Use of a 2,8-bis(trifluoromethyl)-4-hydroxyquinoline derivative for the control of agricultural bacteria

Abstract

The application discloses application of any one of 2,8-bis(trifluoromethyl)-4-hydroxy quinoline derivatives Q-1 to Q-39 in prevention and treatment of agricultural bacterial diseases. Through biological activity tests, the derivatives show excellent inhibitory activity on two kinds of plant bacteria, i.e. rice bacterial leaf blight pathogen and citrus canker pathogen, wherein the MIC values of compound Q-29 on the rice bacterial leaf blight pathogen and the citrus canker pathogen both reach 1.56 μg / mL, and the activity is obviously better than that of thiazolyl salicylhydrazide and thiodiazole copper. 90 The compound involved in the application is low in preparation difficulty, and raw materials are cheap and easy to obtain, so the compound is expected to be developed into a new agricultural antibacterial agent.

Description

Technical Field

[0001] This invention belongs to the field of natural medicinal chemistry and discloses a new use of a 2,8-bis(trifluoromethyl)-4-hydroxyquinoline derivative, specifically involving compounds Q-1 to Q-39 in the prevention and control of agricultural bacterial diseases caused by Xanthomonas oryzae ACCC 11602, the pathogen of rice bacterial blight, and Xanthomonas axonopodis pv. Citri. Background Technology

[0002] Plant bacterial diseases are among the most difficult to control during crop growth, causing severe damage and significant economic losses. Rice bacterial blight can lead to a 20%-50% reduction in rice yield, while citrus canker seriously threaten important citrus fruit crops worldwide. Since the 1960s, the extensive use of chemical pesticides has been the primary method for pest control. Although pesticides have been successful in reducing pest populations, their application has had negative impacts on the environment and the crops themselves. Therefore, researching and developing new, highly effective, low-toxicity, and low-residue pesticides that can effectively protect and treat plants is one of the main goals of pesticide development.

[0003] Quinine, also known as cinchona alkaloid, is an alkaloid extracted from the bark of the cinchona tree (a member of the Rubiaceae family) and related species. Mefloquine, obtained by modifying the structure of quinine, is a third-generation antimalarial drug, 5 to 30 times more potent than quinine. Currently, reports on the bioactivity of this alkaloid and its derivatives mainly focus on antimalarial treatment; however, there are no reports on their application in controlling agricultural bacterial pathogens.

[0004]

[0005] Therefore, using mefloquine as a lead template, we obtained a series of 2,8-bis(trifluoromethyl)-4-hydroxyquinoline derivatives through structural optimization, and evaluated their activity against plant pathogenic bacteria. The test results showed that these compounds exhibited potential inhibitory effects against two types of agricultural bacteria: rice bacterial blight pathogen and citrus canker pathogen, significantly outperforming the control drugs thiabendazole and thiamethoxam. They hold promise for development as a novel agricultural drug against plant pathogenic bacteria. Summary of the Invention

[0006] The purpose of this invention is to provide a novel use of 2,8-bis(trifluoromethyl)-4-hydroxyquinoline derivatives in the control of plant pathogenic bacteria, particularly in the control of diseases caused by rice bacterial blight and citrus canker.

[0007] To achieve the above objectives, the invention employs the following technical method: the compound structure is shown in chemical formula 1.

[0008]

[0009] Chemical Formula 1

[0010]

[0011] The 2,8-bis(trifluoromethyl)-4-hydroxyquinoline derivative of this invention is a compound obtained according to the synthetic method reported in the literature J. Agric. Food Chem. 2021, 69, 12156-12170. The pure product was obtained by conventional methods such as silica gel column chromatography, and the 2,8-bis(trifluoromethyl)-4-hydroxyquinoline derivative described in the claims was identified by nuclear magnetic resonance spectroscopy, mass spectrometry, and other techniques. Activity screening results show that the 2,8-bis(trifluoromethyl)-4-hydroxyquinoline derivative of this invention exhibits good inhibitory effects against rice bacterial blight and citrus canker. Detailed Implementation

[0012] To better understand the present invention, the following detailed description of specific embodiments further illustrates the above-mentioned content of the present invention. However, this should not be construed as a limitation of the present invention. Unless otherwise specified, the experimental methods described in the following embodiments are conventional methods.

