QSAR Study and Molecular Design of Open-Chain Enaminones as Anticonvulsant Agents
Abstract
:1. Introduction
2. Materials and Methods
2.1. Experimental Data
2.2. Geometry Optimization and Molecular Descriptors Calculation
2.3. Model Development
2.3.1. Linear Descriptors Search
2.3.2. Calculation of Flexible Descriptors
2.3.3. Model Validation
3. Results and Discussion
3.1. QSAR on Ringed-Enaminones
3.2. QSAR on Open-Chain Enaminones
4. Conclusions
Supplementary Material
ijms-12-09354-s001.pdfAcknowledgments
References
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Descriptor | Type | Details |
---|---|---|
BELe6 | BCUT | Lowest eigenvalue n. 6 of Burden matrix/weighted by atomic Sanderson electronegativities |
BELp8 | Lowest eigenvalue n. 8 of Burden matrix/weighted by atomic polarizabilities | |
RDF025v | Radial Distribution Function | Radial Distribution Function—2.5/weighted by atomic van der Waals volumes |
RDF025m | Radial Distribution Function—2.5/weighted by atomic masses | |
RDF115m | Radial Distribution Function—11.5/weighted by atomic masses | |
Mor15e | 3D-MoRSE | 3D-MoRSE—signal 15/weighted by atomic Sanderson electronegativities |
R4e+ | GETAWAY | R maximal autocorrelation of lag 4/weighted by atomic Sanderson electronegativities |
G(O..Cl) | Geometrical | Sum of geometrical distances between O..Cl |
Homo-Lumo | Quantum Chemical | HOMO-LUMO energy gap |
No. | Chemical name | ED50 (mg·Kg−1) | Exp. | Equation 3 | Equation 4 | Equation 5 |
---|---|---|---|---|---|---|
1 | Ethyl 6-methyl-4-(5-methylisoxazol-3-ylamino)-2-oxocyclohex-3-enecarboxylate | 68.39 [4] | 1.835 | 1.815 | 1.831 | 1.813 |
2 | Methyl 4-(4-cyanophenylamino)-6-methyl-2-oxocyclohex-3-enecarboxylate | 248.31 [4] | 2.395 | 2.229 | 2.252 | 2.226 |
3 | Methyl 4-(4-chlorophenylamino)-6-methyl-2-oxocyclohex-3-enecarboxylate | 26.18 [4] | 1.418 | 1.509 | 1.466 | 1.517 |
4 | 2-acetamido-N-benzylpropanamide | 76.38 [5] | 1.883 | 1.716 | 1.677 | 1.634 |
5 | 2-acetamido-N-(3-fluorobenzyl)propanamide | 77.27 [5] | 1.888 | 1.945 | 1.791 | 1.994 |
6 | 2-acetamido-N-(2-fluorobenzyl)-2-(furan-2-yl)acetamide | 39.99 [5] | 1.602 | 1.215 | 1.294 | 1.315 |
7 | 2-acetamido-N-(3-fluorobenzyl)-2-(furan-2-yl)acetamide | 13.27 [5] | 1.123 | 1.132 | 1.291 | 1.315 |
8 | 2-acetamido-N-(4-fluorobenzyl)-2-(furan-2-yl)acetamide | 12.68 [5] | 1.103 | 1.302 | 1.228 | 1.315 |
9 | 2-acetamido-N-(2,5-difluorobenzyl)-2-(furan-2-yl)acetamida | 23.77 [5] | 1.376 | 1.577 | 1.522 | 1.448 |
10 | 2-acetamido-N-(2,6-difluorobenzyl)-2-(furan-2-yl)acetamide | 62.95 [5] | 1.799 | 1.604 | 1.631 | 1.687 |
11 | 2-acetamido-N-benzylpent-4-enamide | 33.57 [5] | 1.526 | 1.653 | 1.605 | 1.533 |
12 | 2-acetamido-N-benzyl-2-(tetrahydrofuran-2-yl)acetamide | 51.64 [5] | 1.713 | 1.770 | 1.272 | 1.746 |
