English

• 1. INTRODUCTION

  Pesticides play an important role in improving the yield and quality of crops^[1-3]. However, with the long-term and large-scale use of pesticides, problems such as drug resistance have become increasingly prominent^{[4, 5]}. The development of new and efficient pesticide active molecules can effectively alleviate the problems caused by drug resistance, and the discovery of lead compounds is the basis of innovative drug research^{[6, 7]}.

  Fluopyram successfully developed by Bayer company is a new broad-spectrum amide fungicide acting on succinate dehydrogenase (SDH)^{[8, 9]}. At the same time, it has been widely used in the control of soil nematodes in recent years due to its high efficiency and novel mechanism of action^[10]. At present, researches on the tri-factor relationship among fluopyram structural modification, fungicidal activity and nematicidal activity are relatively lacking.

  In our previous work, combined with the newly reported structures of new active ingredients in fungicide and nematicide^[11-20], four series of amide derivatives with fluopyram as the molecular skeleton were designed and synthesized by introducing sulfide and sulfone substructures into the amide bridge (Fig. 1). Subsequently, the nematicidal and fungicidal activities of the target compounds were measured, and compound h-I-9 displayed excellent fungicidal activity and compounds h-I-11, h-II-6 and h-IV-1~h-IV-6 exhibited good nematicidal activity (Fig. 2)^[21-23]. The structure-activity relationships indicated that the N-sulfonyl amide containing aromatic sulfide substructure showed good nematicidal activity^[21-23]. On this basis, in order to explore the effect of structural modification of the N-sul-fonyl amide on nematicidal and fungicidal activities, a series of N-sulfonyl amide compounds directly connected to the aromatic rings was designed and synthesized by shortening the amide bridge (Fig. 2). The preliminary molecular docking simulation indicated that the designed molecules could interact with the receptor Ascaris suum SDH (PDB ID: 3VRB) (Fig. 2).

  Figure 1

  

  Figure 1.  Structural modification of the amide bridge in our previous work

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  Figure 2

  

  Figure 2.  Design strategy of the target compounds

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  2. EXPERIMENTAL

  2.1 Materials and methods

  All reaction reagents were of analytical grade. Melting points for target compounds were determined on an X-4 binocular microscope (Gongyi Tech. Instrument Co., Henan, China). Proton (¹H)- and carbon-13 (¹³C)-nuclear magnetic resonance (NMR) were obtained on a Bruker-500 MHz spectrometer, and chemical-shift values (δ) were reported as parts per million (ppm) with tetramethylsilane as the internal standard. Elemental analyses (EA) were determined on an Elementar Vario EL elemental analyzer. High resolution mass spectrometry (HRMS) was recorded using a high resolution mass spectrometer (Varian 7.0T FTMS). The X-ray single-crystal structure was determined on a Bruker D8 Venture diffractometer with Mo-Kα radiation (λ = 0.71073 Å). Column chromatography purification was carried out using silica gel (200~300 mesh).

  2.2 Synthesis of the target compounds

  2.2.1   General synthetic procedure for the target compounds I-1~I-4, I-6~I-9 and I-11~I-14

  N-((2-Methoxycarbonylphenyl)sulfonyl)-2-(trifluoromethyl) benzamide (I-1) was synthesized as follows. A mixture of 2-(trifluoromethyl)benzoic acid (0.40 g, 2.1 mmol), 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 0.48 g, 2.5 mmol) and 4-dimethylaminopyridine (DMAP, 0.62 g, 5.0 mmol) in N, N-dimethylformamide (DMF, 10 mL) was stirred for 30 min at room temperature, followed by the addition of methyl 2-sulfamoylbenzoate (0.50 g, 2.3 mmol). The reaction was continued to stir for 8 h, and the progress was monitored by TLC. After completion, the mixture was poured into the dilute hydrochloric acid aqueous solution. The resulting precipitate was filtered to provide the product, which was purified by using ethyl acetate to recrystallize. The products could also be purified by dissolving in potassium carbonate aqueous solution, washing with ethyl acetate and using the dilute hydrochloric acid aqueous solution to acidize the water layer to produce the white precipitate, yield 78%.

  N-((2-Methoxycarbonylphenyl)sulfonyl)-2-(trifluoromethyl) benzamide (I-1): White granules, yield 78%, m.p. 140~141 ℃. ¹H NMR (500 MHz, DMSO-d₆) δ 12.99 (s, 1H, CONHSO₂), 8.22 (dd, J = 7.7, 1.0 Hz, 1H, Ph-H), 7.89~7.70 (m, 6H, Ph–H), 7.64 (d, J = 7.5 Hz, 1H, Ph–H), 3.89 (s, 3H, COOCH₃). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.4, 165.9, 136.3, 134.6, 133.3, 133.0, 132.8, 131.7, 131.2, 129.6, 129.0, 127.1 (q, J = 3.8 Hz), 126.6 (q, J = 32.8 Hz), 123.8 (q, J = 273.4 Hz), 53.6. Anal. Calcd. (%) for C₁₆H₁₂F₃NO₅S: C, 49.62; H, 3.12; N, 3.62. Found (%): C, 49.53; H, 3.30; N, 3.51.

  N-((2-Methoxycarbonylphenyl)sulfonyl)-2-chloro-4-(methylsulfonyl) benzamide (I-2): White granules, yield 79%, m.p. 213~214 ℃. ¹H NMR (500 MHz, DMSO-d₆) δ 13.10 (s, 1H, CONHSO₂), 8.23 (d, J = 7.4 Hz, 1H, Ph–H), 8.09 (d, J = 1.3 Hz, 1H, Ph–H), 7.98 (dd, J = 8.0, 1.4 Hz, 1H, Ph-H), 7.84 (pd, J = 7.5, 1.5 Hz, 2H, Ph-H), 7.79~7.73 (m, 2H, Ph-H), 3.87 (s, 3H, COOCH₃), 3.33 (s, 3H, SO₂CH₃). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.3, 164.4, 144.3, 138.7, 136.5, 134.7, 132.8, 131.5, 131.4, 130.4, 129.7, 128.7, 126.3, 53.7, 43.5. Anal. Calcd. (%) for C₁₆H₁₄ClNO₇S₂: C, 44.50; H, 3.27; N, 3.24. Found (%): C, 44.39; H, 3.44; N, 3.11.

