Design, Synthesis, Crystal Structure, Insecticidal Activity, Molecular

Article pubs.acs.org/JAFC

Design, Synthesis, Crystal Structure, Insecticidal Activity, Molecular Docking, and QSAR Studies of Novel N3‑Substituted Imidacloprid Derivatives Mei-Juan Wang,†,§ Xiao-Bo Zhao,†,§ Dan Wu,† Ying-Qian Liu,*,† Yan Zhang,† Xiang Nan,† Huanxiang Liu,*,† Hai-Tao Yu,‡ Guan-Fang Hu,‡ and Li-Ting Yan† †

School of Pharmacy, Lanzhou University, Lanzhou 730000, P.R. China Institute of Plant Protection, Gansu Academy of Agricultural Sciences, Lanzhou 730070, P.R. China

‡

S Supporting Information *

ABSTRACT: Three novel series of N3-substituted imidacloprid derivatives were designed and synthesized, and their structures were identified on the basis of satisfactory analytical and spectral (1H NMR, 13C NMR, MS, elemental analysis, and X-ray) data. Preliminary bioassays indicated that all of the derivatives exhibited significant insecticidal activities against Aphis craccivora, with LC50 values ranging from 0.00895 to 0.49947 mmol/L, and the insecticidal activities of some of them were comparable to those of the control imidacloprid. Some key structural features related to their insecticidal activities were identified, and the binding modes between target compounds and nAChR model were also further explored by molecular docking. By comparing the interaction features of imidacloprid and compound 26 with highest insecticidal activity, the origin of the high insecticidal activity of compound 26 was identified. On the basis of the conformations generated by molecular docking, a satisfactory 2D-QSAR model with six selected descriptors was built using genetic algorithm−multiple linear regression (GA-MLR) method. The analysis of the built model showed the molecular size, shape, and the ability to form hydrogen bond were important for insecticidal potency. The information obtained in the study will be very helpful for the design of new derivatives with high insecticidal activities. KEYWORDS: synthesis, insecticidal activity, X-ray diffraction, molecular docking, QSAR

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INTRODUCTION Neonicotinoid insecticides (NNs), acting selectively on the insect nicotinic acetylcholine receptors (nAChRs), have attracted the widespread interest of scientists continuously due to their broad spectrum of biological activities and high selectivity for crop protection and public health.1−3 Since imidacloprid (1) was introduced in the 1980s as an insecticide for crop protection, NNs have gained dramatic developments and many new generation NNs, such as thiacloprid (2), acetamiprid (3), nitenpyram (4), thiamethoxam (5), clothianidin (6), and dinotefuran (7), were commercialized successively with their own prominence (Figure 1) and they account for at least 26% of the global insecticide market.4−8 Despite the tremendous amount of effort invested in the development of neonicotinoids, it remains essential to continually explore novel neonicotinoid candidates because significant increases in resistance and cross-resistance have been observed in various insect species after frequent field applications.9−13 Modification of the structures of existing neonicotinoids can be an effective tactic to combat resistance. Accordingly, strategies for designing and synthesizing neonicotinoids remain an ongoing, attractive research area. These modification strategies includes replacement of the pyridine ring with a thiazole or other bioisosteric heterocyclic rings, substitution of the nitroimino group with other electronwithdrawing groups, and transformation of the imidazolidine moiety to novel heterocyclic equivalents.3,8,14−21 Through various modifications, some analogues were found to exhibit © 2014 American Chemical Society

either enhanced or comparable activity to 1. Intriguingly, an acyclic neonicotinoid, sulfoxaflor (8), emerged as an alternative to overcome the drawbacks of 1 and has widely been commercialized for agricultural use now.22 Also, divalent neonicotinoids,23 proinsecticides of imidacloprid,24 nenicotinoids with extended N-substituted-imine,25 bis-neonicotinoid,26 and crown-capped imidacloprid27 have appeared consecutively in the literature in recent years. Overall, the excellent activity profiles of some derivatives, including improved potency, broad insecticidal spectra, low mammalian toxicity, and good systemic properties, suggested this compound class could be optimized through rational structural modification. Although many research papers that discussed the structure optimization of neonicotinoid insecticides (NNs) are based on cyclic NNs, such as imidacloprid, few studies have focused on the structural modification of NNs at 3-position.28 As is wellknown, bioactive functional fragments or skeletons play a crucial role in biologically active chemicals, and modifications in the functional groups could improve or change the biological activity of parent compounds.29−32 Furthermore, amidines33,34 and triazoles35,36 are identified as important pharmacophores and are widely used in pesticide and drug molecular design; also, the introduction of a sulfonyl group into a wide range of Received: Revised: Accepted: Published: 5429

March 5, 2014 May 17, 2014 May 17, 2014 May 17, 2014 dx.doi.org/10.1021/jf501108j | J. Agric. Food Chem. 2014, 62, 5429−5442

Journal of Agricultural and Food Chemistry

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Figure 1. Structures of current commercially available neonicotinoid insecticides.

Scheme 1. Synthesis of Target Compounds 10−54

key structural features responsible for their potency, the quantitative structure−activity relationship model was developed. Furthermore, the binding modes between target compounds and nAChR model were also explored by molecular docking, which generated useful information for future design of new neonicotinoid pesticides.

heterocyclic compounds results in significant changes in the bioactivity of the compounds,37,38 thus it was indicated that sulfonylamidines and sulfonyltriazoles may be useful structural motifs for optimization in the scaffold of bioactive molecules. Given these considerations, we developed an idea that substitution of the hydrogen on the nitrogen atom of imidacloprid with sulfonylamidino or sulfonyltriazolo substituents could optimize physicochemical properties and improve the biological activity of imidacloprid. To verify our speculation, in the present study, we incorporated the functional fragment sulfonylamidino or sulfonyltriazolo into imidacloprid at the N-3 position and synthesized three novel series of imidacloprid derivatives according to Schemes 1-3. As compared to conventional synthetic methods, our studies noted that the one-pot synthesis of a N-sulfonylamidino group using Cu-catalyzed three component coupling of sulfonyl (or phosphoryl) azide, alkyne, and amine could be an efficient and convenient method to combine several active moieties into one molecule, and it could be convenient to implement structural modification via alternation of diverse starting materials. To further study the role of the sulfonyltriazolo substituents played in the biological activities, another series of sulfonyltriazole-derived imidacloprid analogues were also synthesized using modified click chemistry. The insecticidal activities of the target compounds were evaluated against Aphis craccivora, and the median lethal concentrations (LC50) were calculated accordingly. Additionally, to identify some