[0013] Example 1: Synthesis of compounds Q-1 to Q-37

[0014] The synthesis method of compounds Q-1 to Q-37 of the present invention is carried out according to the following reaction formula:

[0015]

[0016] Synthesis of target compounds Q-1 to Q-37:

[0017] Synthesis of Intermediate 1: Under argon protection and stirring under reflux, POBr3 (113.81 mmol) was melted at 75 °C, and 2,8-bis(trifluoromethyl)-4-hydroxyquinoline (28.45 mmol) was added. The mixture was then heated to 150 °C and refluxed for 6 h. Under vigorous stirring, the mixture was added dropwise to ice water, and a large amount of white solid precipitated out. The solid was filtered, washed with water, and air-dried to obtain Intermediate 1, which could be used directly in the next reaction without further purification.

[0018] Synthesis of Intermediate 2: Under argon protection and stirring at room temperature, (±) glycidol (20.93 mmol) was dissolved in THF, and then NaH (26.16 mmol) was added to the reaction system in three portions. After 15–30 min, Intermediate 1 (17.439 mmol) was added. The reaction was monitored by TLC, and the reaction was completed after 6 h. After the solvent was evaporated under vacuum, the mixture was extracted with ethyl acetate and washed three times with distilled water. The organic phase was dried over anhydrous sodium sulfate and then separated by silica gel column chromatography with petroleum ether:ethyl acetate (8:1–3:1) to obtain Intermediate 2.

[0019] Synthesis of final product 3: Under reflux and stirring, different amines (0.71 mmol) and intermediate 2 (0.59 mmol) were added successively with isopropanol (10 mL) as solvent. The reaction was completed after 8 h under TLC detection. No post-treatment was required. After the solvent was evaporated, the product was separated by silica gel column chromatography with dichloromethane:methanol (200:1 to 50:1) to obtain a white solid, which is the final product 3.

[0020]

[0021] Q-1: Yield: 58%; White solid; 1 HNMR (400MHz, DMSO-d6) δ8.64(d,J=8.5Hz,1H),8.31(d,J=7.3Hz,1H),7.86(t,J=7.9Hz,1H),7.58(s,1H),5.30-5.24(m,1H),4 .46(dd,J=10.4,3.3Hz,1H),4.35(dd,J=10.4,5.9Hz,1H),4.15(s,1H),2.64-2.45(m,12H),1.00(t,J=7.2Hz,3H).MS-ESIm / z:C 20 H 23 F6N3O2: 452.1348[M+H] + .

[0022]

[0023] Q-2: Yield: 52%; White solid; 1HNMR (400MHz, DMSO-d6) δ8.63(d,J=8.5Hz,1H),8.31(d,J=7.4Hz,1H),7.86(t,J=7.9Hz,1H),7.58(s,1H),5.19(s,1H), 4.46(dd,J=10.4,3.2Hz,1H),4.35(dd,J=10.4,5.9Hz,1H),4.14(s,1H),2.58-2.38(m,10H),1.08-0.90(m,9H).MS-ESI m / z:C 22 H 27 F6N3O2: 480.1757 [M+H] + .

[0024]

[0025] Q-3: Yield: 54%; White solid; 1 HNMR (400MHz, DMSO-d6) δ8.65(d,J=8.4Hz,1H),8.33(d,J=7.3Hz,1H),7.88(t,J=7.9Hz,1H),7.60(s,1H),5.23(d,J=5.1Hz,1H),4.48(dd,J=10.3 ,3.4Hz,1H),4.37(dd,J=10.4,6.0Hz,1H),4.23-4.13(m,1H),3.46-3.37 (m,4H),2.63-2.55(m,2H),2.49-2.38(m,4H),1.98(s,3H).MS-ESIm / z:C 20 H 21 F6N3O3:466.1001[M+H] + .

[0026]

[0027] Q-4: Yield: 62%; White solid; 1HNMR (400MHz, DMSO-d6) δ8.64(d,J=8.4Hz,1H),8.30(d,J=7.3Hz,1H),7.86(t,J=7.9Hz,1H),7.58(s,1H),7.04-6.97(m,2H),6.93-6.87(m,2H),5.2 3(d,J=5.0Hz,1H),4.48(dd,J=10.3,3.3Hz,1H),4.37(dd,J=10.4,6.0Hz, 1H),4.23-4.14(m,1H),3.08-3.01(m,4H),2.74-2.52(m,6H).MS-ESIm / z:C 24 H 22 F7N3O2: 518.1464 [M+H] + .

[0028]

[0029] Q-5: Yield: 64%; White solid; 1 HNMR (400MHz, DMSO-d6) δ8.64(d,J=8.4Hz,1H),8.30(d,J=7.2Hz,1H),7.85(t,J=8.9Hz,1H),7.58(s,1H),7.19(d,J=8.9Hz,2H),6.90(d,J=8.9Hz,2H ),5.23(d,J=5.1Hz,1H),4.48(dd,J=10.4,3.3Hz,1H),4.37(dd,J=10.3,6 .0Hz,1H),4.24-4.12(m,1H),3.14-3.04(m,4H),2.71-2.52(m,6H).MS-ESI m / z:C 24 H 22 ClF6N3O2: 534.1164 [M+H] + .

