A novel series of benzophenone oxime ether derivatives with tertiary amine groups were synthesized and their herbicidal activities of 24 compounds against
Pesticides are extensively used in agriculture and undoubtedly play a pivotal role in retaining high production and quality of crop [
In recent years, oxime ether derivatives exhibit high potential to be developed as pesticides. For example, flucycloxuron is an insect growth regulator and trifloxystrobin has been used as a fungicide. Moreover, various novel oxime ethers have been reported to possess remarkable antibacterial, insecticidal, and fungicidal activities [
However, very few results on the herbicidal activities of oxime ether compound were reported [
All reagents and solvents (Analytical Reagent grade) were commercially available and used without further purification. Melting points were measured on an RY-2 apparatus. IR spectra were recorded on a Thermo Nicolet FT-IR Avatar 330 instrument with KBr. 1H NMR spectra were collected at room temperature on 400 MHz Bruker AM, 600 MHz Bruker DRX spectrometers. The residual solvent signals were taken as the reference (7.26 ppm in CDCl3 and 2.50 ppm in
Aryl ketone was prepared from substituted benzene and arylcarboxylic chloride through Friedel-Crafts reaction. Reaction of ketone with hydroxylamine hydrochloride in the presence of base would result in corresponding oxime, which converted to substituted benzophenone-
The synthetic route to target compounds.
Benzoyl chloride (0.12 mol) was added dropwise to a mixture of substituted benzene (0.1 mol) and AlCl3 (0.12 mol) at room temperature. After complete addition, the mixture was refluxed for another 6 h. Then, the reaction was quenched with ice-water and extracted with chloroform (3 × 30 mL). The combined organic phase was washed with water, Na2CO3 solution, and brine successively, dried over MgSO4, filtered, and evaporated. The crude product was used directly for next step without any further purification.
Aqueous NaOH solution (10 mL, 20 M) was added to a mixture of substituted benzophenone (0.05 mol) and hydroxylamine hydrochloride (0.1 mol) in ethanol (50 mL) at room temperature. Then, the reaction was heated to 75°C and stirred until the starting material was completely consumed as indicated by TLC. The mixture was cooled to room temperature and filtered. The filtrate was evaporated and dissolved in chloroform, washed with water. The crude compound was recrystallized by ethanol to give a white solid [
Aqueous NaOH solution (10 mL, 25 M) was added to a mixture of substituted benzophenone oxime (0.025 mol), 1,2-dibromoethane (0.03 mol), and
A mixture of substituted benzophenone-
Chemical structure of the target compounds
Compound | R1 | R2 | Compound | R1 | R2 |
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−N(CH2CH2CH3)2 |
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−N(CH2CH2CH2CH3)2 |
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−N(CH2CH2CH3)2 |
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−N(CH2CH2CH2CH3)2 |
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See Scheme
The
The weeds were soaked in 25°C water for 12 h and then transferred to moist gauze, which was put in manual climatic box at 28°C to germinate. 0.12 g of the target compounds was diluted with 3 mL DMF. 0.5 mL of the diluted solution was diluted to 100 mL with 0.1% aqueous Tween-80 solution to prepare a mother solution (200 g/L). The test solutions were then prepared by diluting suitable mother solution to 100 mL with 0.1% aqueous Tween-80 solution. 10 germinating seeds were selected and put in the Petri dish matted with a filtered paper, to which 9 mL of testing solution was added. 0.1% aqueous Tween-80 solution was used as blank control. The Petri dishes were put in manual climatic box setting temperature as 25°C and humidity as 98% in dark condition. The root length was measured after 5 days and the inhibitory rate was calculated with the following equation. All the samples were repeated for 3 times. The abnormal data was got rid of by SPSS19.0. Consider
A coordinate plot was built with concentration as
The analysis is based on SYBYL 7.3 (Tripos Inc., USA). A training set of 19 compounds was used to construct the 3D-QSAR models. Considering the distribution of the structural diversity, 5 compounds were randomly selected as prediction test set to evaluate the obtained 3D-QSAR model.
Since the acceptor is unknown, the low energy conformation was chosen as the active conformation [
Common skeleton of target compounds.
The composite data and pIC90 data were imported to calculate the CoMFA field parameters by Tripos Standard force field (the steric and electrostatic field). Default parameters such as dielectric constant were used to obtain the molecular force parameters [
After a preliminary study, the concentration of testing compounds was set as 1, 2.5, 5, 10, 20, and 40 mg/L in the herbicidal activity investigation. The root growth was observed and the collected data was analyzed by SPSS to calculate the inhibitory rate. The results showed that the inhibitory effect became stronger as the concentration was increased and most of these compounds’ inhibitory rates were up to 80% above at 20 mg/L (see Supporting Information). It indicated that these oxime ether compounds with tertiary amines significantly inhibited the crop root growth, which is another example to support the point that nitrogen functional groups are significant for the biological activity in most agrochemicals [
Calculated IC90 of compounds
Compound | IC90 | |||
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Tribenuron | 12.28 | 13.70 | 11.89 | 11.06 |
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21.11 | 33.55 | 25.28 | 12.71 |
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21.09 | 26.55 | 43.81 | 22.14 |
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42.04 | 17.81 | 35.72 | 17.96 |
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44.92 | 34.27 | 68.52 | 31.56 |
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14.85 | 60.06 | 33.92 | 18.38 |
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13.70 | 48.10 | 32.73 | 34.01 |
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34.19 | 55.20 | 32.17 | 17.32 |
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52.88 | 36.42 | 52.34 | 25.51 |
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24.79 | 17.23 | 28.02 | 11.22 |
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20.13 | 25.54 | 22.84 | 16.83 |
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18.11 | 20.65 | 16.83 | 11.72 |
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20.55 | 35.74 | 17.21 | 15.70 |
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21.28 | 36.87 | 48.70 | 17.69 |
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17.47 | 21.52 | 87.47 | 19.22 |
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20.44 | 11.27 | 23.67 | 14.67 |
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56.79 | 55.64 | 97.02 | 46.68 |
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102.32 | 52.96 | 146.21 | 50.55 |
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72.32 | 244.24 | 439.01 | 53.68 |
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107.40 | 39.85 | 68.15 | 43.25 |
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106.86 | 387.23 | 134.91 | 139.05 |
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67.62 | 194.54 | 108.17 | 203.32 |
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90.00 | 733.00 | 140.28 | 115.99 |
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89.43 | 121.02 | 130.27 | 216.57 |
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121.02 | 133.36 | 147.23 | 379.80 |
It was noteworthy that the benzophenone oxime ethers containing piperidine or piperazine moiety (
The CoMFA analysis results for
Summary of CoMFA results.