  N-((2-Methoxycarbonylphenyl)sulfonyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (I-3): White granules, yield 82%, m.p. 190~191 ℃. ¹H NMR (500 MHz, DMSO-d₆) δ 12.40 (s, 1H, CONHSO₂), 8.60 (s, 1H, pyrazole-H), 8.18~8.13 (m, 1H, Ph-H), 7.82~7.75 (m, 2H, Ph–H), 7.73~7.68 (m, 1H, Ph–H), 7.09 (t, J = 53.7 Hz, 1H, CHF₂), 3.95 (s, 3H, pyrazole-CH₃), 3.88 (s, 3H, OCH₃). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.3, 159.7, 146.4 (t, J = 23.9 Hz), 137.1, 135.4, 134.3, 132.6, 131.3, 131.3, 129.6, 113.5, 109.8 (t, J = 235.6 Hz), 53.6, 40.1. H RMS (ESI) m/z: calcd. for C₁₄H₁₄F₂N₃O₅S⁺ 374.0617, found 374.0612 [M + H]⁺.

  N-((2-Methoxycarbonylphenyl)sulfonyl)-2-methyl-4-(trifluoromethyl) thiazole-5-carboxamide (I-4): White needle, yield 77%, m.p. 141~142 ℃. ¹H NMR (500 MHz, DMSO-d₆) δ 8.14 (d, J = 7.5 Hz, 1H, Ph-H), 7.84~7.75 (m, 2H, Ph-H), 7.70 (dd, J = 7.1, 1.5 Hz, 1H, Ph-H), 3.86 (s, 3H, OCH₃), 2.73 (s, 3H, thiazole-CH₃). ¹³C NMR (126 MHz, DMSO-d₆) δ 169.2, 167.4, 158.9, 141.2, 140.9, 137.1, 134.1, 132.7, 131.3, 131.1, 129.5, 120.4 (q, J = 272.2 Hz), 53.5, 19.2. Anal. Calcd. (%) for C₁₄H₁₁F₃N₂O₅S₂: C, 41.18; H, 2.72; N, 6.86. Found (%): C, 41.03; H, 3.02; N, 6.71.

  N-((4-Acetamidophenyl)sulfonyl)-2-(trifluoromethyl)benzamide (I-6): White granules, yield 81%, m.p. 234~236 ℃. ¹H NMR (500 MHz, DMSO-d₆) δ 12.72 (s, 1H, CONHSO₂), 10.42 (s, 1H, CONH), 7.96~7.90 (m, 2H, Ph–H), 7.87~7.82 (m, 2H, Ph–H), 7.81~7.68 (m, 3H, Ph–H), 7.57 (d, J = 7.4 Hz, 1H, Ph–H), 2.12 (s, 3H, COCH₃). ¹³C NMR (126 MHz, DMSO-d₆) δ 169.7, 165.9, 144.5, 133.6, 133.1, 132.6, 131.5, 129.6, 128.9, 127.0 (q, J = 5.0 Hz), 126.3 (q, J = 31.5 Hz), 123.7 (q, J = 274.7 Hz), 118.8, 24.7. HRMS (ESI) m/z: calcd. for C₁₆H₁₄F₃N₂O₄S⁺ 387.0621, found 387.0619 [M + H]⁺.

  N-((4-Acetamidophenyl)sulfonyl)-2-chloro-4-(methylsulfonyl) benzamide (I-7): White granules, yield 75%, m.p. 256~258 ℃. ¹H NMR (500 MHz, DMSO-d₆) δ 12.89 (s, 1H, CONHSO₂), 10.43 (s, 1H, CONH), 8.06 (d, J = 1.5 Hz, 1H, Ph–H), 7.98~7.91 (m, 3H, Ph–H), 7.85 (d, J = 8.9 Hz, 2H, Ph-H), 7.74 (d, J = 8.0 Hz, 1H, Ph–H), 3.32 (s, 3H, SO₂CH₃), 2.12 (s, 3H, COCH₃). ¹³C NMR (126 MHz, DMSO-d₆) δ 169.7, 164.3, 144.7, 144.2, 138.9, 132.5, 131.3, 130.4, 129.6, 128.6, 126.3, 118.9, 43.5, 24.7. Anal. Calcd. (%) for C₁₆H₁₅ClN₂O₆S₂: C, 44.60; H, 3.51; N, 6.51. Found (%): C, 44.52; H, 3.72; N, 6.39.

  N-((4-Acetamidophenyl)sulfonyl)-3-(difluoromethyl)-1-me-thyl-1H-pyrazole-4-carboxamide (I-8): White needle, yield 83%, decomposed at 228 ℃. ¹H NMR (500 MHz, DMSO-d₆) δ 12.26 (s, 1H, CONHSO₂), 10.39 (s, 1H, CONH), 8.53 (s, 1H, pyrazole-H), 7.92 (d, J = 8.8 Hz, 2H, Ph–H), 7.81 (d, J = 8.8 Hz, 2H, Ph–H), 7.11 (t, J = 53.8 Hz, 1H, CHF₂), 3.93 (s, 3H, pyrazole-CH₃), 2.10 (s, 3H, COCH₃). ¹³C NMR (126 MHz, DMSO-d₆) δ 169.6, 159.7, 146.3 (t, J = 23.9 Hz), 144.4, 135.4, 133.2, 129.5, 118.9, 113.6, 109.8 (t, J = 235.6 Hz), 24.6. Anal. Calcd. (%) for C₁₄H₁₄F₂N₄O₄S: C, 45.16; H, 3.79; N, 15.05. Found (%): C, 45.03; H, 3.95; N, 14.91.

