Synthesis, Structure, and Antifungal Activities of 3-(Difluoromethyl)-Pyrazole-4-Carboxylic Oxime Ester Derivatives

Wang, Bin; Chen, Wei-Ting; Min, Li-Jing; Han, Liang; Sun, Na-Bo; Liu, Xing-Hai

doi:https://doi.org/10.1155/2022/6078017

Heteroatom Chemistry

On this page

Abstract Introduction Materials and Methods Results and Discussion Conclusions Data Availability Conflicts of Interest Acknowledgments Supplementary Materials References Copyright Related Articles

Research Article | Open Access

Volume 2022 | Article ID 6078017 | https://doi.org/10.1155/2022/6078017

Synthesis, Structure, and Antifungal Activities of 3-(Difluoromethyl)-Pyrazole-4-Carboxylic Oxime Ester Derivatives

Bin Wang,^1,3Wei-Ting Chen,^1,3Li-Jing Min,²Liang Han,¹Na-Bo Sun,³and Xing-Hai Liu¹

Academic Editor: David Barker

Received09 Apr 2022

Revised25 Jun 2022

Accepted18 Jul 2022

Published28 Aug 2022

Abstract

Fifteen new pyrazole-4-carboxylic oxime ester derivatives were conveniently synthesized, and their structures were confirmed by ¹H NMR, ¹³C NMR, HRMS, and X-ray diffraction. Antifungal assays indicated that some of these compounds possessed good activity against S. sclerotiorum, B. cinerea, R. solani, P. oryae, and P. piricola at 50 ppm. Structure-activity relationships (SAR) were studied by molecular docking simulation.

1. Introduction

Nitrogen-linked heterocycles are an important skeleton in synthetic chemistry or natural product chemistry because of their diversity of structure and activity [1–5]. Among these nitrogen-linked heterocycles; pyrazole compounds, especially pyrazole carboxamide compounds, exhibit diverse activity, with examples possessing nematocidal [6–10], insecticidal [11, 12], antibacterial [13], IRAK4 inhibitor [14], antiproliferative [15], antimicrobial [16], immunomodulatory [17], and fungicidal activity [18–20]. Some pyrazole amide compounds have been commercialized as fungicides [21] or insecticides [22]. For example, benzovindiflupyr, a new succinate dehydrogenase inhibitor (SDH) fungicide developed by Syngenta. In these SDH fungicides, the pyrazole ring and carboxamide group are the key functional groups accounting for their activity.

In our previous work, many nitrogen-linked heterocyclic compounds with diverse activity were synthesized [23–27], including many fungicidal pyrazole carboxamide derivatives. In this work, the carboxamide group was replaced by an oxime ester group (Figure 1). In this paper, a set of pyrazole oxime esters were synthesized, and their fungicidal activity was assessed. This data was used to assess the structure-activity relationship (SAR) using molecular docking.

2. Materials and Methods

2.1. Instruments

Melting points were measured by an X-4 apparatus (Gongyi, China) and the temperature was uncorrected. ¹H NMR and ¹³C NMR spectra were tested on a Bruker AV III-500 instrument and ¹³C NMR spectra were tested on a Bruker AV-400 instrument in CDCl₃. DART-HRMS was measured on a JEOL AccuTOF instrument. Single crystal diffraction was performed on a Bruker CCD area detector diffractometer.

2.2. Chemicals

All benzaldehydes (98% purity) were purchased from Duodian Chemical Co. Ltd, China. Ethyl difluoroacetate and methyl hydrazine were purchased from Taizhou Yongxiang Pharmaceutical company; triethyl orthoformate, acetic acid, ethanol, hydroxylamine hydrochloride, and dichlorosulfoxide were purchased from Mclean; sodium hydroxide was purchased from Yongda Reagent company; potassium carbonate, hydrochloric acid, and DCM were purchased from Sinopharm Chemical Reagent Co. Ltd.; TEA was purchased from Qidian Reagent company.

2.3. Experimental Methods

2.3.1. Synthesis of Intermediate Oximes

Benzaldehyde (9.5 mmol) was added to a mixture of Na₂CO₃ (0.5 g, 4.7 mmol) in ethanol (10 mL) and the mixture was stirred at room temperature. After 30 min, NH₂OH·HCl (0.7 g, 10.4 mmol) was added, and the reaction was monitored by TLC. The water phase was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with saturated brine (3 × 10 mL), dried with MgSO₄, and evaporated in vacuo. The crude product was recrystallized from ethanol and used without further purification.

2.3.2. Synthesis of Target Compounds 5a-5o

The two key intermediates: benzaldehyde oxime and 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride were synthesized according to our previous reported work [26].

A solution of intermediate benzaldehyde oxime (7.5 mmol) and NEt₃ (1 mL) in dichloromethane (20 mL), 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride (7.5 mmol) was added dropwise at ice bath condition, then the mixture was stirred at 20°C. When the reaction was complete (TLC monitoring (V_EA/V_PE = 1/2)), the solvent was removed in vacuo, and the crude products were purified by flash chromatography to afford the title compound 5a-5o.