[0030]

[0031] Q-6: Yield: 51%; White solid; 1HNMR(400MHz,DMSO-d6)δ8.56(d,J=8.4Hz,1H),8.32(d,J=7.5Hz,1H),7.85(t,J=8.0Hz ,1H),7.58(s,1H),7.36(d,J=7.0Hz,2H),7.28(t,J=7.3Hz,2H),7.25-7.17(m,1H),5.3 4(s,1H),4.48(dd,J=10.2,3.9Hz,1H),4.36(dd,J=10.2,6.0Hz,1H),4.19-4.10(m,1H) ,3.83(s,2H),2.83(dd,J=12.0,5.5Hz,1H),2.76(dd,J=12.0,6.7Hz,1H).MS-ESIm / z:C 21 H 18 F6N2O2:445.0842[M+H] + .

[0032]

[0033] Q-7: Yield: 52%; White solid; 1 HNMR (400MHz, DMSO-d6) δ8.55(d,J=8.5Hz,1H),8.32(d,J=7.3Hz,1H),7.84(t,J=7.9H z,1H),7.58(s,1H),7.36(dd,J=8.4,5.6Hz,2H),7.05(t,J=8.7Hz,2H),5.31(d,J=11.5 Hz,1H),4.47(dd,J=10.2,3.8Hz,1H),4.36(dd,J=10.2,6.0Hz,1H),4.14-4.05(m,1H) ,3.75(s,2H),2.75(dd,J=12.1,5.9Hz,1H),2.69(dd,J=12.0,6.5Hz,1H).MS-ESIm / z:C 21 H 17 F7N2O2: 463.0667 [M+H] + .

[0034]

[0035] Q-8: Yield: 60%; White solid; 1HNMR(400MHz,DMSO-d6)δ8.54(d,J=8.5Hz,1H),8.32(d,J=7.3Hz,1H),7.84(t,J =7.9Hz,1H),7.58(s,1H),7.36(d,J=8.2Hz,2H),7.29(d,J=8.3Hz,2H),5.32(s,1 H),4.47(dd,J=10.2,3.8Hz,1H),4.36(dd,J=10.2,6.0Hz,1H),4.18-4.04(m,1H) ,3.77(s,2H),2.75(dd,J=12.0,5.7Hz,1H),2.70(dd,J=12.0,6.4Hz,1H).MS-ESI m / z:C 21 H 17 ClF6N2O2: 479.0691 [M+H] + .

[0036]

[0037] Q-9: Yield: 55%; White solid; 1 H NMR (400MHz, DMSO-d6) δ8.57(dd,J=8.5,1.4Hz,1H),8.34(d,J=7.3Hz,1H),7.86(t,J =7.9Hz,1H),7.58(s,1H),7.39-7.33(m,2H),6.94-6.85(m,2H),5.76(s,1H),4.46(d d,J=10.4,4.1Hz,1H),4.37(dd,J=10.3,5.8Hz,1H),4.28-4.19(m,1H),3.94(s,2H), 3.73(s,3H),2.96(dd,J=12.2,4.4Hz,1H),2.86(dd,J=12.3,7.7Hz,1H).MS-ESIm / z:C 22 H 20 F6N2O3: 475.0967 [M+H] + .

[0038]

[0039] Q-10: Yield: 49%; White solid; 1HNMR (400MHz, DMSO-d6) δ8.61 (d, J = 8.4Hz, 1H), 8.34 (d, J = 7.3Hz, 1H), 7.87 (t, J = 7.9Hz, 1H), 7.79 ( m,4H),7.59(s,1H),5.33(s,1H),4.49(m,2H),4.27(s,2H),4.15(m,1H),3.40(m,2H).MS-ESIm / z:C 22 H 17 F9N2O2: 513.1932 [M+H] + .

[0040]

[0041] Q-11: Yield: 52%; White solid; 1 HNMR (400MHz, DMSO-d6) δ8.54(d,J=8.4Hz,1H),8.32(d,J=7.3Hz,1H),7.84(t,J=7.9Hz, 1H),7.58(s,1H),7.18(d,J=7.7Hz,2H),7.02(d,J=7.7Hz,2H),5.26(d,J=5.0Hz,1H),4. 46(dd,J=10.2,3.8Hz,1H),4.35(dd,J=10.2,6.0Hz,1H),4.12-4.03(m,1H),3.70(s,2H) ,2.72(dd,J=12.41,6.1Hz,1H),2.68(dd,J=12.4,6.7Hz,1H),2.22(s,3H).MS-ESIm / z:C 22 H 20 F6N2O2:459.0888[M+H] + .