  N-((4-Acetamidophenyl)sulfonyl)-2-methyl-4-(trifluoromethyl) thiazole-5-carboxamide (I-9): White granules, yield 63%, m.p. 215~216 ℃. ¹H NMR (500 MHz, DMSO-d₆) δ 10.41 (s, 1H, CONH), 7.90 (d, J = 8.9 Hz, 2H, Ph-H), 7.82 (d, J = 8.9 Hz, 2H, Ph–H), 2.73 (s, 3H, thiazole-CH₃), 2.11 (s, 3H, COCH₃). ¹³C NMR (126 MHz, DMSO-d₆) δ 169.7, 169.5, 158.4, 144.6, 140.9 (q, J = 36.5 Hz), 132.5, 132.3, 129.6, 120.3 (q, J = 272.2 Hz), 118.9, 24.6, 19.2. HRMS (ESI) m/z: calcd. for C₁₄H₁₃F₃N₃O₄S₂⁺ 408.0294, found 408.0291 [M + H]⁺.

  N-((3-(Dimethylcarbamoyl)pyridin-2-yl)sulfonyl)-2-(trifluoromethyl) benzamide (I-11): White needle, yield 71%, m.p. 190~192 ℃. ¹H NMR (500 MHz, DMSO-d₆) δ 13.15 (s, 1H, CONHSO₂), 8.80 (dd, J = 4.6, 1.4 Hz, 1H, pyridine-H), 8.04 (dd, J = 7.8, 1.4 Hz, 1H, pyridine-H), 7.87~7.79 (m, 3H, Ph–H and pyridine-H), 7.75 (dd, J = 12.4, 7.6 Hz, 2H, Ph–H), 3.02 (s, 3H, CH₃), 2.87 (s, 3H, CH₃). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.9, 166.1, 151.3, 150.0, 137.6, 133.6, 133.1 (q, J = 1.3 Hz), 133.0, 131.8, 129.4, 128.3, 127.1 (q, J = 5.0 Hz), 126.6 (q, J = 32.8 Hz), 123.7 (q, J = 274.7 Hz), 38.7, 34.9. Anal. Calcd. (%) for C₁₆H₁₄F₃N₃O₄S: C, 47.88; H, 3.52; N, 10.47. Found (%): C, 47.75; H, 3.79; N, 10.33.

  N-((3-(Dimethylcarbamoyl)pyridin-2-yl)sulfonyl)-2-chlor-4-(methylsulfonyl)benzamide (I-12): White needle, yield 69%, m.p.: 231~232 ℃. ¹H NMR (500 MHz, DMSO-d₆) δ 13.08 (s, 1H, CONHSO₂), 8.81 (dd, J = 4.6, 1.4 Hz, 1H, pyridine-H), 8.11 (s, 1H, Ph-H), 8.06 (dd, J = 7.8, 1.3 Hz, 1H, pyridine-H), 8.00 (dd, J = 8.0, 1.5 Hz, 1H, Ph–H), 7.85~7.80 (m, 2H, pyridine-H and Ph-H), 3.35 (s, 3H, SO₂CH₃), 3.02 (s, 3H, CH₃), 2.87 (s, 3H, CH₃). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.1, 165.5, 151.2, 150.1, 144.4, 138.4, 137.7, 133.6, 131.5, 130.7, 128.8, 128.5, 126.3, 43.5, 38.7, 34.9. HRMS (ESI) m/z: calcd. for C₁₆H₁₇ClN₃O₆S₂⁺ 446.0242, found 446.0240 [M + H]⁺.

  N-((3-(Dimethylcarbamoyl)pyridin-2-yl)sulfonyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (I-13): Transparent needle, yield 72%, m.p. 200~201 ℃. ¹H NMR (500 MHz, DMSO-d₆) δ 12.63 (s, 1H, CONHSO₂), 8.70 (dd, J = 4.6, 1.3 Hz, 1H, pyridine-H), 8.61 (s, 1H, pyrazole-H), 8.01 (dd, J = 7.8, 1.3 Hz, 1H, pyridine-H), 7.76 (dd, J = 7.8, 4.7 Hz, 1H, pyridine-H), 7.03 (t, J = 53.7 Hz, 1H, CHF₂), 3.96 (s, 3H, pyrazole-CH₃), 3.00 (s, 3H, CH₃), 2.87 (s, 3H, CH₃). ¹³C NMR (126 MHz, DMSO-d₆) δ 166.2, 160.7, 151.7, 149.9, 146.3 (t, J = 235.6 Hz), 137.6, 135.6, 133.2, 128.2, 113.4, 109.7 (t, J = 235.6 Hz), 40.1, 38.7, 34.8. HRMS (ESI) m/z: calcd. for C₁₄H₁₆F₂N₅O₄S⁺ 388.0886, found 388.0881 [M + H]⁺.

  N-((3-(Dimethylcarbamoyl)pyridin-2-yl)sulfonyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide (I-14): White granules, yield 68%, m.p. 193~195 ℃. ¹H NMR (500 MHz, DMSO-d₆) δ 8.78~8.70 (m, 1H, pyridine-H), 8.07~7.98 (m, 1H, pyridine-H), 7.82~7.74 (m, 1H, pyridine-H), 3.00 (s, 3H, CH₃), 2.84 (s, 3H, CH₃), 2.75 (s, 3H, thiazole-H). ¹³C NMR (126 MHz, DMSO-d₆) δ 169.6, 166.1, 159.7, 151.6, 149.8, 141.2, 137.6, 133.3, 132.4, 128.3, 120.3 (q, J = 272.2 Hz), 38.7, 34.8, 19.3. HRMS (ESI) m/z: calcd for C₁₄H₁₄F₃N₄O₄S₂⁺ 423.0403, found 423.0401 [M + H]⁺.

  2.2.2   General synthetic procedure for the target compounds I-5, I-10 and I-15

  N-((2-Methoxycarbonylphenyl)sulfonyl)-3, 4-dichloroiso-thiazole-5-carboxamide (I-5) was prepared according to the following method. A solution of 3, 4-dichloroisothiazole-5-car- boxylic acid (0.40 g, 2.0 mmol) and 2-(1H-benzotriazole- 1-yl)-1, 1, 3, 3-tetramethyluronium tetrafluoroborate (TBTU, 0.78 g, 2.4 mmol) in N, N-dimethylformamide (10 mL) was stirred for 1 h at 40 ℃, followed by the addition of methyl 2-sulfamoylbenzoate (0.47 g, 2.2 mmol) and N, N-diisopropyl- ethylamine (DIEA, 0.57 g, 4.4 mmol). The mixture was reacted for 8 h at 40 ℃, and the progress was monitored by TLC. After completion, the reaction was poured into the dilute hydrochloric acid aqueous solution. The resulting precipitate was filtered to provide the product, which was purified by dissolving in potassium carbonate aqueous solution, filtration and acidizing with the dilute hydrochloric acid aqueous solution to produce the white pure precipitate, yield 47%.