2.3.3. (E)-Benzaldehyde O-(3-(Difluoromethyl)-1-methyl-1h-pyrazole-4-carbonyl) Oxime 5a

White solid, yield 73%, m.p. 171–177°C; ¹H NMR (CDCl₃, 500 MHz), δ:8.46 (s, 1H, CH), 8.03 (s, 1H, pyrazole), 7.80–7.76 (m, 2H, Ph), 7.52–7.42 (m, 3H, Ph), 7.12 (t, J = 53.8 Hz, 1H, CHF₂), 4.01 (s, 3H, CH₃); ¹³C NMR (101 MHz, CDCl₃) δ: 159.2, 156.8, 146.7, 146.5 (t, J = 26.3 Hz, Py-CHF₂), 146.2, 135.3, 131.9, 129.8, 128.9, 128.5, 109.3 (t, J = 238.4 Hz, CHF₂), 110.8, 39.81; HRMS (DART) for C₁₃H₁₁F₂N₃O₂ m/z: calculated, 280.0892, found, 280.0897 [M+H]⁺.

2.3.4. (E)-2-Methylbenzaldehyde O-(3-(Difluoromethyl)-1-methyl-1h-pyrazole-4-carbonyl) Oxime 5b

White solid, yield 72%, m.p. 120–123°C; ¹H NMR (CDCl₃, 500 MHz), δ:8.71 (s, 1H, CH), 8.04 (d, J = 1.0 Hz, 1H, pyrazole), 7.88 (dd, J = 7.8, 1.4 Hz, 1H, Ph), 7.38 (td, J = 7.5, 1.4 Hz, 1H, Ph), 7.28–7.24 (m, 2H, Ph), 7.14 (t, J = 53.8 Hz, 1H, CHF₂), 4.01 (s, 3H, CH₃), 2.51 (s, 3H, CH₃); ¹³C NMR (101 MHz, CDCl₃) δ:159.2, 155.7, 146.6 (t, J = 26.3 Hz, Py-CHF₂), 138.2, 135.1, 131.5, 131.0, 128.3, 128.2, 126.3, 110.8, 109.2 (t, J = 238.4 Hz, CHF₂), 39.8, 19.9; HRMS (DART) for C₁₄H₁₃F₂N₃O₂ m/z: calculated, 294.1049, found, 294.1054 [M+H]⁺.

2.3.5. (E)-3-Methylbenzaldehyde O-(3-(Difluoromethyl)-1-methyl-1h-pyrazole-4-carbonyl) Oxime 5c

White solid, yield 71%, m.p. 119–123°C; ¹H NMR (CDCl₃, 500 MHz), δ:8.42 (s, 1H, CH), 8.03 (s, 1H, pyrazole), 7.65 (d, J = 2.1 Hz, 1H, Ph), 7.53 (d, J = 7.3 Hz, 1H, Ph), 7.34–7.26 (m, 2H, Ph), 7.12 (t, J = 53.8 Hz, 1H, CHF₂), 4.00 (s, 3H, CH₃), 2.39 (s, 3H, CH₃); ¹³C NMR (101 MHz, CDCl₃) δ:159.2, 156.7, 146.5 (t, J = 26.3 Hz, Py-CHF₂), 138.8, 135.2, 132.7, 129.7, 128.7, 128.5, 126.0, 110.8, 109.3 (t, J = 238.4 Hz, CHF₂), 39.8, 21.1; HRMS (DART) for C₁₄H₁₃F₂N₃O₂ m/z: calculated, 294.1049, found, 294.1054 [M+H]⁺.

2.3.6. (E)-4-Methylbenzaldehyde O-(3-(Difluoromethyl)-1-methyl-1h-pyrazole-4-carbonyl) Oxime 5d

White solid, yield 71%, m.p. 147–150°C; ¹H NMR (CDCl₃, 500 MHz), δ:8.42 (s, 1H, CH), 8.02 (s, 1H, Pyrazole), 7.67 (d, J = 8.1 Hz, 2H, Ph), 7.24 (d, J = 8.0 Hz, 2H, Ph), 7.12 (t, J = 53.8 Hz, 1H, CHF₂), 4.00 (s, 3H, CH₃), 2.40 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 101 MHz), δ: 159.3, 156.7, 146.4 (t, J = 26.3 Hz, Py-CHF₂), 142.5, 135.3, 129.6 (2C, Ph), 128.4 (2C, Ph), 126.9, 110.9, 109.3 (t, J = 238.1 Hz, CHF₂), 39.8, 21.6; HRMS (DART) for C₁₄H₁₃F₂N₃O₂ m/z: calculated, 294.1049, found, 294.1054 [M+H]⁺.