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MATERIALS AND METHODS

General. Reagents were purchased from commercial sources and were used as received. All reagents and solvents were of reagent grade or purified according to standard methods before use. Analytical thinlayer chromatography (TLC) and preparative thin-layer chromatography (PTLC) were performed with silica gel plates using silica gel 60 GF254 (Qingdao Haiyang Chemical Co., Ltd.). Melting points were determined in Kofler apparatus and were uncorrected. Mass spectra were recorded on a Bruker Daltonics APEXII49e spectrometer (Bruker Company, USA) with ESI source as ionization. NMR spectra were recorded on a Bruker AM-400 spectrometer (Bruker Company, USA) at 400 and 100 MHz using TMS as the reference. Elemental analyses were determined on a Vario El GmbH elemental analyzer. Synthesis of Key Intermediate 9. Sodium hydride (60% oil dispersion, 80 mg, 2 mmol) was added portionwise to a stirred solution of 1 (514 mg, 2 mmol) in dimethylformamide (DMF) (30 mL) with ice cooling. After the addition, the stirring was continued for a further 30 min at room temperature. The reaction mixture was cooled again with an ice bath and treated with propargyl bromide (297.5 mg, 2.5 mmol). The mixture was stirred overnight at room temperature and then 9 h at 50 °C. After quenching the reaction with a drop of acetic 5430

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acid, the DMF was distilled off. The remaining solid was subjected to column chromatography on silica gel with ethyl acetate until no further I was detected in the fractions, then the elution was continued by replacing the eluting medium with ethyl acetate/methanol 5:1. The separated product was recrystallized from ethanol. Yield: 82%. General Synthetic Procedure for Target Compounds 10−54. Intermediate 9 (0.5 mmol) was added in CH2Cl2 (15 mL), and this mixture was stirred for 5 min when a clear solution was obtained. Under an N2 atmosphere, sulfonyl azide (0.6 mmol), amines (0.5 mmol), and CuI (0.05 mmol) was added into this reaction mixture at room temperature. Triethylamine (0.6 mmol) was added. After the reaction was completed, as monitored by TLC, the reaction mixture was diluted by adding CH2Cl2 (4 mL) and aqueous NH4Cl solution (6 mL). The mixture was stirred for an additional 30 min, and two layers were separated. The aqueous layer was extracted with CH2Cl2 (3 mL × 3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatograph with an appropriate eluting solvent system. Data for Compound 10. Yield 52%; white solid; mp 120−123 °C. 1 H NMR (DMSO-d6, 400 MHz) δ: 8.80 (s, 1H, NH), 8.37 (s, 1H, C5H), 7.80 (d, 1H, J = 8.0 Hz, C3-H), 7.69 (d, 2H, J = 8.0 Hz, Ts-H), 7.52 (d, 1H, J = 8.4 Hz, C2-H), 7.33(d, 2H, J = 8.0 Hz, Ts-H), 4.42 (s, 2H, C6-H), 3.78 (t, 2H, J = 8.8 Hz, C7-H), 3.6 4(t, 2H, J = 9.6 Hz, C8-H), 3.58 (t, 2H, J = 6.8 Hz, C9-H), 3.07 (q, 2H, J = 6.4 Hz, −CH2CH2CH3), 2.91 (t, 2H, J = 6.8 Hz, C10-H), 2.50 (s, 3H, Ts-CH3), 1.45 (q, 2H, J = 7.6 Hz, −CH2CH2CH3), 0.82 (t, 3H, J = 7.6 Hz, −CH2CH2CH3). 13C NMR (DMSO-d6, 100 MHz) δ: 165.0,

160.5, 149.6, 149.5, 141.5, 141.4, 139.4, 130.3, 129.2, 125.6, 124.2, 46.6, 45.8, 45.2, 44.0, 43.1, 31.2, 20.9, 11.4. MS-ESI m/z: 544.1 [M + Na]+. Anal. Calcd For C22H28ClN7O4S: C, 50.62; H, 5.41; N, 18.78. Found: C, 50.49; H, 5.48; N, 18.67. General Synthetic Procedure for Target Compounds 55−57. Amine nucleophile (0.75 mmol, 1.5 equiv) was added to the mixture of phosphoryl azide (0.5 mmol, 1.0 equiv), 9 (1 mmol, 2.0 equiv), and CuI (0.05 mmol, 10 mol %) in CH2Cl2 (1 mL) at room temperature under N2 atmosphere. Triethylamine (0.75 mmol) was added after the addition of the amine if necessary. After the reaction was completed, the same procedure was followed as for N3-sulfonyl amidines 10−54. Data for Compound 55. Yield 56%; white solid; mp 80−82 °C. 1H NMR (CDCl3, 400 MHz) δ: 8.28 (s, 1H, C5-H), 7.65 (d, 1H, J = 6.4 Hz, C3-H), 7.22−7.64 (m, 9H, C2-H, −(OPh)2-H), 7.12 (t, 2H, J = 7.6 Hz, −(OPh)2-H), 4.45 (s, 2H, C6-H), 4.21 (m, 1H, −N(CH(CH3)2)2), 3.88 (t, 2H, J = 9.2 Hz, C7-H), 3.48 (m, 5H, C8-H, C9-H, −N(CH(CH3)2)2), 3.19 (t, 2H, J = 8.8 Hz, C10-H), 1.24 (d, 6H, J = 6.4 Hz, −N(CH(CH3)2)2), 1.14 (d, 6H, J = 6.4 Hz, −N(CH(CH3)2)2). 13C NMR (CDCl3, 100 MHz) δ: 163.9, 160.6, 151.6, 151.5, 149.2, 138.8, 129.3, 128.9, 124.7, 124.2, 120.4, 50.8, 47.9, 46.9, 46.3, 44.9, 44.8, 31.9, 20.7, 19.4. MS-ESI m/z: 749.3 [M + H]+. Anal. Calcd For C30H37ClN7O5P: C, 56.12; H, 5.81; N, 15.27. Found: C, 56.03; H, 5.93; N, 15.34. General Synthetic Procedure for Target Compounds 58−64. Copper(I) thiophene-2-carboxylate (CuTC) (13.0 mg, 0.068 mmol) was added in 20 mL of CHCl3. Then a solution of 9 (200 mg, 0.68 mmol) in 20 mL of CHCl3 and a solution of sulfonyl azide 5431