  N-((2-Methoxycarbonylphenyl)sulfonyl)-3, 4-dichloroiso-thiazole-5-carboxamide (I-5): White granules, yield 47%, m.p. 135~136 ℃. ¹H NMR (500 MHz, DMSO-d₆) δ 8.07 (d, J = 7.7 Hz, 1H, Ph–H), 7.66~7.58 (m, 2H, Ph–H), 7.51~7.45 (m, 1H, Ph–H), 3.77 (s, 3H, COOCH₃). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.5, 159.9, 159.5, 148.0, 141.2, 132.6, 131.8, 130.2, 130.1, 128.3, 120.8, 52.9. Anal. Calcd. (%) for C₁₂H₈Cl₂N₂O₅S₂: C, 36.47; H, 2.04; N, 7.09. Found (%): C, 36.40; H, 2.25; N, 6.93.

  N-((4-Acetamidophenyl)sulfonyl)-3, 4-dichloroisothiazole-5-carboxamide (I-10): White needle, yield 42%, decomposed at 209 ℃. ¹H NMR (500 MHz, DMSO-d₆) δ 10.30 (s, 1H, CONH), 7.90~7.84 (m, 2H, Ph–H), 7.78~7.72 (m, 2H, Ph–H), 2.09 (s, 3H, COCH₃). ¹³C NMR (126 MHz, DMSO-d₆) δ 169.4, 158.5, 157.0, 147.9, 143.6, 135.1, 129.3, 121.7, 118.7, 24.6. HRMS (ESI) m/z: calcd. for C₁₂H₁₀Cl₂N₃O₄S₂⁺ 393.9484, found 393.9482 [M + H]⁺.

  N-((3-(Dimethylcarbamoyl)pyridin-2-yl)sulfonyl)-3, 4-dichloroisothiazole-5-carboxamide (I-15): White granular, yield 41%, m.p. 219~220 ℃. ¹H NMR (500 MHz, DMSO-d₆) δ 8.72~8.68 (m, 1H, pyridine-H), 7.93~7.88 (m, 1H, pyridine-H), 7.71~7.67 (m, 1H, pyridine-H), 3.01 (s, 3H, CH₃), 2.89 (s, 3H, CH₃). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.0, 160.1, 158.3, 154.6, 149.2, 148.1, 137.3, 132.4, 126.7, 121.3, 38.8, 34.8. HRMS (ESI) m/z: calcd. for C₁₂H₁₁Cl₂N₄O₄S₂⁺ 408.9593, found 408.9589 [M + H]⁺.

  2.3 X-ray crystal structure determination

  The crystals of the target compounds I-8 and I-9 were cultivated from a mixed solvent of methanol, dichloromethane and n-hexane, respectively. All measurements were made on a Bruker D8 Venture diffractometer with Mo-Kα radiation (λ = 0.71073 Å). The crystal data of compound I-8 were collected at 296.15 K and the colorless crystal is of triclinic system, space group P2₁/n with a = 7.9151(10), b = 8.5637(11), c = 12.2022(15) Å, α = 87.740(2)º, β = 86.865(2)º, γ = 77.869(2)º, V = 807.09(18) ų, Z = 2, F(000) = 384, density (calculated) = 1.532 g/cm³, and linear absorption coefficient 0.251 mm^-1. All of the non-H atoms were refined anisotropically by full-matrix least-squares to give the final R = 0.0408 and wR = 0.1068 (w = 1/[σ²(F_o²) + (0.0547P)² + 0.4910P], where P = (F_o² + 2F_c²)/3) with (Δ/σ)_max = 0.000 and S = 1.070 by using the SHELXL program. The crystal data of compound I-9 were collected at 298 K and the colorless crystal is of triclinic system, space group P2₁/n with a = 8.4911(8), b = 8.6053(9), c = 14.5808(15) Å, α = 80.745(2)º, β = 77.1190(10)º, γ = 74.6030(10)º, V = 995.44(17) ų, Z = 2, F(000) = 416, density (calculated) = 1.359 g/cm³, and linear absorption coefficient 0.317 mm^-1. All of the non-H atoms were refined anisotropically by full-matrix least-squares to give the final R = 0.0567 and wR = 0.1779 (w = 1/[σ²(F_o²) + (0.2000P)²], where P = (F_o² + 2F_c²)/3) with (Δ/σ)_max = 0.001 and S = 0.723 by using the SHELXL program. The crystal structures were solved by direct methods with SHELXS-2014/6 program.

  2.4 Biological activity screening

  2.4.1   Fungicidal activity

  The in vitro fungicidal activities of target compounds were investigated using a mycelia growth inhibition method as previously reported^[24]. The target compound (5.0 mg) was dissolved in dimethyl sulfoxide (40 μL), and then diluted with sterilized water containing 0.1% tween-80 to obtain a mother liquor with a concentration of 500 μg⋅mL^-1. 1 mL of the stock solution was transferred into a Petri dish with a diameter of 10 cm, and 9 mL of PDA was added to prepare the plate containing 50 μg⋅mL^-1 of the test compound. After solidifica- tion, fungi cake with a diameter of 7 mm was inoculated onto the plate and cultured at 25 ℃. After 3 days, the fungal colony diameters were used to calculate the growth inhibition rates. Common agricultural pathogens, including Gibberella zeae, Rhizoctonia solani, Physalospora piricola, Alternaria kikuchiana Tanaka, Colletotrichum capsici, Alternaria sp., were taken as the test objects. Fluopyram and carbendazim were adopted as the positive controls, and each treatment was performed with at least three replicates.