13 | 2-acetamido-N-benzyl-2-(furan-2-yl)acetamide | 10.28 [5] | 1.012 | 1.383 | 1.252 | 1.182 |
14 | 2-acetamido-N-benzyl-2-(5-methylfuran-2-yl)acetamide | 19.19 [5] | 1.283 | 1.450 | 1.200 | 1.282 |
15 | 2-acetamido-N-benzyl-2-(1H-pyrrol-2-yl)acetamide | 16.07 [5] | 1.206 | 1.486 | 1.299 | 1.315 |
16 | 2-acetamido-N-benzyl-2-(5-methyl-1H-pyrrol-2-yl)acetamide | 36.48 [5] | 1.562 | 1.530 | 1.376 | 1.415 |
17 | 2-acetamido-N-benzyl-2-(thiophen-2-yl)acetamide | 44.77 [5] | 1.651 | 1.388 | 1.628 | 1.593 |
18 | 2-acetamido-N-benzyl-2-(thiophen-3-yl)acetamida | 87.70 [5] | 1.943 | 1.783 | 1.770 | 1.979 |
19 | 2-acetamido-N-benzyl-2-(1H-pyrrol-1-yl)acetamide | 80.17 [5] | 1.904 | 1.572 | 1.538 | 1.399 |
20 | 2-acetamido-N-benzyl-2-(1H-pyrazol-1-yl)acetamide | 16.48 [5] | 1.217 | 1.249 | 1.294 | 1.325 |
21 | 2-acetamido-N-benzyl-2-(pyridin-2-yl)acetamide | 10.79 [5] | 1.033 | 0.880 | 1.037 | 1.195 |
22 | 2-acetamido-3-amino-N-benzyl-3-thioxopropanamide | 86.50 [5] | 1.937 | 1.550 | 1.921 | 1.981 |
23 | 2-acetamido-N-benzyl-2-(ethylamino)acetamide | 42.36 [5] | 1.627 | 1.525 | 1.635 | 1.679 |
24 | 2-acetamido-N-benzyl-2-(hydroxy(methyl)amino)acetamide | 29.99 [5] | 1.477 | 1.465 | 1.215 | 1.712 |
25 | 2-acetamido-N-benzyl-2-(1-phenylhydrazinyl)acetamide | 42.76 [5] | 1.631 | 1.524 | 1.663 | 1.811 |
26 | 2-acetamido-N-benzyl-2-ethoxyacetamide | 61.94 [5] | 1.792 | 1.795 | 1.922 | 1.368 |
27 | 2-acetamido-N-benzyl-3-methoxypropanamide | 8.30 [5] | 0.919 | 0.954 | 1.135 | 1.201 |
28 | 2-acetamido-N-benzyl-3-ethoxypropanamide | 16.98 [5] | 1.230 | 1.232 | 1.385 | 1.197 |
29 | 2-acetamido-N-benzyl-2-(pyrazin-2-yl)acetamide | 14.79 [5] | 1.170 | 0.929 | 1.015 | 0.893 |
30 | 2-acetamido-N-benzyl-2-(pyrimidin-2-yl)acetamida | 8.09 [5] | 0.908 | 1.151 | 1.344 | 1.121 |
31 | 2-acetamido-N-benzyl-2-(oxazol-5-yl)acetamide | 10.50 [5] | 1.021 | 0.998 | 1.149 | 0.88 |
32 | 2-acetamido-N-benzyl-2-(thiazol-5-yl)acetamide | 11.99 [5] | 1.079 | 1.417 | 1.717 | 1.291 |
33 | 2-acetamido-2-(3-aminophenylamino)-N-benzylacetamide | 98.40 [5] | 1.993 | 2.102 | 2.023 | 1.85 |
34 | 2-acetamido-N-benzyl-2-(furan-2-yl)acetamide | 18.37 [5] | 1.264 | 1.396 | 1.255 | 1.182 |
35 | Ethyl 4-(4-chlorophenylamino)-6-methyl-2-oxo-3-cyclohexene-1-carboxylate | 16.67 [7] | 1.222 | 1.085 | 1.184 | 1.124 |
36 | Ethyl 4-(4-bromophenylamino)-6-methyl-2-oxo-3-cyclohexene-1-carboxylate | 7.89 [7] | 0.897 | 1.259 | 0.861 | 1.383 |
37 | Ethyl 6-methyl-2-oxo-4-(4-(trifluoromethoxy)phenylamino)cyclohex-3-enecarboxylate | 37.07 [7] | 1.569 | 1.708 | 1.831 | 1.553 |
38 | Ethyl 4-(4-cianophenylamino)-6-methyl-2-oxo-3-cyclohexene-1-carboxylate | 63.10 [7] | 1.800 | 1.852 | 1.847 | 1.595 |
39 | 3-(4-chlorophenylamino)-5-methyl-2-cyclohexenone | 40.36 [7] | 1.606 | 1.804 | 1.570 | 1.576 |