[0042]

[0043] Q-12: Yield: 56%; White solid; 1H NMR (400MHz, DMSO-d6) δ8.61(d,J=8.5Hz,1H),8.33(d,J=7.0Hz,1H),7.87(t,J= 7.9Hz,1H),7.59(s,1H),7.56(d,J=1.9Hz,1H),6.37(m,1H),6.27(d,J=3.2Hz,1H ),5.36(s,1H),4.46(dd,J=10.3,3.7Hz,1H),4.33(dd,J=10.2,6.2Hz,1H),4.13- 4.07(m,1H),3.77(s,2H),2.94(m,1H),2.76(dd,J=11.3,6.1Hz,1H).MS-ESIm / z:

[0044] C 19 H 16 F6N2O3: 435.0319[M+H] + .

[0045]

[0046] Q-13: Yield: 59%; White solid; 1 HNMR(400MHz,DMSO-d6)δ8.58(d,J=8.5Hz,1H),8.32(d,J=7.3Hz,1H),7.86(t,J=7.9Hz,1H) ,7.58(s,1H),7.34(dd,J=5.0,1.3Hz,1H),6.98(d,J=3.4Hz,1H),6.93(dd,J=5.1,3.4Hz,1H) ,5.37-5.28(m,1H),4.47(dd,J=10.2,3.8Hz,1H),4.35(dd,J=10.2,6.1Hz,1H),4.21-4.07( m,1H),3.97(s,2H),2.82(dd,J=12.0,5.7Hz,1H),2.75(dd,J=12.1,6.5Hz,1H).MS-ESIm / z:C 19 H 16 F6N2O2S: 451.1263 [M+H] + .

[0047]

[0048] Q-14: Yield: 64%; White solid; 1HNMR(400MHz,DMSO-d6)δ8.58(d,J=8.5Hz,1H),8.32(d,J=7.4Hz,1H),7.85( t,J=7.9Hz,1H),7.58(s,1H),7.46(t,J=7.7Hz,1H),7.30-7.20(m,1H),7.15- 7.06(m,2H),5.32(d,J=6.6Hz,1H),4.47(dd,J=10.2,3.8Hz,1H),4.36(dd,J =10.2,6.1Hz,1H),4.18-4.05(m,1H),3.81(s,2H),2.82-2.67(m,2H).MS-ESI m / z:C 21 H 17 F7N2O2:463.0718[M+H] + .

[0049]

[0050] Q-15: Yield: 56%; White solid; 1 H NMR (400MHz, DMSO-d6) δ8.56(d,J=8.4Hz,1H),8.33(d,J=7.2Hz,1H),7.84(t,J=7.9Hz,1 H),7.59(s,1H),7.29(d,J=8.5Hz,1H),7.20-7.13(m,2H),6.98(td,J=8.5,2.7Hz,1H),5. 25(d,J=5.5Hz,1H),4.47(dd,J=10.2,3.8Hz,1H),4.36(dd,J=10.2,6.0Hz,1H),4.11(m,1 H),3.79(s,2H),2.75(dd,J=12.0,5.9Hz,1H),2.69(dd,J=11.9,6.3Hz,1H).MS-ESIm / z:C 21 H 17 F7N2O2: 463.1934 [M+H] + .

[0051]

[0052] Q-16: Yield: 75%; White solid; 1HNMR (400MHz, DMSO-d6) δ8.42(d,J=8.4Hz,1H),8.31(d,J=7.3Hz,1H),7.80(t,J=7.9Hz,1H),7.5 3(s,1H),7.26(dd,J=8.3,5.6Hz,2H),6.88(t,J=8.7Hz,2H),5.17(d,J=5.3Hz,1H),4.41(dd,J=1 0.2,3.4Hz,1H),4.33(dd,J=10.2,5.0Hz,1H),4.16-4.09(m,1H),3.56(d,J=13.1Hz,1H),3.43(d ,J=13.2Hz,1H),2.67(dd,J=12.6,7.5Hz,1H),2.43(dd,J=12.6,5.6Hz,1H),2.26(s,3H).MS-ESI m / z:C 22 H 19 F7N2O2:477.0867[M+H] + .