  2.4.2   Nematicidal activity

  The stock solution with a concentration of 100 μg⋅mL^-1 was prepared by dissolving the target compounds (5.0 mg) in dimethyl sulfoxide and diluting with sterilized water, and then 50 μL of the test solution was introduced into the wells of 24-well tissue culture plates. In each well, 50 μL of the third-stage juvenile suspension of Bursaphelenchus xylophilus was added, and the final concentration of nematodes was approximately 50 juveniles per 100 μL of water. The plates were covered and maintained at 25 ± 1 ℃, and each treatment was replicated three times. Nematode mortality was observed under a stereomicroscope after 24 h, and fluopyram and avermectin were used as the positive controls.

  3. RESULTS AND DISCUSSION

  3.1 Synthetic chemistry

  Herein, the target compounds I-1~I-15 were synthesized according to the procedures in Scheme 1. Firstly, EDCI and DMAP were adopted as condensing agents to prepare the target compounds I-1~I-4, I-6~I-9 and I-11~I-14. Subsequently, considering the low reactivity of 3, 4-dichloro- isothiazole-5-carboxylic acid, the target compounds I-5, I-10 and I-15 were synthesized by using the stronger condensing agents TBTU and DIEA. Finally, fifteen novel N-sulfonyl aromatic amide derivatives were identified and characterized by ¹H-NMR, ¹³C-NMR, EA and HRMS. In addition, the polarity of the target compounds was high so that it could only use dichloromethane and methanol as eluent for column chromatography to purify the products. For the purification methods of the target compounds, it would be more convenient to be dissolved in potassium carbonate aqueous solution, filtered and acidified with dilute hydrochloric acid to produce precipitation. On the other hand, column chroma- tography was not recommended due to wasting time and solvents.

  Figure 1

  

  Figure 1.  Synthetic route for the target compounds

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  3.2 Crystal structures and packing

  The crystal structures and packing of the target compounds I-8 and I-9 are shown in Fig. 3, respectively. The selected bond lengths and bond angles are listed in Table 1, and the dihedral angles in Table 2. From the data, the sum of bond angles O(4)–C(13)–N(4), O(4)–C(13)–C(14) and N(4)–C(13)–C(14) in compound I-8 is 360º, indicating the sp² hybridization state of atom C(13). Similarly, the atoms C(1) in I-8 and I-9 and C(13) in I-9 also adopt sp² hybridization state. In compound I-8, the bond angles of O(2)–S(1)–C(7), O(2)–S(1)–N(3), O(2)–S(1)–O(3), O(3)–S(1)–C(7), O(3)–S(1)–N(3) and C(7)–S(1)–N(3) are 109.56(10)°, 108.49(10)°, 119.29(10)°, 108.26(10)°, 103.54(10)° and 106.93(10)°, respectively, revealing that the atom S(1) is at the center of a tetrahedron. On this basis, the entire molecular configuration forms an "L" shape due to the planar structures of benzene ring, pyrazole ring and amide bond (O=C–N). Likewise, the entire molecular configuration of compound I-9 also forms an "L" shape. However, due to the difference in molecular structure, the configuration of the amide bonds in crystals I-8 and I-9 is completely opposite. The torsion angles of O(1)–C(1)–N(3)–H(3) and O(4)–C(13)–N(4)–H(4) in compound I-8, and O(1)–C(1)–N(2)–H(2) and O(4)–C(13)–N(3)–H(3) in compound I-9 are –130.4(2)°, –174.2(2)°, –169.7(2)° and 176.8(8)°, respectively, implying that the amide bond O(1)–C(1)–N(2)–H(2) is apparently non-planar. In addition, the dihedral angles between the amide plane (O(1)–C(1)–N(3)) and pyrazole ring and between the amide plane (O(1)–C(1)–N(2)) and thiazole ring are 16.95(0.14)° and 65.11(0.19)°, respectively, which indicates that a weak conjugation effect maybe exist between the amide plane (O(1)–C(1)–N(3)) and pyrazole ring. Therefore, under the combined influence of conjugation and induction effects, the bond lengths of O(1)=C(1) (1.210(3) Å) and O(4)=C(13) (1.223(3) Å) in compound I-8 are longer than those correspondingly in compound I-9. At the same time, owing to the direct connection to the sulfonyl group and pyrazole or thiazole ring, the corresponding amide bond length of O(1)=C(1) (1.210(3) Å for I-8 and 1.200(4) Å for I-9) is shorter than that of O(4)=C(13) (1.223(3) Å for I-8 and 1.218(4) Å for I-9). From Table 2, the planes between amide bond (O(4)–C(13)–N(4)) and benzene ring in I-8, between amide bond (O(1)–C(1)–N(3)) and pyrazole ring in I-8, and between amide bond (O(4)–C(13)–N(3)) and benzene ring in I-9, are approximately coplanar. On the other hand, the planes among the amide bonds O(1)–C(1)–N(2) and O(4)–C(13)–N(3) and between amide bond (O(1)–C(1)–N(2)) and benzene ring in I-9 are nearly vertical with the dihedral angles of 86.84(0.11)° and 87.99(0.15)°, respectively. Furthermore, from the crystal configurations of compounds I-8 and I-9, it could be found that there may be an electronic repulsion between the trifluoromethyl group and the carbonyl oxygen atom in compound I-9, while the presence of hydrogen atom in the difluoromethyl group reduced this repulsion effect. Based on the above reasons, the dihedral angle between the amide bond (O(1)–C(1)–N(3)) and the pyrazole ring in compound I-8 is smaller than that between the amide bond (O(1)–C(1)–N(2)) and the thiazole ring in I-9, with the corresponding dihedral angles of 16.95(0.14)° and 65.11(0.19)°, respectively (Fig. 3a and 3b). From the crystal packing, π-π interactions occur between the benzene rings, between the pyrazole rings and between the thiazole rings of the adjacent molecules, thus strengthening the integration of the crystal molecules (Figs. 3c and 3d).