2.3.7. (E)-2-Methoxybenzaldehyde O-(3-(Difluoromethyl)-1-methyl-1h-pyrazole-4-carbonyl) Oxime 5e

Light yellow solid, yield 70%, m.p. 116–120°C; ¹H NMR (CDCl₃, 500 MHz), δ:8.86 (s, 1H, CH), 8.02–8.01 (m, 2H, pyrazole, Ph), 7.46 (ddd, J = 8.8, 7.5, 1.8 Hz, 1H, Ph), 7.16 (t, J = 53.8 Hz, 1H, CHF₂), 7.00 (t, J = 7.5 Hz, 1H, Ph), 6.93 (dd, J = 8.5, 0.9 Hz, 1H, Ph), 4.00 (s, 3H, CH₃), 3.89 (s, 3H, CH₃O), 1.26 (d, J = 7.0 Hz, 3H, CH₃); ¹³C NMR (101 MHz, CDCl₃) δ: 159.3, 158.4, 152.7, 146.4 (t, J = 26.3 Hz, Py-CHF₂), 135.1, 133.2, 127.4, 120.7, 118.1, 111.0, 110.8, 109.1 (t, J = 238.4 Hz, CHF₂), 55.5, 39.7; HRMS (DART) for C₁₄H₁₃F₂N₃O₃ m/z: calculated, 310.0998, found, 310.1003 [M+H]⁺.

2.3.8. (E)-4-Methoxybenzaldehyde O-(3-(Difluoromethyl)-1-methyl-1h-pyrazole-4-carbonyl) Oxime 5f

Light yellow solid, yield 70%, m.p. 131–138°C; ¹H NMR (CDCl₃, 500 MHz), δ:8.40 (s, 1H, CH), 8.02 (s, 1H, pyrazole), 7.73 (d, J = 8.8 Hz, 2H, Ph), 7.12 (t, J = 53.8 Hz, 1H, CHF₂), 6.96 (d, J = 8.8 Hz, 2H, Ph), 4.00 (s, 3H, CH₃), 3.86 (s, 3H, CH₃O); ¹³C NMR (CDCl₃, 101 MHz), δ: 162.5, 159.4, 156.3, 146.4 (t, J = 26.3 Hz, Py-CHF₂), 135.3, 132.3, 130.2 (2C, Ph), 122.2, 114.4 (2C, Ph), 109.3 (t, J = 237.1 Hz, CHF₂), 55.4, 39.4; HRMS (DART) for C₁₄H₁₃F₂N₃O₃ m/z: calculated, 310.0998, found, 310.1003 [M+H]⁺.

2.3.9. (E)-3,4,5-Trimethoxybenzaldehyde O-(3-(Difluoromethyl)-1-methyl-1h-pyrazole-4-carbonyl) Oxime 5g

White solid, yield 68%, m.p. 153–157°C; ¹H NMR (CDCl₃, 500 MHz), δ:8.37 (s, 1H, CH), 8.03 (s, 1H, pyrazole), 7.10 (t, J = 53.8 Hz, 1H, CHF₂), 6.99 (s, 2H, Ph), 4.00 (s, 3H, CH₃), 3.91 (d, J = 3.4 Hz, 9H, CH₃O); ¹³C NMR (101 MHz, CDCl₃) δ:159.2, 156.7, 153.4, 146.3 (t, J = 26.3 Hz, Py-CHF₂), 141.1, 135.3, 125.0, 110.7, 109.3 (t, J = 237.0 Hz, CHF₂), 105.5, 60.7, 56.2 (2C, OCH₃), 39.7; HRMS (DART) for C₁₄H₁₃F₂N₃O₃ m/z: calculated, 370.1209, found, 370.1213 [M+H]⁺.

2.3.10. (E)-2-Bromobenzaldehyde O-(3-(Difluoromethyl)-1-methyl-1h-pyrazole-4-carbonyl) Oxime 5h

Light yellow solid, yield 70%, m.p. 124–130°C; ¹H NMR (CDCl₃, 500 MHz), δ:8.86 (s, 1H, CH), 8.11 (dd, J = 7.6, 2.0 Hz, 1H, Ph), 8.05 (s, 1H, pyrazole), 7.63 (dd, J = 7.8, 1.5 Hz, 1H, Ph), 7.39–7.33 (m, 2H, Ph), 7.14 (t, J = 53.8 Hz, 1H, CHF₂), 4.01 (s, 3H, CH₃); ¹³C NMR (101 MHz, CDCl₃) δ:158.9, 155.8, 146.6 (t, J = 26.3 Hz, Py-CHF₂), 135.1, 133.1, 132.9, 129.3, 128.6, 127.7, 124.8, 110.3, 109.1 (t, J = 238.4 Hz, CHF₂), 39.7. HRMS (DART) for C₁₃H₁₀⁷⁹BrF₂N₃O₂ m/z: calculated, 357.9997, found, 358.0003 [M+H]⁺; for C₁₃H₁₀⁸¹BrF₂N₃O₂ m/z: calculated, 359.9977, found, 359.9972 [M+H]⁺.