[0053]

[0054] Q-17: Yield: 66%; White solid; 1 HNMR (400MHz, DMSO-d6) δ8.57(d,J=8.5Hz,1H),8.31(d,J=7.3Hz,1H),7.84(t,J=7.9Hz,1H ),7.57(s,1H),7.51(dd,J=6.8,2.7Hz,1H),7.36(dd,J=6.8,2.5Hz,1H),7.26-7.17(m,2H), 5.35-5.31(m,1H),4.47(dd,J=10.2,3.8Hz,1H),4.36(dd,J=10.2,5.9Hz,1H),4.15-4.06(m ,1H),3.84(s,2H),2.79(dd,J=12.0,5.7Hz,1H),2.73(dd,J=12.0,6.4Hz,1H).MS-ESIm / z:C 21 H 17 ClF6N2O2: 479.0436 [M+H] + .

[0055]

[0056] Q-18: Yield: 65%; White solid; 1HNMR (400MHz, DMSO-d6) δ8.41(d,J=8.5Hz,1H),8.29(d,J=7.4Hz,1H),7.79(t,J=7.9Hz,1H),7.52(s, 1H),7.27(s,1H),7.19(d,J=7.6Hz,1H),7.11(t,J=7.7Hz,1H),7.02(d,J=7.9Hz,1H),5.20(d,J=5.1H z,1H),4.41(dd,J=10.2,3.4Hz,1H),4.32(dd,J=10.2,4.9Hz,1H),4.16-4.08(m,1H),3.58(d,J=13.5 Hz,1H),3.46(d,J=13.4Hz,1H),2.69(dd,J=12.6,7.3Hz,1H),2.48-2.41(m,1H),2.27(s,3H).MS-ESI m / z:C 22 H 19 ClF6N2O2: 493.0727 [M+H] + .

[0057]

[0058] Q-19: Yield: 55%; White solid; 1 HNMR(400MHz,DMSO-d6)δ8.54(d,J=8.5Hz,1H),8.33(d,J=7.4Hz,1H),7.84( t,J=7.9Hz,1H),7.58(s,1H),7.41(d,J=8.0Hz,2H),7.28(d,J=8.0Hz,2H),5 .28(s,1H),4.46(dd,J=10.1,3.8Hz,1H),4.35(dd,J=10.2,6.0Hz,1H),4.15 -4.03(m,1H),3.73(s,2H),2.76(m,1H),2.67(dd,J=12.2,6.4Hz,1H).MS-ESI m / z:C 21 H 17 BrF6N2O2: 524.9768 [M+2H] + .

[0059]

[0060] Q-20: Yield: 68%; White solid; 1HNMR (400MHz, DMSO-d6) δ8.45(d,J=8.4Hz,1H),8.30(d,J=7.3Hz,1H),7.81(t,J=7.9Hz,1H),7.53(s, 1H),7.24(d,J=8.1Hz,2H),7.12(t,J=7.4Hz,2H),7.05(t,J=7.3Hz,1H),5.18(d,J=5.2Hz,1H),4.43(d d,J=10.2,3.2Hz,1H),4.32(dd,J=10.2,5.2Hz,1H),4.17-4.09(m,1H),3.59(d,J=13.2Hz,1H),3.45(d ,J=13.1Hz,1H),2.68(dd,J=12.6,7.4Hz,1H),2.45(dd,J=12.7,5.7Hz,1H),2.26(s,3H).MS-ESIm / z:C 22 H 20 F6N2O2:459.0970[M+H] + .

[0061]

[0062] Q-21: Yield: 61%; White solid; 1 HNMR(400MHz,DMSO-d6)δ8.54(d,J=8.4Hz,1H),8.31(d,J=7.3Hz,1H),7.83(t,J =7.9Hz,1H),7.57(s,1H),7.08-7.01(m,2H),6.99-6.91(m,1H),5.31(s,1H),4.4 7(dd,J=10.1,3.9Hz,1H),4.37(dd,J=10.2,5.8Hz,1H),4.13-4.05(m,1H),3.79 (s,2H),2.75(dd,J=12.1,5.9Hz,1H),2.69(dd,J=12.0,6.3Hz,1H).MS-ESIm / z:C 21 H 16 F8N2O2:481.0783[M+H] + .

[0063]

[0064] Q-22: Yield: 70%; White solid; 1HNMR (400MHz, DMSO-d6) δ8.67(d,J=8.4Hz,1H),8.33(d,J=7.3Hz,1H),7.88(t,J=7.9Hz,1H),7.61(s,1H),5.53(s,1H),4.48(dd,J=10 .3,3.6Hz,1H),4.38(dd,J=10.4,5.8Hz,1H),4.22(m,1H),2.96(dd,J=12.6,5.8Hz,1H),2.78(m,5H),1.93-1.70(m,4H).MS-ESIm / z:C 18 H 20 F6N2O2: 411.1068 [M+H] + .