  Figure 3

  

  Figure 3.  Crystal structures of I-8 (a), I-9 (b), and crystal packing of I-8 (c), I-9 (d)

  DownLoad: Full-Size Img PowerPoint

  Table 1

  

  Table 1.  Selected Bond Lengths (Å) and Bond Angles (°) for the Target Compounds I-8 and I-9

  DownLoad: CSV

  Compound I-8			Compound I-9
  Bond	Dist.		Bond	Dist.
  C(13)=O(4)	1.223(3)		C(13)=O(4)	1.218(4)
  C(13)–N(4)	1.359(3)		C(13)–N(3)	1.360(4)
  C(10)–N(4)	1.407(3)		C(10)–N(3)	1.400(4)
  C(10)=C(11)	1.379(3)		C(10)=C(9)	1.394(4)
  C(7)=C(12)	1.374(3)		C(7)=C(8)	1.375(4)
  C(7)–S(1)	1.753(2)		C(7)–S(2)	1.751(3)
  S(1)=O(2)	1.425(3)		S(2)=O(2)	1.419(2)
  S(1)–N(3)	1.653(3)		S(2)–N(2)	1.660(3)
  N(3)–C(1)	1.397(3)		N(2)–C(1)	1.370(4)
  C(1)=O(1)	1.210(3)		C(1)=O(1)	1.200(4)
  C(1)–C(2)	1.472(3)		C(1)–C(2)	1.498(5)
  N(1)=C(4)	1.331(3)		N(1)=C(4)	1.291(5)
  N(2)–C(3)	1.335(3)		S(1)–C(2)	1.697(4)
  C(2)–C(4)	1.417(3)		C(2)–C(3)	1.346(5)
  Angle	(°)		Angle	(°)
  O(1)–C(1)–N(3)	122.4(2)		O(1)–C(1)–N(2)	123.9(3)
  O(4)–C(13)–N(4)	122.4(2)		O(4)–C(13)–N(3)	121.9(3)
  O(4)–C(13)–C(14)	122.5(2)		O(4)–C(13)–C(14)	122.7(4)
  N(4)–C(13)–C(14)	115.1(2)		N(3)–C(13)–C(14)	115.4(4)
  O(2)–S(1)–O(3)	119.2(2)		O(2)–S(2)–O(3)	119.4(2)
  C(7)–S(1)–N(3)	106.9(2)		C(7)–S(2)–N(2)	104.3(2)
  O(2)–S(1)–N(3)	108.5(2)		O(2)–S(2)–N(2)	109.5(1)
  C(1)–C(2)–C(4)	124.6(2)		C(1)–C(2)–C(3)	127.0(3)
  C(7)–C(8)–C(9)	121.2(2)		C(7)–C(12)–C(11)	120.0(3)
  C(3)–N(2)–N(1)	112.6(2)		C(2)–S(1)–C(4)	89.9(2)
  C(13)–N(4)–C(10)	128.6(2)		C(13)–N(3)–C(10)	128.3(3)
  N(4)–C(10)–C(9)	123.1(2)		N(3)–C(10)–C(11)	123.7(3)

  Table 2

  

  Table 2.  Selected Dihedral Angles (°) for the Target Compounds I-8 and I-9

  DownLoad: CSV

  Compounds	Groups		Dihedral angles (°)
  I-8	Benzene ring	Pyrazole ring	65.19(0.10)
  I-8	Amide (O(4)–C(13)–N(4))	Benzene ring	14.63(0.17)
  I-8	Amide (O(4)–C(13)–N(4))	Pyrazole ring	59.30(0.21)
  I-8	Amide (O(4)–C(13)–N(4))	Amide (O(1)–C(1)–N(3))	69.05(0.24)
  I-8	Amide (O(1)–C(1)–N(3))	Benzene ring	71.07(0.22)
  I-8	Amide (O(1)–C(1)–N(3))	Pyrazole ring	16.95(0.14)
  I-9	Benzene ring	Thiazole ring	65.64(0.13)
  I-9	Amide (O(4)–C(13)–N(3))	Benzene ring	12.28(0.10)
  I-9	Amide (O(4)–C(13)–N(3))	Thiazole ring	54.33(0.27)
  I-9	Amide (O(4)–C(13)–N(3))	Amide (O(1)–C(1)–N(2))	86.84(0.11)
  I-9	Amide (O(1)–C(1)–N(2))	Benzene ring	87.99(0.15)
  I-9	Amide (O(1)–C(1)–N(2))	Thiazole ring	65.11(0.19)

  3.3 Biological activity

  The nematicidal activity of the target compounds against Bursaphelenchus xylophilus, with fluopyram and avermectin as the positive controls, was first screened at the test concentration of 50 μg⋅mL^-1. The results showed that the mortality rates of the positive controls were 100%, while the corresponding mortality rates of the target compounds were less than 30%. Combined with the structure-activity relationships obtained in the previous work, the N-sulfonyl amide directly connected to the aromatic rings was unbeneficial to the nematicidal activity, which may be related to the strong polarity of the target compounds. Subsequently, the fungicidal activity of the target compounds was evaluated and the results are displayed in Table 3. From the data, compared with the positive controls, the target compounds exhibited weak fungicidal activity. From the structural characteristics, there was no obvious regularity among the fungicidal activities of the target compounds. Interestingly, compound I-5 showed good fungicidal activity against Colletotrichum capsici with the inhibition rate of 61.7%. In a given category, compounds I-6~I-10 exhibited higher inhibition rates against Gibberella zeae than other target compounds in the preliminary activity screening. In addition, compounds I-11 and I-13~I-15 displayed better fungicidal activity against Alternaria sp. than other target compounds.