2.3.11. (E)-4-Bromobenzaldehyde O-(3-(Difluoromethyl)-1-methyl-1h-pyrazole-4-carbonyl) Oxime 5i

Light yellow solid, yield 69%, m.p.180–183°C; ¹H NMR (CDCl₃, 500 MHz), δ:8.41 (s, 1H, CH), 8.03 (s, 1H, pyrazole), 7.66 (d, J = 8.5 Hz, 2H, Ph), 7.60 (d, J = 8.5 Hz, 2H, Ph), 7.09 (t, J = 53.8 Hz, 1H, CHF₂), 4.00 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 125 MHz) δ: 155.7, 153.7, 145.9 (t, J = 25.6 Hz, Py-CHF₂), 135.5, 132.3 (2C, Ph), 129.8 (2C, Ph), 128.8, 126.5, 109.3 (t, J = 237.3 Hz, CHF₂), 49.1, 40.2; HRMS (DART) for C₁₃H₁₀⁷⁹BrF₂N₃O₂ m/z: calculated, 357.9997, found, 358.0003 [M+H]⁺; for C₁₃H₁₀⁸¹BrF₂N₃O₂ m/z: calculated, 359.9977, found, 359.9977 [M+H]⁺.

2.3.12. (E)-2-Nitrobenzaldehyde O-(3-(Difluoromethyl)-1-methyl-1h-pyrazole-4-carbonyl) Oxime 5j

White solid, yield 73%, m.p. 146–149°C; ¹H NMR (CDCl₃, 500 MHz), δ:9.09 (s, 1H, CH), 8.19 (ddd, J = 17.1, 8.0, 1.4 Hz, 2H, Ph), 8.06 (s, 1H, pyrazole), 7.76 (td, J = 7.6, 1.3 Hz, 1H, Ph), 7.70 (td, J = 7.8, 1.5 Hz, 1H, Ph), 7.13 (t, J = 53.7 Hz, 1H, CHF₂), 4.02 (s, 3H, CH₃); ¹³C NMR (101 MHz, CDCl₃) δ:158.8, 153.6, 148.0, 146.9 (t, J = 24.8 Hz, Py-CHF₂), 135.3, 134.1, 132.0, 130.1, 125.5, 125.1, 110.2, 109.1 (t, J = 237.3 Hz, CHF₂), 39.9; HRMS (DART) for C₁₃H₁₀F₂N₄O₄ m/z: calculated, 325.0743, found, 325.0748 [M+H]⁺.

2.3.13. (E)-3-Nitrobenzaldehyde O-(3-(Difluoromethyl)-1-methyl-1h-pyrazole-4-carbonyl) Oxime 5k

Light yellow solid, yield 71%, m.p.172–176°C; ¹H NMR (CDCl₃, 500 MHz), δ:8.59 (t, J = 1.9 Hz, 1H, Ph), 8.56 (s, 1H, CH), 8.35 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H, Ph), 8.21 (dt, J = 7.9, 1.4 Hz, 1H, Ph), 8.06 (s, 1H, pyrazole), 7.67 (t, J = 8.0 Hz, 1H, Ph), 7.07 (t, J = 53.8 Hz, 1H, CHF₂), 4.02 (s, 3H, CH₃); ¹³C NMR (101 MHz, CDCl₃) δ: 157.7, 153.4, 145.8, 145.5 (t, J = 27.3 Hz, Py-CHF₂), 145.3, 134.6, 132.5, 130.8, 129.1, 125.2, 122.5, 108.4 (t, J = 238.4 Hz, CHF₂), 38.9; HRMS (DART) for C₁₃H₁₀F₂N₄O₄ m/z: calculated, 325.0743, found, 325.0748 [M+H]⁺.

2.3.14. (E)-4-Fluorobenzaldehyde O-(3-(Difluoromethyl)-1-methyl-1h-pyrazole-4-carbonyl) Oxime 5l

Light yellow solid, yield 71%, m.p. 144–147°C; ¹H NMR (CDCl₃, 500 MHz), δ:8.43 (s, 1H, CH), 8.03 (s, 1H, pyrazole), 7.79 (dd, J = 8.8, 5.3 Hz, 2H, Ph), 7.14 (t, J = 8.6 Hz, 2H, Ph), 7.14 (t, J = 53.8 Hz, 1H, CHF₂), 4.00 (s, 3H, CH₃); ¹³C NMR (101 MHz, CDCl₃) δ 163.5, 159.1, 155.50, 146.4 (t, J = 26.3 Hz, Py-CHF₂), 135.3, 130.5 (d, J = 8.1 Hz, 2C, Ph), 126.1 (d, J = 3.0 Hz, Ph), 116.3 (d, J = 11.1 Hz, 2C, Ph), 110.7, 109.3 (t, J = 238.4 Hz, CHF₂), 39.8; HRMS (DART) for C₁₃H₁₀F₃N₃O₂ m/z: calculated, 298.0798, found, 298.0803 [M+H]⁺.