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(0.75 mmol) in 5 mL of CHCl3 were added, and the reaction mixture was stirred for 6 h at room temperature. The resulting mixture was diluted with saturated NH4Cl aq (50 mL) and extracted with CHCl3 (3 × 50 mL). The combined organics were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatograph with an appropriate eluting solvent system. Data for Compound 58. Yield 55%; white solid; mp 68−69 °C. 1H NMR (CDCl3, 400 MHz) δ: 8.28 (s, 2H, C5-H, triazole-H), 8.01 (d, 2H, J = 8.0 Hz, Ts-H), 7.66 (d, 1H, J = 8.0 Hz, C3-H), 7.42 (d, 1H, J = 8.0 Hz, C2-H), 7.35 (d, 2H, J = 8.0 Hz, Ts-H), 4.56 (s, 3H, C6-H), 4.47 (s, 3H, C9-H), 3.83 (t, 2H, J = 8.8 Hz, C7-H), 3.54 (t, 2H, J = 10.4 Hz, C8-H), 2.47 (s, 3H, Ts-CH3). 13C NMR (DMSO-d6, 100 MHz) δ: 160.5, 149.7, 149.5, 145.0, 140.3, 139.5, 138.1, 130.5, 128.3, 125.5, 124.3, 46.5, 45.7, 45.5, 41.0, 20.8. MS-ESI m/z: 513.1 [M + Na]+. Anal. Calcd For C19H19ClN8O4S: C, 46.48; H, 3.90; N, 22.83. Found: C, 46.59; H, 4.06; N, 22.98. X-ray Crystallography. X-ray quality crystal of 11 was obtained from a solution of acetone/methanol after 7 d. The crystal structure of compound 11 was determined, and X-ray intensity data were recorded on a Bruker APEX II diffractometer using graphite monochromated Mo Kα radiation (λ = 1.54180 Å). A total of 13962 reflections were measured, of which 4913 were unique (Rint = 0.1631) in the range of 3.802 < θ < 70.070° (h, −22 to 23; k, −17 to 18; l, −7 to 11), and 2576 observed reflections with I > 2σ (I) were used in the refinement on F2. The structure was solved by direct method with the SHELXTL-97 program. All of the non-H atoms were refined anisotropically by fullmatrix least-squares to give the final R = 0.1319 and WR = 0.3098. All hydrogen atoms were computed and refined using a riding model. The atomic coordinates for 11 have been deposited at the Cambridge Crystallographic Data Centre. CCDC-970304 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via CCDC CIF Depository Request Form for data published from 1994. Insecticidal Assay. All compounds were dissolved in acetone and diluted with water containing Triton X-100 (0.1 mg/L) to obtain series concentrations of 500, 250, 100, 50, and 10 mg L−1 and others for bioassays. For comparative purposes, imidacloprid was tested under the same conditions. Each concentration was tested three times in parallel. The insecticidal activities of title compounds against Aphis craccivora were tested by leaf-dip method according to a previously reported procedure.23 Horsebean plant leaves with 30 apterous adults were dipped in diluted solutions of the chemicals containing Triton X-100 (0.1 mg L−1) for 5 s, and the excess dilution was sucked out with filter paper; the burgeons were placed in the conditioned room (25 ± 1 °C, 50% relative humidity (RH)). Water containing Triton X-100 (0.1 mg L−1) was used as control. Assessments were made after 24 h by the number of killed and size of live insects relative to that in the negative control, and evaluations were based on a percentage scale of 0−100, in which 0 = no activity and 100 = total kill. The deviation of values was ±5%. The mortality rates were subjected to probit analysis, and the median lethal concentrations (LC50) were calculated accordingly. All bioassay results are summarized in Tables 1−4. Molecular Docking Study. All molecular structures were sketched in SYBYL6.939 software package. Energy minimizations were performed using the Tripos force field with a distance dependent dielectric function and Powell method with a convergence criterion of 0.05 kcal/mol. Partial atomic charges were calculated using Geisteiger− Huckel method. The local minimum energy conformations of these minimized compounds were generated using the multisearch method. Schrödinger’s LigPrep program40 was used to process the generated conformations. The crystal structure of the acetylcholine binding protein (AChBP) from Lymnaea stagnalis (Ls-AChBP) in complex with imidacloprid (IMI) (PDB: 2ZJU) was used for the molecular docking studies because there is still no crystal structure of nAChR of insect Aphis craccivora and Ls-AChBP has high homology to the extracellular domain of nAChR. Actually, Ls-AChBP has been used to study the interaction between compounds with nAChR.41−43 Chain A, chain B, and crystal waters were selected and prepared for subsequent grid generation using the Protein Preparation Wizard in the Schrodinger Suite. The