  Table 3

  

  Table 3.  Nematicidal and Fungicidal Activities of the Target Compounds at 50 μg⋅mL^-1

  DownLoad: CSV

  Compounds	Mortality of B. xylophilus (%)	Fungicidal inhibition rate (%)
  		GZ	RS	PP	AK	CC	AS
  I-1	21.3 ± 1.37	18.4 ± 0.47	12.9 ± 0.32	13.3± 0.86	8.7 ± 0.39	15.4 ± 0.62	8.9 ± 0.90
  I-2	12.4 ± 0.88	20.1 ± 0.26	11.3 ± 0.81	12.4 ± 0.29	10.0 ± 0.52	8.5 ± 0.29	17.2 ± 0.43
  I-3	8.9 ± 0.67	21.3 ± 0.37	5.8 ± 0.39	36.6 ± 0.41	7.8 ± 0.63	11.1 ± 0.24	11.6 ± 0.41
  I-4	13.3 ± 1.01	8.9 ± 0.71	12.7 ± 0.93	8.5 ± 0.40	9.4 ± 0.86	19.5 ± 0.62	16.7 ± 0.30
  I-5	17.8 ± 0.76	17.9 ± 0.78	11.6 ± 0.22	19.9 ± 0.59	9.3 ± 0.48	61.7 ± 0.58	8.1 ± 0.43
  I-6	19.4 ± 1.11	30.1 ± 0.42	10.9 ± 0.98	6.2 ± 0.29	6.2 ± 0.24	4.1 ± 0.24	2.9 ± 0.55
  I-7	25.8 ±1.34	26.7 ± 0.46	5.4 ± 0.66	3.5 ± 0.63	10.8 ± 0.58	5.0 ± 0.41	3.1 ± 0.70
  I-8	14.6 ± 0.93	22.0 ± 0.21	9.2 ± 0.98	7.8 ± 0.71	9.8 ± 0.53	9.7 ± 0.33	6.2 ± 0.60
  I-9	5.6 ± 0.55	32.1 ± 0.73	6.7 ± 0.53	5.4 ± 0.54	11.5 ± 0.75	9.0 ± 0.29	13.0 ± 0.49
  I-10	23.2 ± 1.42	20.1 ± 1.29	4.7 ± 0.39	10.6 ± 0.71	9.7 ± 0.48	9.2 ± 0.51	2.4 ± 0.49
  I-11	11.7 ± 0.79	16.5 ± 0.70	3.0 ± 0.59	5.6 ± 0.66	13.0 ± 0.29	12.6 ± 0.75	29.8 ± 0.85
  I-12	15.4 ± 0.92	15.8 ± 0.52	11.6 ± 0.78	4.3 ± 0.52	12.7 ± 0.82	15.7 ± 0.62	6.7 ± 0.25
  I-13	10.1 ± 0.37	8.6 ± 0.47	8.4 ± 0.55	22.1 ± 0.90	6.3 ± 0.48	20.6 ± 0.82	20.6 ± 0.65
  I-14	18.7 ± 0.78	13.4 ± 0.95	5.6 ± 0.50	3.9 ± 0.24	10.8 ± 0.41	16.7 ± 0.58	24.3 ± 1.20
  I-15	13.4 ± 0.66	17.1 ± 0.56	11.8 ± 0.27	12.2 ± 0.63	7.3 ± 0.29	3.6 ± 0.29	19.6 ± 0.90
  Carbendazim	--	100	100	100	53.6 ± 0.44	100	19.7 ± 0.52
  Fluopyram	100	92.3 ± 0.23	54.2 ± 0.47	56.9 ± 0.33	97.3 ± 0.53	50.5 ± 0.55	98.8 ± 0.66
  Avermectin	100	--	--	--	--	--	--
  GZ, Gibberella zeae; RS, Rhizoctonia solani; PP, Physalospora piricola; AK, Alternaria kikuchiana Tanaka; CC, Colletotrichum capsici; AS, Alternaria sp

  4. CONCLUSION

  In summary, fifteen novel N-sulfonyl aromatic amide derivatives were designed and synthesized, and their structures were characterized by ¹H- and ¹³C-NMR, EA and HRMS. The crystal structures of compounds I-8 and I-9 were obtained from X-ray diffraction, and the corresponding crystal configurations were discussed. The preliminary bioassay results indicated that the target compounds showed weak namaticidal activity, while compound I-5 displayed good fungicidal activity against Colletotrichum capsici with the inhibition rate of 61.7%.

  
  
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• 

  Figure 1  Structural modification of the amide bridge in our previous work

  下载: 全尺寸图片 幻灯片
  

  Figure 2  Design strategy of the target compounds

  下载: 全尺寸图片 幻灯片
  

  Figure 1  Synthetic route for the target compounds

  下载: 全尺寸图片 幻灯片
  

  Figure 3  Crystal structures of I-8 (a), I-9 (b), and crystal packing of I-8 (c), I-9 (d)

  下载: 全尺寸图片 幻灯片

  Table 1.  Selected Bond Lengths (Å) and Bond Angles (°) for the Target Compounds I-8 and I-9

  Compound I-8			Compound I-9
  Bond	Dist.		Bond	Dist.
  C(13)=O(4)	1.223(3)		C(13)=O(4)	1.218(4)
  C(13)–N(4)	1.359(3)		C(13)–N(3)	1.360(4)
  C(10)–N(4)	1.407(3)		C(10)–N(3)	1.400(4)
  C(10)=C(11)	1.379(3)		C(10)=C(9)	1.394(4)
  C(7)=C(12)	1.374(3)		C(7)=C(8)	1.375(4)
  C(7)–S(1)	1.753(2)		C(7)–S(2)	1.751(3)
  S(1)=O(2)	1.425(3)		S(2)=O(2)	1.419(2)
  S(1)–N(3)	1.653(3)		S(2)–N(2)	1.660(3)
  N(3)–C(1)	1.397(3)		N(2)–C(1)	1.370(4)
  C(1)=O(1)	1.210(3)		C(1)=O(1)	1.200(4)
  C(1)–C(2)	1.472(3)		C(1)–C(2)	1.498(5)
  N(1)=C(4)	1.331(3)		N(1)=C(4)	1.291(5)
  N(2)–C(3)	1.335(3)		S(1)–C(2)	1.697(4)
  C(2)–C(4)	1.417(3)		C(2)–C(3)	1.346(5)
  Angle	(°)		Angle	(°)
  O(1)–C(1)–N(3)	122.4(2)		O(1)–C(1)–N(2)	123.9(3)
  O(4)–C(13)–N(4)	122.4(2)		O(4)–C(13)–N(3)	121.9(3)
  O(4)–C(13)–C(14)	122.5(2)		O(4)–C(13)–C(14)	122.7(4)
  N(4)–C(13)–C(14)	115.1(2)		N(3)–C(13)–C(14)	115.4(4)
  O(2)–S(1)–O(3)	119.2(2)		O(2)–S(2)–O(3)	119.4(2)
  C(7)–S(1)–N(3)	106.9(2)		C(7)–S(2)–N(2)	104.3(2)
  O(2)–S(1)–N(3)	108.5(2)		O(2)–S(2)–N(2)	109.5(1)
  C(1)–C(2)–C(4)	124.6(2)		C(1)–C(2)–C(3)	127.0(3)
  C(7)–C(8)–C(9)	121.2(2)		C(7)–C(12)–C(11)	120.0(3)
  C(3)–N(2)–N(1)	112.6(2)		C(2)–S(1)–C(4)	89.9(2)
  C(13)–N(4)–C(10)	128.6(2)		C(13)–N(3)–C(10)	128.3(3)
  N(4)–C(10)–C(9)	123.1(2)		N(3)–C(10)–C(11)	123.7(3)