2.3.15. (E)-4-(Trifluoromethyl)benzaldehyde O-(3-(Difluoromethyl)-1-methyl-1h-pyrazole-4-carbonyl) Oxime 5m

White solid, yield 70%, m.p. 129–133°C; ¹H NMR (CDCl₃, 500 MHz), δ:8.51 (s, 1H, CH), 8.05 (s, 1H, pyrazole), 7.90 (d, J = 8.1 Hz, 2H, Ph), 7.70 (d, J = 8.2 Hz, 2H, Ph), 7.08 (t, J = 53.8 Hz, 1H, CHF₂), 4.01 (s, 3H, CH₃); ¹³C NMR (101 MHz, CDCl₃) δ:158.9, 155.3, 146.3 (t, J = 25.3 Hz, Py-CHF₂), 135.8, 135.6 (2C, Ph), 133.3, 128.7 (2C, Ph), 125.9 (q, J = 3.8 Hz, Ph), 124.9 (q, J = 272.8 Hz, CF₃), 110.0, 109.3 (t, J = 236.9 Hz, CHF₂), 39.8; HRMS (DART) for C₁₄H₁₀F₅N₃O₂ m/z: calculated, 348.0766, found, 348.0771 [M+H]⁺.

2.3.16. (E)-4-Chlorobenzaldehyde O-(3-(Difluoromethyl)-1-methyl-1h-pyrazole-4-carbonyl) Oxime 5n

White solid, yield 69%, m.p.163–169°C; ¹H NMR (CDCl₃, 500 MHz), δ:8.43 (s, 1H, CH), 8.03 (s, 1H, pyrazole), 7.73 (d, J = 8.5 Hz, 2H, Ph), 7.44 (d, J = 8.5 Hz, 2H, Ph), 7.09 (t, J = 53.8 Hz, 1H, CHF₂), 4.00 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 101 MHz), δ: 159.0, 155.5, 146.5 (t, J = 24.3 Hz, Py-CHF₂), 138.0, 135.4, 132.3, 129.6 (2C, Ph), 129.3 (2C, Ph), 128.3, 109.3 (t, J = 237.0 Hz, CHF₂), 39.9; HRMS (DART) for C₁₃H₁₀³⁵ClF₂N₃O₂ m/z: calculated, 314.0502, found, 314.0508 [M+H]⁺; for C₁₃H₁₀³⁷ClF₂N₃O₂ m/z: calculated, 316.0502, found, 316.0508 [M+H]⁺.

2.3.17. (E)-2,4-Dichlorobenzaldehyde O-(3-(Difluoromethyl)-1-methyl-1h-pyrazole-4-carbonyl) Oxime 5o

White solid, yield 67%, m.p. 173–176°C; ¹H NMR (CDCl₃, 500 MHz), δ:8.83 (s, 1H, CH), 8.10 (d, J = 8.5 Hz, 1H, Ph), 8.05 (s, 1H, pyrazole), 7.47 (d, J = 2.1 Hz, 1H, Ph), 7.33 (ddd, J = 8.5, 2.0, 0.7 Hz, 1H, Ph), 7.11 (t, J = 53.8 Hz, 1H, CHF₂), 4.01 (s, 3H, CH₃); ¹³C NMR (101 MHz, CDCl₃) δ:158.9, 152.7, 146.8 (t, J = 26.3 Hz, Py-CHF₂), 138.4, 135.7, 135.3, 129.9, 129.2, 127.9, 126.4, 110.4, 109.2 (t, J = 238.4 Hz, CHF₂), 39.9; HRMS (DART) for C₁₃H₉³⁵Cl₂F₂N₃O₂ m/z: calculated, 348.0113, found, 348.0118 [M+H]⁺; for C₁₃H₉³⁷Cl₂F₂N₃O₂ m/z: calculated, 350.0113, found, 350.0118 [M+H]⁺.

2.4. Structure Determination

One colorless crystal was cultivated in EtOH by self-volatilization with dimensions of 0.28 mm × 0.22 mm × 0.14 mm for X-ray on a Bruker CCD area detector diffractometer equipped with a graphite-monochromatic MoKα radiation (λ = 0.71073 Å). The structure of compound 5d was solved using direct methods by ShelXS [28] structure solution program and refined with the ShelXL [29] refinement package using least squares minimization in Olex2 software [30]. The detailed crystal data are listed in Table 1.

2.5. Fungicidal Activity

Fungicidal activities of pyrazole-4-carboxylic oxime ester derivatives 5a∼5o were tested according to reported work [31, 32]. The antifungal activities of compounds 5a-5o and fluxapyroxad were tested in vitro against Gibberella zeae (GZ), Fusarium oxysporum (FO), Phytophthora infestans (PI), Phytophthora capsici (PC), Rhizoctonia solani (RS), Sclerotinia sclerotiorum (SS), Alternaria solani (AS), Physalospora piricola (PP), Cercospora arachidicola (CA), and Botrytis cinerea (BC). The relative percent inhibition (%) has been determined using the mycelium growth rate method. The inhibition of the test compounds compared to the blank assay was calculated via the following equation:where CK is the average diameter of mycelia in the blank test and CI is the average diameter of mycelia in the presence of those compounds. All experiments were replicated three times.