structure was further treated by adding hydrogen atoms, assigning protonation states. Grids were then generated based on the ligand in the crystal structure using the Receptor Grid Generation module in Glide.44 Lastly, the docking was performed using Glide. Quantitative Structure−Activity Relationships Analysis. The docked conformations of these derivatives were imported into Dragon software45 and molecular descriptors calculated. These descriptors are respectively 0D molecular descriptors (constitutional descriptors), 1D molecular descriptors (functional groups counts, atom-centered fragments), 2D molecular descriptors (topological descriptors, walk and path counts, connectivity indices, information indices, 2D autocorrelations, edge adjacency indices, Burden eigenvalues, topological charge index, eigenvalue-based index), 3D molecular descriptors (Randic molecular profiles, geometrical descriptors, RDF descriptors, 3D-MoRSE descriptors, WHIM descriptors, GETAWAY descriptors), and other molecular descriptors (charge descriptors and molecular properties). To reduce the nonuseful and redundant information, constant variables, near-constant variables, and one of any two descriptors with a correlation coefficient of 0.98 or higher were excluded, and thus 694 descriptors were used in next step. To build and validate the QSAR model, 55 compounds were used as training set and test set, respectively. The insecticidal activities of these compounds against A. craccivora expressed as pLC50 values were defined as dependent variable for the following analysis. To search the feature space and select descriptors related with the insecticidal activities, a combination of genetic algorithm and multiple linear regression (GA-MLR)46 was used. GA-MLR method has been applied in many studies.47,48 MobyDigs software49 was used to build QSAR model of these derivatives. The leave-one-out (LOO) cross validation correlation coefficient (Q2loo) was used as the fitness function. The population size was set to 100, and maximum allowed variables in a model was 6. Other corresponding parameters were set as default. To validate the built model, several statistic terms including correlation coefficient (R2), leave-one-out (LOO) cross-validated correlation coefficient (Q2loo), and root-mean-square error (RMSE) were used. Moreover, the external validation correlation coefficient (Q2ext) of these compounds from the test set was used to evaluate the predictive ability of the QSAR model. The hat value was used to evaluate the applicability domain (AD) of the model, defined as follows:

hi = xi(XT X )−1xiT (i = 1, ..., m) where xi, m, and X are respectively row vector of the descriptors of the query compound i, the number of query compounds, and the n × k matrix of the descriptors of the training set (n and k are the number of descriptors of training set and the model, respectively). The plot of hat values and cross-validated standardized errors (the Williams plot) visually display the application domain of the built model. The horizontal and vertical dashed lines display the limits of normal values in the plot. For example, if the hat value of one compound id greater than h*, this compound is considered as an X outlier. The crossvalidated standardized error of a compound is more than 3.0 standard deviation units, and thus the compound is a Y outlier in a model. The warning hat (h*) is defined by 3k′/n. Here, n and k are the number of compounds in training set and the number of descriptors plus 1, respectively.

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RESULTS AND DISCUSSION Synthesis. The synthetic routes to target compounds are outlined in Schemes 1−3. As outlined in Schemes 1−2, briefly, starting from imidacloprid 1, a propargyl group was first introduced in the N3-position of 1 upon reaction with propargyl bromide in the presence of sodium hydride to give key precursor 9 in 82% yield. Subsequently, key precursor 9 was successfully employed as an efficient reacting partner in the Cucatalyzed three-component reaction with sulfonyl azides and amines to produce the corresponding N3-imidacloprid sulfonyl amidines 10−54 in moderate yields. Under the optimized 5432



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Figure 2. X -ray crystal structure of compound 11.

As shown in Tables1−4, all of the derivatives exhibited moderate to potent insecticidal activities against Aphis craccivora, with LC50 values ranging from 0.00895 to 0.49947 mmol/L. Among them, some of compounds were found to be equally potent or superior insecticidal activities to imidacloprid. For example, when Aphis craccivora were fed with the diet containing 500 mg L−1, the corrected mortality rates of most of compounds had 100% inhibitory effect after 1 day. At reduced dosages, most of the target compounds still remaining had excellent inhibitory activity and had >80% mortality at 250 mg L−1. Even at a 50 mg L−1 diet, compounds 18, 26, 41, 47, 48, 49, 62, and 64 exhibited good insecticidal activity against Aphis craccivora and had >60% mortality. The LC50 values of those compounds were 0.05948, 0.00895, 0.07745, 0.07550, 0.06222, 0.07286, 0.06196, and 0.04470 mmol L−1, respectively, whereas that of imidacloprid was 0.03602 mmol L−1. Intriguingly, the insecticidal activity of compound 26 (LC50: 0.00895 mmol L−1) showed approximately 4-fold higher activities than that of imidacloprid based on the value of LC50, which implied further possibilities for lead compound development. As for the sulfonylamidine series 10−54, the effects of different substituent groups in the sulfonylamidine side chains were investigated. As shown in Table 1, when the R1 group was fixed as methylphenyl (10−31), changing the NR2R3 on in the sulfonylamidine side chains could lead to a remarkable change in activity. For example, linear alkyl groups, like n-propyl in 10, lead to a much better efficacy than branched alkyl groups, like isopropyl in 14. Substitution of the NR2R3 group with cycloalkyl (15), heterocycloalkyl (16−19), and amino esters (52−54) did not display a significant improvement in insecticidal activity as compared to 10. Moreover, the potency of compounds with the aromatic or heterocycle rings (20−31) depended significantly upon the nature of the substitutes and their position at the aromatic ring, and compound 26 (p-Cl-C6H5) gave the best result compared with other synthetic derivatives. Interestingly, when the R1 group was changed from methylphenyl to other substitutions (pyridinyl, dimethylamino, methyl, p-fluorophenyl, 2-naphthyl, etc.), the order of potency was somehow changed, and the substituents R1 present in the functional group N SO2R1 were also a crucial factor that governed activity. For example, the introduction of a pyridinyl group (35, 0.08106) into NSO2R1 increased the insecticidal activities of the compounds (e.g., compounds 32−34). While for compounds 37−39, compound 39 bearing a fluorophenyl R1 group displayed more potent activity than 38 with a pyridinyl R1 group. Overall, considering the discussion above, these findings suggested that their insecticidal potency was dual-controlled by both the R1 and NR2R3 groups in the sulfonylamidine side chain.