[0065]

[0066] Q-23: Yield: 65%; White solid; 1 HNMR (400MHz, DMSO-d6) δ8.67(d,J=8.4Hz,1H),8.33(d,J=7.3Hz,1H),7.88(t,J=7.9Hz,1H),7.61(s,1H),5.53(s,1H),4.48(dd,J=10 .3,3.6Hz,1H),4.38(dd,J=10.4,5.8Hz,1H),4.22(m,1H),2.96(dd,J=12.6,5.8Hz,1H),2.78(m,5H),1.93-1.70(m,4H).MS-ESIm / z:C 18 H 18 F6N2O2:409.0844[M+H] + .

[0067]

[0068] Q-24: Yield: 57%; White solid; 1 HNMR (400MHz, DMSO-d6) δ8.65(d,J=8.4Hz,1H),8.33(d,J=7.2Hz,1H),7.88(t,J=7.9Hz,1H),7.60(s,1H),5.30(s,1H),4.47(dd,J=10.3 ,3.2Hz,1H),4.34(dd,J=10.3,6.0Hz,1H),4.21-4.06(m,1H),2.61(dd,J=12.5,6.5Hz,1H),2.51-2.44(m,1H),2.29(s,6H).MS-ESIm / z:C 18H 20 F6N2O2: 383.0790 [M+H] + .

[0069]

[0070] Q-25: Yield: 58%; White solid; 1 HNMR (400MHz, DMSO-d6) δ8.62(d,J=8.4Hz,1H),8.31(d,J=7.3Hz,1H),7.86(t,J=7.9Hz,1H),7.56(s,1H),7.29–7.10(m,5H),5.28(s,1H),4.43(dd ,J=10.2,3.8Hz,1H),4.31(dd,J=10.2,6.1Hz,1H),4.12–4.02(m,1H),2.8 5–2.80(m,2H),2.79(dd,J=7.1,4.1Hz,2H),2.72(t,J=7.2Hz,2H).MS-ESI m / z:calcd forC 22 H 20 F6N2O2:458.1429; found:459.2243[M+H] + .

[0071]

[0072] Q-26: Yield: 60%; White solid; 1 HNMR (400MHz, DMSO-d6) δ8.62(d,J=8.4Hz,1H),8.31(d,J=7.3Hz,1H),7.86(t,J=7.9Hz,1H),7.56(s,1H),7.27(d,J=8.5Hz,2H),7.22( d,J=8.5Hz,2H),5.27(s,1H),4.43(dd,J=10.2,3.8Hz,1H),4.31(dd,J=10.2,6.2Hz,1H),4.08–4.03(m,1H),2.83–2.67(m,6H).MS-ESI m / z:calcd for C 22 H 19 ClF6N2O2:492.1039; found:493.1960[M+H] + .

[0073]

[0074] Q-27: Yield: 62%; White solid; 1HNMR (400MHz, DMSO-d6) δ8.62(d,J=8.4Hz,1H),8.31(d,J=7.3Hz,1H),7.86(t,J=7.9Hz,1H),7.55(s,1H),7.27(s,1H),7.23(d,J=7.6Hz ,1H),7.20–7.12(m,2H),5.27(s,1H),4.43(dd,J=10.1,3.7Hz,1H),4.31(dd,J=10.2,6.2Hz,1H),4.06(s,1H),2.84–2.68(m,6H).MS-ESI m / z:calcd for C 22 H 19 ClF6N2O2:492.1039; found:493.1960[M+H] + .

[0075]

[0076] Q-28: Yield: 59%; White solid; 1 HNMR (400MHz, DMSO-d6) δ8.00(d,J=7.3Hz,1H),7.55(d,J=7.9Hz,1H),7.25(s,1H),7.18(d,J=2.4Hz,1H),7.10–7.02(m,1H),6.96(dd,J =8.3,2.4Hz,1H),5.45(s,1H),4.13(dd,J=10.2,3.7Hz,1H),4.01(dd,J=10.2,6.2Hz,1H),3.81–3.72(m,1H),2.55–2.42(m,6H).MS-ESI m / z:calcd for C 22 H 20 F6N2O2:526.0650; found:527.1625[M+H] + .

