAL224 [Alkyl–Pi]LEU217 [Alkyl–Alkyl] | 3.78, 4.45 4.78 |
Entry | miLogp | %ABS | TPSA (A2) | MW | n-ON Acceptors | nOHNH Donors | Lipinski’s Violations | n-ROTB | MV |
---|---|---|---|---|---|---|---|---|---|
Rule | ≤5 | — | ≤140 | ≤500 | ≤10 | ≤5 | ≤1 | ≤10 | — |
4 | 1.33 | 88.41 | 59.67 | 192.17 | 4 | 1 | 0 | 1 | 162.15 |
8 | 1.64 | 92.21 | 48.68 | 206.20 | 4 | 0 | 0 | 2 | 179.68 |
9 | 2.01 | 92.21 | 48.68 | 220.22 | 4 | 0 | 0 | 3 | 196.48 |
10 | 2.52 | 92.21 | 48.68 | 234.25 | 4 | 0 | 0 | 4 | 213.28 |
11 | 2.38 | 92.21 | 48.68 | 234.25 | 4 | 0 | 0 | 3 | 213.07 |
12 | 3.07 | 92.21 | 48.68 | 248.28 | 4 | 0 | 0 | 5 | 230.08 |
13 | 2.76 | 92.21 | 48.68 | 248.28 | 4 | 0 | 0 | 4 | 229.87 |
14 | 2.51 | 92.21 | 48.68 | 246.26 | 4 | 0 | 0 | 4 | 219.51 |
15 | 3.04 | 92.21 | 48.68 | 260.29 | 4 | 0 | 0 | 3 | 236.31 |
16 | 3.54 | 92.21 | 48.68 | 274.32 | 4 | 0 | 0 | 3 | 253.11 |
17 | 3.92 | 92.21 | 48.68 | 288.34 | 4 | 0 | 0 | 4 | 269.91 |
18 | 3.23 | 92.21 | 48.68 | 282.30 | 4 | 0 | 0 | 4 | 251.33 |
19 | 3.68 | 92.21 | 48.68 | 296.32 | 4 | 0 | 0 | 4 | 267.89 |
20 | 4.94 | 92.21 | 48.68 | 338.40 | 4 | 0 | 0 | 5 | 317.51 |
21 | 3.19 | 76.40 | 94.50 | 327.29 | 7 | 0 | 0 | 5 | 274.66 |
22 | 4.51 | 92.21 | 48.68 | 351.19 | 4 | 0 | 0 | 4 | 278.40 |
23 | 3.91 | 92.21 | 48.68 | 316.74 | 4 | 0 | 0 | 4 | 264.86 |
24 | 4.13 | 92.21 | 48.68 | 350.29 | 4 | 0 | 0 | 5 | 282.62 |
25 | 4.20 | 89.02 | 57.91 | 366.29 | 5 | 0 | 0 | 6 | 291.61 |
26 | 0.74 | 82.17 | 77.78 | 263.25 | 6 | 1 | 0 | 4 | 227.87 |
27 | 1.12 | 82.17 | 77.78 | 277.28 | 6 | 1 | 0 | 5 | 244.67 |
28 | 1.62 | 82.17 | 77.78 | 291.30 | 6 | 1 | 0 | 6 | 261.47 |
29 | 1.42 | 82.17 | 77.78 | 291.30 | 6 | 1 | 0 | 5 | 261.25 |
30 | 2.18 | 82.17 | 77.78 | 305.33 | 6 | 1 | 0 | 7 | 278.27 |
31 | 2.14 | 82.17 | 77.78 | 339.35 | 6 | 1 | 0 | 6 | 299.51 |
32 | 2.79 | 82.17 | 77.78 | 373.79 | 6 | 1 | 0 | 6 | 313.05 |
33 | 2.82 | 82.17 | 77.78 | 373.79 | 6 | 1 | 0 | 6 | 313.05 |
34 | 3.42 | 82.17 | 77.78 | 408.24 | 6 | 1 | 0 | 6 | 326.59 |
35 | 2.59 | 82.17 | 77.78 | 353.37 | 6 | 1 | 0 | 6 | 316.08 |
36 | 2.20 | 78.98 | 87.01 | 369.37 | 7 | 1 | 0 | 7 | 325.06 |
37 | 3.85 | 82.17 | 77.78 | 395.45 | 6 | 1 | 0 | 7 | 365.70 |
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Luo, J.; Lai, T.; Guo, T.; Chen, F.; Zhang, L.; Ding, W.; Zhang, Y. Synthesis and Acaricidal Activities of Scopoletin Phenolic Ether Derivatives: QSAR, Molecular Docking Study and in Silico ADME Predictions. Molecules 2018, 23, 995. https://doi.org/10.3390/molecules23050995
Luo J, Lai T, Guo T, Chen F, Zhang L, Ding W, Zhang Y. Synthesis and Acaricidal Activities of Scopoletin Phenolic Ether Derivatives: QSAR, Molecular Docking Study and in Silico ADME Predictions. Molecules. 2018; 23(5):995. https://doi.org/10.3390/molecules23050995
Chicago/Turabian StyleLuo, Jinxiang, Ting Lai, Tao Guo, Fei Chen, Linli Zhang, Wei Ding, and Yongqiang Zhang. 2018. "Synthesis and Acaricidal Activities of Scopoletin Phenolic Ether Derivatives: QSAR, Molecular Docking Study and in Silico ADME Predictions" Molecules 23, no. 5: 995. https://doi.org/10.3390/molecules23050995