conditions, a wide range of amines including primary, secondary, aliphatic, aryl, acyclic, and/or cyclic types were all efficiently coupled to furnish the corresponding amidines. Amino esters were likewise incorporated with almost the same efficiency. Moreover, the scope of the azide counterpart also turned out to be broad, and various types of such as sulfonyl azides and phosphoryl azides (55−57) were readily employed with high efficiency. The coupling reaction has a wide substrate scope, a high tolerance to various functional groups, and very mild reaction conditions. The reaction proceeds through a ketenimine intermediate, which is generated in situ from the triazole cycloadduct upon release of N2 gas.50 As shown in Scheme 3, it has been reported that the introduction of a sulfonyl group into a wide range of heterocyclic compounds resulted in significant changes in the bioactivity of the compounds. Next, we initiate a new search for bioactive sulfonyl triazole molecules for structural modification using similar click chemistry. Interestingly, N-sulfonyl-1,2,3triazoles 58−64 were expectedly obtained from 9 and sulfonyl azides in the absence of amines in good yields by the action of copper catalysts. In contrast to the traditional click methodology, the traditional click reaction using the CuSO4/sodium ascorbate system resulted in both poorer conversions and selectivity. Addition of tert-butyl sulfide to the CuSO4/sodium ascorbate system resulted in an improved ratio and maintained high conversion. During our attempts to achieve high conversion and selectivity by screening different copper(I) catalysts, copper(I) thiophene-2-carboxylate (CuTC) (Liebeskind’s reagent) was found to be a convenient, effective catalyst for the synthesis of N-sulfonyl1,2,3-triazoles at ambient temperature under anhydrous conditions. Furthermore, dichloromethane and chloroform were identified as optimal solvents for the CuTC-catalyzed 1-sulfonyl triazole synthesis, with both leading to complete reactions after 2−5 h. All newly synthesized compounds were purified by column chromatography, and their structures were confirmed by 1H NMR, 13C NMR, ESI-MS, and elemental analysis. To obtain precise three-dimensional structural information and absolute configurations for 10−54, compound 11 was recrystallized by slow evaporation from a solution of acetone/methanol and its single crystal structure was determined by X-ray crystallography as illustrated in Figure 2. Insecticidal Activity against Aphis craccivora. On the basis of the methodology in Schemes 1−3, with 55 derivatives 10− 64 in hand, we next examined their insecticidal activity against Aphis craccivora, imidacloprid was tested under the same conditions as a comparison compound. The results were summarized in Tables 1−4. 5433



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Table 1. Insecticidal Activities of Compounds 1, 9, and 10−51 against Aphis craccivora

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Table 1. continued

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Table 1. continued

Table 2. Insecticidal Activities of Compounds 52−54 against Aphis craccivora

In addition to sulfonyl amidines, another two series of phosphoryl amidine derivatives (55−57) and sulfonyltriazolosubstituted 1-derivatives (58−64) were investigated as well. As indicated in Tables 3 and 4, all of the title compounds showed moderate to good insecticidal activities against A. craccivora, and some of them were either similar or better than that of imidacloprid. Significantly, compound 57 displayed the most potent activity among the tested compounds against A. craccivora and better than the positive control imidacloprid. In contrast, the activity of compounds with sulfonylamidino groups were predominantly higher than those of phosphoryl amidine or

sulfonyltriazolo-substituted 1 derivatives, indicating that the electron distribution and substituents on N3-position of 1 play an important role in the derivatives’ activity. Taken together, these observations further underlined the insecticidal differences could be ascribed to a combination of factors, like the nature of the substituents (which may depend on the size of substituents, electronic characteristics of substituents, or other factors) or a different interaction at the site. Meanwhile, it has been widely known that the physical properties of an insecticidal compound may be manipulated to obtain products with other selected types of activity by proper 5436



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selection of the derivative moiety. Encouraged by these investigations, some N3-substituted imidacloprid derivatives, such as bis-imidacloprid,26 crown-capped imidacloprid,27 N3oxalyl imidacloprid derivatives,51 have been prepared by different groups in recent years. It should be noted that these reported N3-substituted compounds may act as pro-drug by hydrolyzing to IMI. Further biological data supported this conclusion that these N3-substituted compounds as proinsecticides would likely be in vivo activated to release of the parent imidacloprid and such an assumption was supported by Kagabu et al.’s reported experimental method.24 In the present study, the insecticidal effects of these derivatives may be similar to those seen in Kagabu’s study. Therefore, one possibility is that these derivatives may be metabolized in vivo to regenerate imidacloprid, exerting insecticidal effects, although the exact mode is unknown. Molecular Docking Analysis. It is noteworthy that the initially observed effects of these derivatives on A. craccivora were excitatory symptoms, such as tremors, followed by paralysis and mortality (personal observations). It could be postulated that the insecticidal activity of these synthetic derivatives could be due to potential effects on the insect nervous system, similar to the neuroactive imidacloprid.52 To prove this hypothesis, imidacloprid and these derivatives were docked into the active site of AChBP. The most likely binding conformations were selected based on the score and the binding mode. In this way, the most possible conformations for all compounds were obtained. Imidacloprid was redocked to validate the docking reliability. The binding mode of redocked and co-crystallized imidacloprid is almost same in the active site

of AChBP (Figures 3 and 4). For example, the nitrogen atom of the pyridine ring interacts with the carbonyl group of Leu102 and the amide group of Met114 by water-mediated hydrogen bonds. These H-bond interactions play important roles in the interaction of imidacloprid with the residues in the active site of AChBP.41 The guanidine moiety of imidacloprid forms π−π stacking interactions with the aromatic ring of Tyr185. The methylene (CH2−CH2) bridge of imidacloprid and Trp143 form CH−π contacts. After validating the docking reliability, all these derivatives were docked into the active site of AChBP. The 55 compounds show similar binding modes. To more clearly identify the origins of the high insecticidal activity of the compound 26, the detailed interactions of compounds 26 and 11 with AChBP are shown in Figure 5. In the docked complex of compound 26 and AChBP, the imidacloprid skeleton of compound 26 is buried deep in the binding site and mainly interacts with loop D (Phe52-Trp58), loop B (Gly141-His145), and loop C (Tyr185Glu193). Some studies have shown that these loops are essential to the high neonicotinoid sensitivity of insect nAChRs.41 The nitro and sulfonyl group of compound 26 form hydrogen bonds with the side chain atoms of Tyr192 and Gln73, respectively. The pyridine ring forms π−π stacking interactions with conserved Tyr185, which are crucial to the binding of imidacloprid derivatives with AChBP. The pyridine ring also contacts with the aromatic ring of Trp143 and side chain of Met114. The chlorine atom on the pyridine ring contacts the hydroxyl group of conserved Tyr185. The guanidine moiety of imidacloprid contacts the side chain of Tyr192. Arg104 and the nitro group have electrostatic interactions. The methylene (CH2−CH2) bridge of imidacloprid contacts the side chains of Cys187 and Cys188. The methylbenzene group of compound 26 has van der Waals 5437