Fields | LOO | NV | Steric | Electrostatic | |||
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SEE |
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0.567 | 2 | 0.997 | 0.020 | 751.322 | 0.446 | 0.554 |
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0.621 | 3 | 0.879 | 0.185 | 53.325 | 0.481 | 0.519 |
The CoMFA model for
The 3D-QSAR models established with the training set were further validated with the test set. The CoMFA model gave reasonable predictions of both training and test set compounds. The experimental activity and predicted activity of the compounds and their residuals are listed in Tables
Observed and predicted activities for training and test set of
Compound | pIC90 | ||
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Observed | Predicted | Residual | |
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1.32 | 1.345 | −0.025 |
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1.32 | 1.311 | 0.009 |
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1.62 | 1.600 | 0.020 |
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1.65 | 1.591 | 0.059 |
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1.17 | 1.207 | −0.037 |
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1.14 | 1.158 | −0.018 |
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1.53 | 1.558 | −0.028 |
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1.72 | 1.716 | 0.004 |
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1.39 | 1.361 | 0.029 |
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1.30 | 1.326 | −0.026 |
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1.26 | 1.248 | 0.012 |
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1.31 | 1.274 | 0.036 |
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1.33 | 1.352 | −0.022 |
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1.24 | 1.259 | 0.019 |
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1.31 | 1.511 | −0.201 |
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1.75 | 1.746 | 0.004 |
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2.01 | 1.992 | 0.018 |
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1.86 | 2.156 | −0.296 |
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2.03 | 2.056 | −0.026 |
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2.03 | 2.019 | 0.011 |
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1.83 | 1.807 | 0.023 |
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1.95 | 1.943 | 0.007 |
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1.95 | 1.921 | 0.029 |
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2.08 | 2.103 | −0.023 |
The compound marked with
Observed and predicted activities for training and test set of
Compound | pIC90 | ||
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Observed | Predicted | Residual | |
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1.10 | 1.414 | −0.314 |
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1.35 | 1.307 | 0.043 |
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1.25 | 1.110 | 0.140 |
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1.50 | 1.456 | 0.044 |
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1.26 | 1.268 | −0.008 |
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1.53 | 1.539 | −0.009 |
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1.24 | 1.261 | −0.021 |
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1.41 | 1.313 | 0.097 |
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1.05 | 1.199 | −0.149 |
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1.23 | 1.059 | 0.171 |
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1.07 | 1.065 | 0.005 |
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1.20 | 1.004 | −0.196 |
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1.25 | 0.971 | −0.279 |
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1.28 | 1.083 | 0.197 |
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1.17 | 1.075 | 0.095 |
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1.67 | 1.775 | −0.105 |
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1.70 | 1.402 | 0.298 |
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1.73 | 1.409 | 0.321 |
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1.64 | 1.891 | −0.251 |
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2.14 | 1.904 | 0.236 |
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2.31 | 2.134 | 0.176 |
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2.06 | 2.165 | −0.105 |
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2.34 | 2.461 | −0.121 |
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2.58 | 2.480 | 0.10 |
The compound marked with
The 3D contour maps were generated as scalar products of coefficients and standard deviation associated with each CoMFA. The active compound
In Figure
CoMFA contour map for
In Figure
CoMFA contour map for
On the whole, the structural insights obtained from molecular docking and 3D-QSAR contour maps are consistent with the experimental data, indicating that the molecular docking and the developed 3D-QSAR models are reliable to some extent. The 3D-QSAR contour maps show that the electronic effect contributes to the strong herbicidal activity. Introduction of electron-positive group to the amino group of the test compounds may facilitate improving the inhibitory effect on
A series of benzophenone oxime ether derivatives with tertiary amines were synthesized and characterized. These compounds exhibited good herbicidal activities to both monocotyledon and dicotyledon. Based on the experimental results, the combined 3D-QSAR modeling and molecular docking analysis was performed with the data of
The authors declare that there is no conflict of interests regarding the publication of this paper.
Jimei Ma and Mingwei Ma contributed equally to this paper.
The financial support (Program nos. 2013PY121 and 2012BQ029) provided by the Fundamental Research Funds for the Central Universities, China, is gratefully acknowledged.