[0077]

[0078] Q-29: Yield: 60%; White solid; 1HNMR (400MHz, DMSO-d6) δ8.62(d,J=8.5Hz,1H),8.31(d,J=7.3Hz,1H),7.86(t,J=7.9Hz,1H),7.55(d,J=7.2Hz,3H),7.42(d,J=7.9Hz, 2H),5.27(s,1H),4.42(dd,J=10.2,3.7Hz,1H),4.30(dd,J=10.3,6.2Hz,1H),4.13–4.00(m,1H),2.88–2.69(m,6H).MS-ESIm / z:calcd for C 23 H 19 F9N2O2:526.1303; found:527.2287[M+H] + .

[0079]

[0080] Q-30: Yield: 64%; White solid; 1 H NMR (400MHz, DMSO-d6) δ8.62 (dd, J=8.5, 1.4Hz, 1H), 8.31 (dd, J=7.3, 1.4Hz, 1H),7.85(t,J=7.9Hz,1H),7.57(s,1H),6.81–6.73(m,2H),6.65(dd,J=7.9, 1.7Hz,1H),5.92(s,2H),4.44(dd,J=10.2,3.8Hz,1H),4.32(dd,J=10.2,6.2 Hz,1H),4.11–4.03(m,1H),2.85–2.70(m,4H),2.64(t,J=7.2Hz,2H).MS-ESI m / z:calcd for C 23 H 20 F6N2O4:502.1327; found:503.2138[M+H] + .

[0081]

[0082] Q-31: Yield: 58%; White solid; 1HNMR (400MHz, DMSO-d6) δ8.62(d,J=8.4Hz,1H),8.31(d,J=7.3Hz,1H),7.86(t,J=7.9Hz,1H),7.56(s,1H),7.06(d,J=7.8Hz,2H),7.01(d,J=7.8Hz, 2H),5.25(s,1H),4.43(dd,J=10.2,3.8Hz,1H),4.31(dd,J=10.2,6.1Hz,1H),4.12–4.00(m,1H),2.83–2.62(m,6H),2.21(s,3H).MS-ESIm / z:calcd for C 23 H 20 F6N2O4:472.1585; found:473.2365[M+H] + .

[0083]

[0084] Q-32: Yield: 57%; White solid; 1 HNMR (400MHz, DMSO-d6) δ8.62(d,J=8.4Hz,1H),8.31(d,J=7.3Hz,1H),7.86(t,J=7.9Hz,1H),7.56(s,1H),7.34(td,J=7.0,2.2Hz,2H),7.19(tt,J=7 .5,5.5Hz,2H),5.27(s,1H),4.44(dd,J=10.2,3.7Hz,1H),4.32(dd,J=10.2,6.2Hz,1H),4.07(t,J=5.1Hz,1H),2.91–2.71(m,6H).MS-ESIm / z:calcd forC 22 H 19 ClF6N2O2:492.1039; found:493.1966[M+H] + .

[0085]

[0086] Q-33: Yield: 60%; White solid; 1HNMR(400MHz,DMSO-d6)δ8.61(d,J=7.0Hz,1H),8.32–8.28(m,1H),7.85(dq ,J=11.2,7.4,5.3Hz,1H),7.57–7.51(m,1H),7.25(q,J=7.4Hz,1H),7.06–6. 99(m,2H),6.94(t,J=9.1Hz,1H),5.26(s,1H),4.43(dd,J=10.2,3.8Hz,1H) ,4.31(dd,J=10.2,6.2Hz,1H),4.09–4.04(m,1H),2.85–2.65(m,6H).MS-ESI m / z:calcd for C 22 H 19 F7N2O2:476.1335; found:477.2250[M+H] + .

[0087]

[0088] Q-34: Yield: 62%; White solid; 1 HNMR (400MHz, DMSO-d6) δ8.62(d,J=8.4Hz,1H),8.31(d,J=7.3Hz,1H),7.86(t,J=7.9Hz,1H),7.56(s,1H),7.23(dd,J=8.3,5.5Hz,2H),7. 03(t,J=8.6Hz,2H),5.27(s,1H),4.43(dd,J=10.3,3.7Hz,1H),4.31(dd,J=10.2,6.1Hz,1H),4.08–4.04(m,1H),2.81–2.66(m,6H).MS-ESI m / z:calcd for C 22 H 19 F7N2O2:476.1335; found:477.2044[M+H] + .