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Figure 3. (a) The comparison of imidacloprid in the crystal structure and imidacloprid, compounds 26 and 11 in the docked complex by superimposing the coordinates of protein together. (b) A molecular surface of the active site of Ls-AChBP color-coded by amino acid hydrophobicity. The surface ranges from dodger blue for the most polar residues to orange−red for the most hydrophobic, with white in between. Imidacloprid in the crystal structure and imidacloprid, compounds 26 and 11 in the docked complex are shown in green, hot pink, orange, and cyan, respectively.

interactions with Cys188 and Pro189 of loop C. The main chain and side chain atoms of Arg104 form hydrogen bonds with main chain atom of Leu112 and side chain atom of Gln73, respectively (these H-bond interactions are not given in Figure 5). Under the influence of these hydrogen bonds, the side chain atoms of Leu112 contact with the aromatic ring of chloro-phenyl group. The detailed interactions of compound 11 and residues of the active site of AChBP are shown in Figure 5b. The nitrogen atom (N4) of compound 11 and the side chain atom of Gln73 form one hydrogen bond. Like in compound 26, the butyl group of compound 11 also contacts the side chain atoms of Leu112. The other interactions of compound 11 with AChBP are similar to the ones of compound 26. By comparing the binding mode and docking score of newly synthesized compounds and imidacloprid (shown in Figure 3.), the origin of the high insecticidal activity of the compound 26 can be identified. The docking scores of compound 26, imidacloprid, and compound 11 are −7.078, −6.991, and −6.461, which are consistent with the insecticidal activity of these compounds. From the binding mode, in common, imidacloprid and the imidacloprid skeleton of compounds 26 and 11 are buried in the binding site and mainly interact with loop D (Phe52-Trp58), loop B (Gly141His145), and loop C (Tyr185-Glu193). Several residues including Trp53, Met114, Trp143, Tyr185, and Tyr192 in the binding pocket form favorable hydrophobic and van der Waals interactions with imidacloprid and imidacloprid moieties of compound 26 and 11. Differently, the methylbenzene groups of compound 26 and 11 form the additional van der Waals interactions with Cys188 and Pro189 compared with imidacloprid. The aromatic ring of chloro-phenyl group of compound 26 and the butyl group of compound 11 have favorable hydrophobic interactions with the side chain atoms of Leu112. Moreover, the hydrophobic contributions of aromatic ring of chloro-phenyl group of compound 26 are more favorable than ones of the butyl group of compound 11. The nitrogen atom of the pyridine ring of imidacloprid forms hydrogen bonds with the carbonyl group of Leu102 and the amide group of Met114 by water. However, for compound 26, there are two hydrogen bonds formed between the nitro group and the side chain atoms of Tyr192 and between the sulfonyl group and the side chain atoms of Gln73. For compound 11, the nitrogen atom (N4) and the side

chain atom of Gln73 form one hydrogen bond. Thus, the more favorable hydrophobic and van der Waals interactions and stronger hydrogen bonding interactions of compound 26 with the binding pocket contribute to its higher insecticidal activity. QSAR Analysis. On the basis of the reasonable docked conformations, the following QSAR analysis was performed. GA method was used to select the most relevant descriptors to the insecticidal activities of these derivatives based on the training samples. The population size for the evolution was set to 100. Other parameters were set to the default value. The optimum number of variables (Vn) was selected when adding new descriptors did not improve the performance of the model significantly. Compared with the four-parameter model and five-parameter model, the six-parameter model with both higher internal and external predictive ability was adopted here. The four-parameter and five-parameter models and corresponding statistical parameters were given as below: pLC50 = 0.01035T(O..Cl) − 0.66704EEig08d + 0.04511RDF140u + 0.4984Mor12m + 4.62595 Ntr = 46, Ntst = 10 R tr2 = 0.7878, RMSEtr = 0.1397 2 Q loo = 0.7370, RMSE loo = 0.1555 2 Q ext = 0.7306, RMSEext = 0.1574

pLC50 = 0.0097T(O..Cl) − 0.52152EEig08x + 0.04153RDF140u + 0.56465Mor12m + 0.40228Mor16m + 4.55723 Ntr = 46, Ntst = 10 R tr2 = 0.9283, RMSEtr = 0.0812 2 Q loo = 0.9103, RMSE loo = 0.0908 2 Q ext = 0.8780, RMSEext = 0.1059

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Compared with five-parameter model, the external predictive ability of six-parameter model with Q2ext of 0.9270 was improved obviously by introducing the descriptor BELm7 (the lowest eigenvalue n, 7 of Burden matrix weighted by atomic masses). The above results indicate that the built six-parameter model is stable, robust and predictive. The model exhibits a good external predictive ability with Q2ext of 0.9270 and RMSEext of 0.0819. The experimental and predicted pLC50 are given in Table 5. The correlation plot of predicted and experimental values is shown in Figure 6. Figure 7 showed the Williams plot of the built model.

Figure 4. Interactions between imidacloprid and Ls-AChBP.

Compared with four-parameter model, the introduction of descriptor Mor16m into five-parameter model significantly improves the internal and external predictive abilities. The fiveparameter model is statistically good with correlation coefficient R2tr of 0.9283, cross-validated correlation coefficient Q2loo of 0.9103, and the external validation coefficient Q2ext of 0.8780. The best six-parameter model and corresponding statistical parameters were given as below:

Figure 6. Experimental and predicted activities of target compounds in the training and test sets.

pLC50 = 0.00948T(O..Cl) − 0.65887EEig08x + 0.52682BELm7 + 0.03658RDF140u + 0.62012Mor12m + 0.40791Mor16m + 4.31497

From Figure 7, it can be seen that the hat value (0.683) of imidacloprid is larger than the warning value (h* = 0.457), and thus imidacloprid is considered as an X outlier. The molecular structure of imidacloprid differs greatly from other compounds. Moreover, the molecule docking also indicated the binding modes of this compound and other compounds with AChBP are different. According to the regression model, the standardized regression coefficients (Std.Reg.Coeff) of the selected descriptors are 0.48696 (T(O..Cl)), −0.8566 (EEig08x), 0.25435 (BELm7), 0.47561 (RDF140u), 0.78685 (Mor12m), and 0.38254 (Mor16m),