3. Results and Discussion

3.1. Chemistry

The intermediate 4 (pyrazole-4-carbonyl chloride) was prepared by a previously reported method [20] in four synthetic steps from commercial starting materials. For the intermediate substituted-benzaldehyde oximes (Scheme 1), commercially available substituted benzaldehydes were condensed with excess NH₂OH·HCl and were used without purification. Finally, the oximes were condensed with acid chloride 4 to afford the target compounds as white or light-yellow solids 5a-5o (Scheme 2). From Figure 2, the torsion angles, C (6)-O (2)-N (3)-C (7) was 172.50 (15)°, which indicated the two C=N groups are E configuration.

3.2. Fungicidal Activity

Fungicidal activities of compounds 5a∼5o and positive control fluxapyroxad against Rhizoctonia solani (RS), Phytophthora capsici (PC), Alternaria solani (AS), Pyricularia oryae (PO), Gibberella zeae (GZ), Botrytis cinerea (BC), Sclerotinia sclerotiorum (SS), Fusarium oxysporum (FO), Physalospora piricola (PP), and Cercospora arachidicola were tested at 50 ppm, the results are shown in Table 2. The fungicidal activity results showed some compounds exhibited good inhibition against S. sclerotiorum, B. cinerea, P. oryae, R. solani, and P. piricola. For the P. oryae, compounds 5g (85.7%) and 5j (71.4%) possessed good inhibition, compared to that of the control fluxapyroxad (27.3%). Compound 5k (42.9%) exhibited moderate activity against P. oryae. For S. sclerotiorum, compounds 5f (60.7%) and 5i (71.4%) possessed good inhibition, but was weaker than that of fluxapyroxad (96.4%). While compound 5b (44.6%), 5g (44.6%), 5h (53.6%), 5k (50.0%), and 5n (44.6%) displayed moderate activity against S. sclerotiorum. For R. solani, compound 5e (62.1%) possessed good inhibition, however, it was weaker than the control fluxapyroxad (88.4%). Compound 5c (43.1%), 5f (44.8%), 5h (50.0%), and 5j (55.2%) exhibited moderate activity against R. solani. For B. cinerea, only compound 5h (75.0%) possessed good inhibition. For P. piricola, compound 5e (53.1%), 5h (46.9%), 5j (62.5%), and 5o (56.3%) possessed moderate activity. Most of the title pyrazole oxime ester compounds showed weak activity against A. solani, G. zeae, P. capsici, F. oxysporum, and C. arachidicola.

3.3. Docking Study

In order to study the mode of action of these compounds, molecular docking was carried out between the compound 5g and the enzyme SDH (PDB:2FBW) using DS 2.5. The docking results indicated that compound 5g can well occupy the active site of SDH (Figure 3). From Figure 3 (above), two π-cation interactions exist between Arg 43 amino acid residue of SDH and the compound 5g with the distances of 3.6 Å and 3.9 Å, respectively. There are two hydrogen bonds between the compound 5g and SDH. One is between the Ser 39 amino acid residue of SDH and the O atom of carboxamide group in compound 5g and with the distance of 2.3 Å. The other is between the Tyr 58 amino acid residue of SDH and the O atom of MeO group with the distance of 2.0 Å. From the docking results, the pyrazole ring and amide group are key active groups in this fungicide, which is the same as the lead compound pydiflumetofen (Figure 3).

4. Conclusions

In conclusion, a series of pyrazole-4-carboxylic oxime ester derivatives were synthesized using a bioisosterism strategy. The X-ray analysis results showed that the oxime has an E configuration. The antifungal activity of the target pyrazole-4-carboxylic oxime ester compounds against ten fungi was tested at 50 ppm, and some of the target compounds showed good fungicidal activity against B. cinerea, S. sclerotiorum, R. solani, P. oryae, and P. piricola. These structures can be further optimized for discovering new fungicides.

Data Availability

The data used to support the study can be made available upon request to the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

This work was funded in part by Zhejiang Provincial Natural Science Foundation of China (Nos. LY19C140002 and LY19B020009), the Chemical Company for Research (KYY-HX-20210140 and KYY-HX-20190720), and the Opening Foundation of the Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University (No. 2018GDGP0104). The authors thank Dr. Charles L. Cantrell for HRMS.