40 | 3-(4-iodophenylamino)-5-methyl-2-cyclohexenone | 76.91 [7] | 1.886 | 1.924 | 1.829 | 1.835 |
41 | Methyl 6-methyl-4-(5-methylisoxazol-3-ylamino)-2-oxocyclohex-3-cyclohexene-1-carboxylate | 149.28 [8] | 2.174 | 1.867 | 2.001 | 2.087 |
42 | Tert-butyl 6-methyl-4-(5-methylisoxazol-3-ylamino)-2-oxocyclohex-3-cyclohexene-1-carboxylate | 119.67 [8] | 2.078 | 1.974 | 1.861 | 2.181 |
43 | Methyl 4-(benzylamino)-6-methyl-2-oxocyclohex-3-cyclohexene-1-carboxylate | 64.57 [9] | 1.810 | 2.005 | 2.062 | 2.019 |
44 | Methyl 4-(4-fluorobenzylamino)-6-methyl-2-oxocyclohex-3-cyclohexene-1-carboxylate | 158.85 [9] | 2.201 | 2.030 | 2.164 | 2.118 |
45 | 3-(benzylamino)-5,5-dimethylcyclohex-2-cyclohexenone | 52.97 [9] | 1.724 | 1.633 | 1.678 | 1.892 |
46 | Methyl 4-(benzylamino)-6,6-dimethyl-2-oxocyclohex-3-enecarboxylate | 131.83 [10] | 2.120 | 2.219 | 2.107 | 1.904 |
47 * | Methyl 6-methyl-4-(4-nitrophenylamino)-2-oxocyclohex-3-enecarboxylate | 299.92 [4] | 2.477 | 2.441 | 2.793 | 2.599 |
48 * | 2-acetamido-N-benzyl-2-phenylacetamide | 20.28 [7] | 1.307 | 1.505 | 1.347 | 1.269 |
49 * | 2-acetamido-N-benzyl-2-(dimethylamino)acetamide | 45.29 [7] | 1.656 | 1.413 | 1.540 | 1.804 |
50 * | 2-acetamido-2-(furan-2-yl)-N-(pyridin-3-ylmethyl)acetamide | 29.99 [7] | 1.477 | 1.396 | 1.255 | 1.182 |
51 * | 5,5-dimethyl-3-(phenylamino)cyclohex-2-enone | 109.14 [10] | 2.038 | 1.812 | 1.990 | 1.434 |
Molecule | Equation 3 | Equation 4 | PSA a |
---|---|---|---|
1A | 2.051 | 2.041 | 2 |
2A | 2.426 | 2.093 | 2 |
3A | 2.456 | 2.229 | 2 |
4A | 2.323 | 2.037 | 2 |
1B | 0.956 | 0.245 | 1 |
2B | 1.529 | 0.903 | 1 |
3B | 1.103 | 0.667 | 1 |
4B | 1.393 | 0.758 | 1 |
1C | 1.329 | 1.241 | 1 |
2C | 1.462 | 1.556 | 1 |
3C | 1.794 | 1.446 | 1 |
4C | 1.505 | 1.177 | 1 |
1D | 1.295 | 1.416 | 1 |
2D | 1.583 | 1.375 | 1 |
3D | 2.172 | 1.980 | b |
4D | 1.291 | 1.183 | 1 |
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Garro Martinez, J.C.; Duchowicz, P.R.; Estrada, M.R.; Zamarbide, G.N.; Castro, E.A. QSAR Study and Molecular Design of Open-Chain Enaminones as Anticonvulsant Agents. Int. J. Mol. Sci. 2011, 12, 9354-9368. https://doi.org/10.3390/ijms12129354
Garro Martinez JC, Duchowicz PR, Estrada MR, Zamarbide GN, Castro EA. QSAR Study and Molecular Design of Open-Chain Enaminones as Anticonvulsant Agents. International Journal of Molecular Sciences. 2011; 12(12):9354-9368. https://doi.org/10.3390/ijms12129354
Chicago/Turabian StyleGarro Martinez, Juan C., Pablo R. Duchowicz, Mario R. Estrada, Graciela N. Zamarbide, and Eduardo A. Castro. 2011. "QSAR Study and Molecular Design of Open-Chain Enaminones as Anticonvulsant Agents" International Journal of Molecular Sciences 12, no. 12: 9354-9368. https://doi.org/10.3390/ijms12129354