Ntr = 46, Ntst = 10 R tr2 = 0.9479, RMSEtr = 0.0692 2 Q loo = 0.9287, RMSE loo = 0.0810 2 Q ext = 0.9270, RMSEext = 0.0819

Figure 5. Binding mode of compounds 26 and 11 with Ls-AChBP. (a) Detailed interactions of compound 26 with the active site of Ls-AChBP. (b) Detailed interactions of compound 11 with the active site of Ls-AChBP. 5439



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Table 5. Experimental and Predicted Activities against A. craccivora in the QSAR Model

a

no.

compd

exp pLC50

pred pLC50

absolute error

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56

1 10 11a 12 13a 14 15 16 17 18a 19 20 21a 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38a 39 40 41a 42 43 44 45 46 47 48 49a 50 51 52 53 54 55 56 57 58a 59 60 61 62 63a 64a

4.44 4.1 4.05 3.97 3.93 3.93 3.45 3.3 4.03 4.23 3.93 4 3.9 3.8 4.25 4.3 3.91 5.05 3.68 4.3 3.96 3.84 4.38 3.96 3.9 3.36 4.09 3.83 3.89 3.8 4.15 3.89 4.11 3.82 4.12 4.27 4.16 3.56 4.12 4.21 4.14 3.57 4.12 3.98 4.07 4.07 3.91 4.04 4.61 3.87 3.9 4.12 4.04 4.21 3.99 4.35

4.4 3.96 4.01 4.07 3.89 3.95 3.46 3.27 3.98 4.32 4.04 3.95 4.05 3.73 4.13 4.19 4.02 5.05 3.69 4.25 3.94 3.84 4.32 4.08 3.95 3.48 4.09 3.93 3.79 3.89 4.07 3.88 4.25 3.91 4.07 4.22 4.11 3.57 4.18 4.25 4.18 3.61 4.14 3.95 4.09 3.97 3.95 4.16 4.71 3.81 3.89 4.08 4.05 4.18 3.99 4.33

−0.04 −0.14 −0.04 0.1 −0.04 0.02 0.01 −0.03 −0.05 0.09 0.11 −0.05 0.15 −0.07 −0.12 −0.11 0.11 0 0.01 −0.05 −0.02 0 −0.06 0.12 0.05 0.12 0 0.1 −0.1 0.09 −0.08 −0.01 0.14 0.09 −0.05 −0.05 −0.05 0.01 0.06 0.04 0.04 0.04 0.02 −0.03 0.02 −0.1 0.04 0.12 0.1 −0.06 −0.01 −0.04 0.01 −0.03 0 −0.02

Figure 7. Williams plot of the training and test sets. The dashed lines are the warning value of hat (h* = 0.457) and the 3σ limit, respectively.

respectively. The Std.Reg.Coeff determined the relative importance of these descriptors. The most important descriptor is an edge adjacency index EEig08x (eigenvalue 8 from edge adjacency matrix weighted by edge degrees).53 This descriptor can reflect the molecular complexity and branching. The negative correlation coefficient of this descriptor indicates the larger the value of this descritpor is, the lower the biological activity of the compound is. The second important descriptor Mor12m is a 3D-molecule representation of structures based on electron diffraction (3DMoRSE) descriptor. Mor12m is weighted by atomic masses.54 It suggested that the molecular size has a close correlation with the activities of the studied compounds. The third important descriptor is T(O..Cl) descriptor (topological descriptors) representing the sum of topological distances between O and Cl.55 From the above molecular docking analysis, the O and Cl atoms are involved in the formation of hydrogen bond between these derivatives and AChBP. The selection of the descriptor T(O..Cl) indicates the ability to form hydrogen bond of compounds has a high correlation with their activities. RDF140u (radial distribution function at 14.0 Å/unweighted) belongs to RDF descriptors which can be interpreted as the probability distribution of finding an atom in a spherical volume of radius R.56 The RDF descriptors can provide information such as interatomic distances in the entire molecule, bond distances, ring types, planar, and nonplanar systems and atom types. Mor16m descriptor is another 3D-MoRSE descriptor. BELm7 is the lowest eigenvalue n 7 of Burden matrix weighted by atomic masses.57 The Burden descriptors can reflect relevant aspects of molecular structure and are therefore useful for similarity searching. Except EEig08x, all other five descriptors have a positive correlation with the insecticidal activities of the studied compounds, indicating that the increase of the value of the descriptor will improve the biological activity of the compound in the application domain of the built model. In summary, three novel series of N3-substituted imidacloprid derivatives were designed and synthesized, and their structures were characterized by NMR spectroscopy, mass spectrometry, elemental analysis, and single-crystal X-ray diffraction analysis. The insecticidal activities against Aphis craccivora were evaluated. Preliminary bioassays indicated that some title compounds exhibited excellent insecticidal activities against Aphis craccivora, and their insecticidal activities against Aphis craccivora were comparable to those of the control imidacloprid. SAR analysis indicated that the size, electron density, and distribution of the substituents at the N3 position are critical to the derivatives’ activity. Furthermore, the