Supplementary Materials

¹H NMR, ¹³C NMR, and HRMS spectra of compounds prepared in this study are available as a supplementary file. (Supplementary Materials)

References

X. H. Liu, W. Yu, L. J. Min et al., “Synthesis and pesticidal activities of new quinoxalines,” Journal of Agricultural and Food Chemistry, vol. 68, no. 28, pp. 7324–7332, 2020.
View at: Publisher Site | Google Scholar
Q. Fu, P. P. Cai, L. Cheng et al., “Synthesis and herbicidal activity of novel pyrazole aromatic ketone analogs as HPPD inhibitor,” Pest Management Science, vol. 76, no. 3, pp. 868–879, 2020.
View at: Publisher Site | Google Scholar
C. S. Yu, Q. Wang, J. Bajsa-Hirschel, C. L. Cantrell, S. O. Duke, and X. H. Liu, “Synthesis, crystal structure, herbicidal activity and SAR study of novel N-(arylmethoxy)-2-chloronicotinamides derived from nicotinic acid,” Journal of Agricultural and Food Chemistry, vol. 69, no. 23, pp. 6423–6430, 2021.
View at: Publisher Site | Google Scholar
X. H. Liu, Y. H. Wen, L. Cheng, T. M. Xu, and N. J. Wu, “Design, synthesis, and pesticidal activities of pyrimidin-4-amine derivatives bearing a 5-(trifluoromethyl)-1, 2, 4-oxadiazole moiety,” Journal of Agricultural and Food Chemistry, vol. 69, no. 25, pp. 6968–6980, 2021.
View at: Publisher Site | Google Scholar
Y. H. Wen, L. Cheng, T. M. Xu, X. H. Liu, and N. J. Wu, “Synthesis, insecticidal activities and DFT study of pyrimidin-4-amine derivatives containing the 1, 2, 4-oxadiazole motif,” Frontiers of Chemical Science and Engineering, vol. 16, no. 7, pp. 1090–1100, 2022.
View at: Publisher Site | Google Scholar
S. J. Kang, W. Zhao, C. X. Tan, J. Q. Weng, W. L. Peng, and X. H. Liu, “Synthesis, nematicidal activity, and molecular docking of some new pyrazole-5-carboxamide derivatives,” Indian Journal of Heterocyclic Chemistry, vol. 31, pp. 51–56, 2021.
View at: Google Scholar
L. Cheng, W. Zhao, Z. H. Shen et al., “Synthesis, nematicidal activity and docking study of novel pyrazole-4-carboxamide derivatives against Meloidogyne incognita,” Letters in Drug Design and Discovery, vol. 16, no. 1, pp. 29–35, 2018.
View at: Publisher Site | Google Scholar
L. Cheng, Z. H. Shen, T. M. Xu et al., “Synthesis and nematocidal activity of N-substituted 3-methyl-1H-pyrazole-4-carboxamide derivatives against Meloidogyne incognita,” Journal of Heterocyclic Chemistry, vol. 55, no. 4, pp. 946–950, 2018.
View at: Publisher Site | Google Scholar
W. Zhao, J. H. Xing, T. M. Xu, W. Peng, and X. Liu, “Synthesis and in vivo nematocidal evaluation of novel 3-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives,” Frontiers of Chemical Science and Engineering, vol. 11, no. 3, pp. 363–368, 2017.
View at: Publisher Site | Google Scholar
W. Zhao, Z. H. Shen, J. H. Xing et al., “Synthesis, characterization, nematocidal activity and docking study of novel pyrazole-4-carboxamide derivatives,” Journal of Structural Chemistry, vol. 36, pp. 423–428, 2017.
View at: Google Scholar
J. J. Shi, G. H. Ren, N. J. Wu et al., “Design, synthesis and insecticidal activities of novel anthranilic diamides containing polyfluoroalkyl pyrazole moiety,” Chinese Chemical Letters, vol. 28, no. 8, pp. 1727–1730, 2017.
View at: Publisher Site | Google Scholar
X. H. Lv, J. J. Xiao, Z. L. Ren et al., “Design, synthesis and insecticidal activities of N-(4-cyano-1-phenyl-1H-pyrazol-5-yl)-1, 3-diphenyl-1H-pyrazole-4-carboxamide derivatives,” RSC Advances, vol. 5, no. 68, pp. 55179–55185, 2015.
View at: Publisher Site | Google Scholar
M. B. Palkar, A. Patil, G. A. Hampannavar et al., “Design, synthesis and QSAR studies of 2-amino benzo[d]thiazolyl substituted pyrazol-5-ones: novel class of promising antibacterial agents,” Medicinal Chemistry Research, vol. 26, no. 9, pp. 1969–1987, 2017.
View at: Publisher Site | Google Scholar
J. Lim, M. D. Altman, J. Baker et al., “Identification of N-(1H-pyrazol-4-yl)carboxamide inhibitors of interleukin-1 receptor associated kinase 4: bicyclic core modifications,” Bioorganic & Medicinal Chemistry Letters, vol. 25, no. 22, pp. 5384–5388, 2015.
View at: Publisher Site | Google Scholar
H. B. Huo, W. Q. Jiang, F. F. Sun, J. Li, and B. Shi, “Synthesis and biological evaluation of novel steroidal pyrazole amides as highly potent anticancer agents,” Steroids, vol. 176, pp. 108931–112021, 2021.
View at: Publisher Site | Google Scholar