  下载: 导出CSV

  Table 2.  Selected Dihedral Angles (°) for the Target Compounds I-8 and I-9

  Compounds	Groups		Dihedral angles (°)
  I-8	Benzene ring	Pyrazole ring	65.19(0.10)
  I-8	Amide (O(4)–C(13)–N(4))	Benzene ring	14.63(0.17)
  I-8	Amide (O(4)–C(13)–N(4))	Pyrazole ring	59.30(0.21)
  I-8	Amide (O(4)–C(13)–N(4))	Amide (O(1)–C(1)–N(3))	69.05(0.24)
  I-8	Amide (O(1)–C(1)–N(3))	Benzene ring	71.07(0.22)
  I-8	Amide (O(1)–C(1)–N(3))	Pyrazole ring	16.95(0.14)
  I-9	Benzene ring	Thiazole ring	65.64(0.13)
  I-9	Amide (O(4)–C(13)–N(3))	Benzene ring	12.28(0.10)
  I-9	Amide (O(4)–C(13)–N(3))	Thiazole ring	54.33(0.27)
  I-9	Amide (O(4)–C(13)–N(3))	Amide (O(1)–C(1)–N(2))	86.84(0.11)
  I-9	Amide (O(1)–C(1)–N(2))	Benzene ring	87.99(0.15)
  I-9	Amide (O(1)–C(1)–N(2))	Thiazole ring	65.11(0.19)

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  Table 3.  Nematicidal and Fungicidal Activities of the Target Compounds at 50 μg⋅mL^-1

  Compounds	Mortality of B. xylophilus (%)	Fungicidal inhibition rate (%)
  		GZ	RS	PP	AK	CC	AS
  I-1	21.3 ± 1.37	18.4 ± 0.47	12.9 ± 0.32	13.3± 0.86	8.7 ± 0.39	15.4 ± 0.62	8.9 ± 0.90
  I-2	12.4 ± 0.88	20.1 ± 0.26	11.3 ± 0.81	12.4 ± 0.29	10.0 ± 0.52	8.5 ± 0.29	17.2 ± 0.43
  I-3	8.9 ± 0.67	21.3 ± 0.37	5.8 ± 0.39	36.6 ± 0.41	7.8 ± 0.63	11.1 ± 0.24	11.6 ± 0.41
  I-4	13.3 ± 1.01	8.9 ± 0.71	12.7 ± 0.93	8.5 ± 0.40	9.4 ± 0.86	19.5 ± 0.62	16.7 ± 0.30
  I-5	17.8 ± 0.76	17.9 ± 0.78	11.6 ± 0.22	19.9 ± 0.59	9.3 ± 0.48	61.7 ± 0.58	8.1 ± 0.43
  I-6	19.4 ± 1.11	30.1 ± 0.42	10.9 ± 0.98	6.2 ± 0.29	6.2 ± 0.24	4.1 ± 0.24	2.9 ± 0.55
  I-7	25.8 ±1.34	26.7 ± 0.46	5.4 ± 0.66	3.5 ± 0.63	10.8 ± 0.58	5.0 ± 0.41	3.1 ± 0.70
  I-8	14.6 ± 0.93	22.0 ± 0.21	9.2 ± 0.98	7.8 ± 0.71	9.8 ± 0.53	9.7 ± 0.33	6.2 ± 0.60
  I-9	5.6 ± 0.55	32.1 ± 0.73	6.7 ± 0.53	5.4 ± 0.54	11.5 ± 0.75	9.0 ± 0.29	13.0 ± 0.49
  I-10	23.2 ± 1.42	20.1 ± 1.29	4.7 ± 0.39	10.6 ± 0.71	9.7 ± 0.48	9.2 ± 0.51	2.4 ± 0.49
  I-11	11.7 ± 0.79	16.5 ± 0.70	3.0 ± 0.59	5.6 ± 0.66	13.0 ± 0.29	12.6 ± 0.75	29.8 ± 0.85
  I-12	15.4 ± 0.92	15.8 ± 0.52	11.6 ± 0.78	4.3 ± 0.52	12.7 ± 0.82	15.7 ± 0.62	6.7 ± 0.25
  I-13	10.1 ± 0.37	8.6 ± 0.47	8.4 ± 0.55	22.1 ± 0.90	6.3 ± 0.48	20.6 ± 0.82	20.6 ± 0.65
  I-14	18.7 ± 0.78	13.4 ± 0.95	5.6 ± 0.50	3.9 ± 0.24	10.8 ± 0.41	16.7 ± 0.58	24.3 ± 1.20
  I-15	13.4 ± 0.66	17.1 ± 0.56	11.8 ± 0.27	12.2 ± 0.63	7.3 ± 0.29	3.6 ± 0.29	19.6 ± 0.90
  Carbendazim	--	100	100	100	53.6 ± 0.44	100	19.7 ± 0.52
  Fluopyram	100	92.3 ± 0.23	54.2 ± 0.47	56.9 ± 0.33	97.3 ± 0.53	50.5 ± 0.55	98.8 ± 0.66
  Avermectin	100	--	--	--	--	--	--
  GZ, Gibberella zeae; RS, Rhizoctonia solani; PP, Physalospora piricola; AK, Alternaria kikuchiana Tanaka; CC, Colletotrichum capsici; AS, Alternaria sp

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