Compounds in test set. 5440



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(8) Kovganko, N. V.; Kashkan, Z. N. Advances in the Synthesis of Neonicotinoids. Russ. J. Org. Chem. 2004, 40, 1709−1726. (9) Nauen, R.; Denholm, I. Resistance of insect pests to neonicotinoid insecticides: current status and future prospects. Arch. Insect Biochem. Physiol. 2005, 58, 200−215. (10) Ninsin, K. D. Acetamiprid resistance and cross-resistance in the diamondback moth Plutella xylostella. Pest Manage. Sci. 2004, 60, 839− 841. (11) Sanchez, D. M.; Hollingworth, R. M.; Grafius, E. J.; Moyer, D. D. Resistance and cross-resistance to neonicotinoid insecticides and spinosad in the Colorado potato beetle, Leptinotarsa decemlineata (Say) (Coleoptera: Chrysomelidae). Pest. Manage. Sci. 2006, 62, 30− 37. (12) Gorman, K. G.; Devine, G.; Bennison, J.; Coussons, P.; Punchard, N.; Denholm, I. Report of resistance to the neonicotinoid insecticide imidacloprid in Trialeurodes vaporariorum (Hemiptera: Aleyrodidae). Pest. Manage. Sci. 2007, 63, 555−558. (13) Liu, Z. W.; Williamson, M. S.; Lansdell, S. J.; Denholm, I.; Han, Z. J.; Millar, N. S. A nicotinic acetylcholine receptor mutation conferring target-site resistance to imidacloprid in Nilaparvata lugens (brown planthopper). Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 8420− 8425. (14) Jeschke, P.; Nauen, R.; Sparks, T. C.; Loso, M. R.; Watson, G. B.; Babcock, J. M.; Kramer, V. J.; Zhu, Y.; Nugent, B. M.; Thomas, J. D.; Crouse, G. D.; Dripps, J. E.; Waldron, C.; Salgado, V. L.; Schnatterer, S.; Holmes, K. A.; Pitterna, T. Nervous System. In Modern Crop Protection Compounds, 2nd ed.; Krämer, W., Schirmer, U., Jeschke, P., Witschel, M. Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2012; Vol. 1−3, Chapter 32. (15) Su, W. C.; Zhou, Y. H.; Ma, Y. Q.; Wang, L.; Zhang, Z.; Rui, C. H.; Duan, H. X.; Qin, Z. H. N′-Nitro-2-hydrocarbylidenehydrazinecarboximidamides: design, synthesis, crystal structure, insecticidal activity, and structure−activity relationships. J. Agric. Food Chem. 2012, 60, 5028−5034. (16) Tian, Z. Z.; Shao, X. S.; Li, Z.; Qian, X. H.; Huang, Q. C. Synthesis, insecticidal activity, and QSAR of novel nitromethylene neonicotinoids with tetrahydropyridine fixed cis configuration and exoring ether modification. J. Agric. Food Chem. 2007, 55, 2288−2292. (17) Shao, X. S.; Li, Z.; Qian, X. H.; Xu, X. Y. Design, synthesis, and insecticidal activities of novel analogues of neonicotinoids: replacement of nitromethylene with nitroconjugated system. J. Agric. Food Chem. 2009, 57, 951−957. (18) Tomizawa, M.; Durkin, K. A.; Ohno, I.; Nagura, K.; Manabe, M.; Kumazawa, S.; Kagabu, S. N-Haloacetylimino neonicotinoids: potency and molecular recognition at the insect nicotinic receptor. Bioorg. Med. Chem. Lett. 2011, 21, 3583−3586. (19) Ye, Z. J.; Shi, L. N.; Shao, X. S.; Xu, X. Y.; Xu, Z. P.; Li, Z. Pyrrole- and Dihydropyrrole-Fused Neonicotinoids: Design, Synthesis, and Insecticidal Evaluation. J. Agric. Food Chem. 2013, 61, 312−319. (20) Zhang, W. W.; Yang, X. B.; Chen, W. D.; Xu, X. Y.; Li, L.; Zhai, H. B.; Li, Z. Design, multicomponent synthesis, and bioactivities of novel neonicotinoid analogues with 1,4-dihydropyridine scaffold. J. Agric. Food Chem. 2010, 58, 2741−2745. (21) Yu, H. B.; Qin, Z. F.; Dai, H.; Zhang, X.; Qin, X.; Wang, T. T.; Fang, J. X. Synthesis and insecticidal activity of N-substituted (1,3thiazole)alkyl sulfoximine derivatives. J. Agric. Food Chem. 2008, 56, 11356−11360. (22) Zhu, Y. M.; Loso, M. R.; Watson, G. B.; Sparks, T. C.; Rogers, R. B.; Huang, J. X.; Gerwick, B. C.; Babcock, J. M.; Kelley, D.; Hegde, V. B.; Nugent, B. M.; Renga, J. M.; Denholm, I.; Gorman, K.; DeBoer, G. J.; Hasler, J.; Meade, T.; Thomas, J. D. Discovery and characterization of sulfoxaflor, a novel insecticide targeting sap-feeding pests. J. Agric. Food Chem. 2011, 59, 2950−2957. (23) Shao, X. S.; Fu, H.; Xu, X. Y.; Xu, X. L.; Liu, Z. W.; Li, Z.; Qian, X. H. Divalent and oxabridged neonicotinoids constructed by dialdehydes and nitromethylene analogues of imidacloprid: design, synthesis, crystal structure, and insecticidal activities. J. Agric. Food Chem. 2010, 58, 2696−2702.

molecular docking analysis indicated that imidacloprid and compounds 26 and 11 form the similar hydrophobic and van der Waals interactions with Trp53, Met114, Trp143, Tyr185, and Tyr192 in the binding pocket. Compared with imidacloprid, the more favorable van der Waals and hydrophobic interactions from the methylbenzene group and the aromatic ring of chloro-phenyl group of compound 26, and stronger hydrogen bonding interactions from the nitro and sulfonyl group with the binding pocket contribute to higher insecticidal activity. From the QSAR analysis, the molecular size, shape, and the ability to form hydrogen bond are important for insecticidal potency. From the built QSAR model, the decrease of the value of selected descriptor EEig08x and the increase of the value of other descriptors will be favorable to improve the insecticidal activity of compound. These results can promote the understanding the interaction mechanism of these derivatives and nAChR and provide the useful information for further structural modification. Further structural optimization and mode of action studies are currently underway in our laboratories

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ASSOCIATED CONTENT

S Supporting Information *

Melting point,1H NMR, 13C NMR, elemental analysis, and ESI-MS spectra for the target compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*For Y.-Q.L.: phone, +86(0)931-8618795; fax, +86(0)931-8915686; E-mail, [email protected]. *For H.-X.L.: phone, +86(0)931-8618795; fax, +86(0)931-8915686; E-mail, [email protected]. Author Contributions §

These authors contributed equally to this work.

Funding

This work was supported financially by the National Natural Science Foundation of China (30800720, 31371975, 31360451), the Fundamental Research Funds for the Central Universities (lzujbky-2013-69), and the Young Scholars Science Foundation of Lanzhou Jiaotong University (2011011). Notes

The authors declare no competing financial interest.

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REFERENCES

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