K. M. Pandya, S. Battula, and P. J. Naik, “Tetrahedron Pd-catalyzed post-Ugi intramolecular cyclization to the synthesis of isoquinolone-pyrazole hybrid pharmacophores & discover their antimicrobial and DFT studies,” Tetrahedron Letters, vol. 81, pp. 153353–2021, 2021.
View at: Google Scholar
A. S. Hassan, A. A. Askar, A. M. Naglah, A. A. Almehizia, and A. Ragab, “Discovery of new schiff bases tethered pyrazole moiety: design, synthesis, biological evaluation, and molecular docking study as dual targeting DHFR/DNA gyrase inhibitors with immunomodulatory activity,” Molecules, vol. 25, no. 11, pp. 2593–2020, 2020.
View at: Publisher Site | Google Scholar
X. W. Hua, W. R. Liu, Y. Chen et al., “Synthesis, fungicidal activity, and mechanism of action of pyrazole amide and ester derivatives based on natural products l-serine and waltherione alkaloids,” Journal of Agricultural and Food Chemistry, vol. 69, no. 38, pp. 11470–11484, 2021.
View at: Publisher Site | Google Scholar
L. J. Min, Z. W. Zhai, Y. X. Shi et al., “Synthesis and biological activity of acyl thiourea containing difluoromethyl pyrazole motif,” Phosphorus, Sulfur, and Silicon and the Related Elements, vol. 195, no. 1, pp. 22–28, 2020.
View at: Publisher Site | Google Scholar
L. Qiao, Z. W. Zhai, P. P. Cai et al., “Synthesis, crystal structure, antifungal activity, and docking study of difluoromethyl pyrazole derivatives,” Journal of Heterocyclic Chemistry, vol. 56, no. 9, pp. 2536–2541, 2019.
View at: Publisher Site | Google Scholar
R. Rajan, H. Walter, and D. Stierli, Novel Pyrazole-4-Nalkoxycarboxamides as Microbiocides, 2010, WO 2010063700.
C. Defierer, S. Soergel, D. Saelinger et al., Novel Pesticidal Pyrazole Compounds, 2012, WO2012143317.
L. J. Min, L. Qiao, and H. Wang, “Synthesis, crystal structure, herbicidal activity and docking study of 4-Cyclopropyl-3-((4-fluorobenzyl) sulfonyl)-5-methyl-4H-1, 2, 4-triazole,” Chinese Journal of Structural Chemistry, vol. 38, pp. 1356–1361, 2019.
View at: Google Scholar
N. B. Sun, Z. W. Zhai, and J. Y. Tong, “Synthesis, crystal structure and fungicidal activity of 3-(Difluoromethyl)-1-methyl-N-((2(trifluoromethyl)phenyl) carbamoyl)-1H-pyrazole-4-carboxamide,” Chinese Journal of Structural Chemistry, vol. 38, pp. 706–712, 2019.
View at: Google Scholar
T. Jin, Z. W. Zhai, L. Han, J. Q. Weng, C. X. Tan, and X. H. Liu, “Synthesis, crystal structure, docking and antifungal activity of a new pyrazole acylurea compound,” Chinese Journal of Structural Chemistry, vol. 37, pp. 1259–1264, 2018.
View at: Google Scholar
H. Wang, Z. W. Zhai, Y. X. Shi et al., “Novel trifluoromethylpyrazole acyl urea derivatives: synthesis, crystal structure, fungicidal activity and docking study,” Journal of Molecular Structure, vol. 1171, pp. 631–638, 2018.
View at: Publisher Site | Google Scholar
X. H. Liu, L. Qiao, Z. W. Zhai et al., “Novel 4-pyrazole carboxamide derivatives containing flexible chain motif: design, synthesis and antifungal activity,” Pest Management Science, vol. 75, no. 11, pp. 2892–2900, 2019.
View at: Publisher Site | Google Scholar
G. M. Sheldrick, “A short history of SHEL,” Acta crystallographica, vol. A64, pp. 112–122, 2008.
View at: Google Scholar
G. M. Sheldrick, “Crystal structure refinement with SHELXL,” Acta crystallographica, vol. C71, pp. 3–8, 2015.
View at: Google Scholar
O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard, and H. Puschmann, “OLEX2: a complete structure solution, refinement and analysis program,” Journal of Applied Crystallography, vol. 42, no. 2, pp. 339–341, 2009.
View at: Publisher Site | Google Scholar
L. J. Min, H. Wang, J. Bajsa-Hirschel et al., “Novel dioxolane ring compounds for the management of phytopathogen diseases as ergosterol biosynthesis inhibitors: synthesis, biological activities, and molecular docking,” Journal of Agricultural and Food Chemistry, vol. 70, no. 14, pp. 4303–4315, 2022.
View at: Publisher Site | Google Scholar
J. X. Mu, C. S. Yu, L. J. Min, and X. H. Liu, “Synthesis, crystal structure, antifungal activity and computational study on 4-(((8-Chloro-3-oxo-[1, 2, 4]-triazolo[4, 3-a]pyridin-2(3H)-yl)thio)methyl)benzonitrile,” Chinese Journal of Structural Chemistry, vol. 40, pp. 424–430, 2021.
View at: Google Scholar

Copyright

Copyright © 2022 Bin Wang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

532

Downloads

661

Citations