[0089]

[0090] Q-35: Yield: 64%; White solid; 1HNMR (400MHz, DMSO-d6) δ8.63(d,J=8.4Hz,1H),8.32(d,J=7.3Hz,1H),7.86(t,J=7. 9Hz,1H),7.58(s,1H),6.82–6.76(m,2H),6.69(dd,J=8.2,1.9Hz,1H),5.30(s,1H), 4.45(dd,J=10.2,3.8Hz,1H),4.33(dd,J=10.2,6.1Hz,1H),4.08(t,J=5.3Hz,1H),3 .71(s,3H),3.68(s,3H),2.86–2.71(m,4H),2.66(t,J=7.3Hz,2H).MS-ESIm / z:calcd for C 24 H 24 F6N2O4:518.1640; found:519.2439[M+H] + .

[0091]

[0092] Q-36: Yield: 59%; White solid; 1 H NMR (400MHz, DMSO-d6) δ8.63(d,J=8.5Hz,1H),8.31(d,J=7.3Hz,1H),7.85(t,J=7 .9Hz,1H),7.58(s,1H),7.23(t,J=7.5Hz,2H),7.15(d,J=7.6Hz,3H),5.31(s,1H) ,4.47(dd,J=10.2,3.7Hz,1H),4.35(dd,J=10.3,6.1Hz,1H),4.16–3.98(m,1H),2 .84–2.68(m,2H),2.59(t,J=7.4Hz,4H),1.72(p,J=7.3Hz,2H).MS-ESIm / z:calcd for C 23 H 22 F6N2O2:472.1585; found:473.2525[M+H] + .

[0093]

[0094] Q-37: Yield: 64%; White solid; 1H NMR (400MHz, DMSO-d6) δ8.62(d,J=8.5Hz,1H),8.31(d,J=7.3Hz,1H),7.85(t ,J=7.9Hz,1H),7.55(s,1H),7.28(t,J=7.6Hz,1H),7.19(q,J=7.0Hz,1H),7. 06(q,J=8.3,7.0Hz,2H),5.27(s,1H),4.43(dd,J=10.1,3.7Hz,1H),4.30(dd ,J=10.2,6.2Hz,1H),4.09–4.03(m,1H),2.84–2.72(m,6H).MS-ESIm / z:calcd forC 22 H 19 F7N2O2:476.1335; found:477.2190[M+H] + .

[0095] Example 2: Synthesis of compounds Q-38 to Q-39

[0096] The synthesis method of compounds Q-38 to Q-39 of the present invention is carried out according to the following reaction formula:

[0097]

[0098] Synthesis of intermediate 1: The synthesis method of intermediate 1 is the same as that in Example 1.

[0099] Synthesis of Intermediate 4: Under argon protection, Intermediate 1 (1.453 mmol) was dissolved in toluene (10 mL). Pd2(dba)3 (0.00727 mmol), P(t-Bu)3 (0.01743 mmol), and tributylvinyltin (1.599 mmol) were added sequentially with stirring at room temperature. The reaction was complete after 4 h under TLC monitoring. Then, potassium fluoride (2 mL, 1 M in H2O) and ethyl acetate (5 mL) were added, and stirring continued for 30 min. The reaction mixture was filtered through diatomaceous earth, washed with an appropriate amount of ethyl acetate, concentrated under vacuum, and separated by silica gel column chromatography with petroleum ether:ethyl acetate (8:1–3:1) to obtain Intermediate 4.

[0100] Synthesis of intermediate 5: Intermediate 4 (1.17 mmol) was dissolved in dichloromethane (10 mL), and m-CPBA (2.919 mmol) and potassium carbonate (1.40 mmol) were added. The mixture was stirred and refluxed overnight. After the reaction was completed by TLC, the reaction mixture was filtered with diatomaceous earth and washed with dichloromethane:methanol (4:1). The mixture was then concentrated under vacuum and separated by silica gel column chromatography with petroleum ether:ethyl acetate (8:1 to 3:1) to obtain intermediate 5.

[0101] Synthesis of final product 6: The synthesis method of final product 6 is the same as that in Example 1.

[0102]

[0103] Q-38: Yield: 33%; White solid; 1 HNMR (400MHz, DMSO-d6) δ8.57(d,J=8.6Hz,1H),8.34(d,J=7.3Hz,1H),8.12(s,1H),7.88(t,J=8.0Hz,1H),7.29-7.20(m,2H),7.08-6.99 (m,2H),6.02(d,J=4.4Hz,1H),5.64-5.57(m,1H),3.71(s,2H),2.87(dd,J=12.5,4.3Hz,1H),2.77(dd,J=12.5,6.8Hz,1H).MS-ESIm / z:C 20 H 15 F7N2O: 433.1434[M+H] + .

[0104]

[0105] Q-39: Yield: 36%; White solid; 1 HNMR (400MHz, DMSO-d6) δ8.57(d,J=8.6Hz,1H),8.34(d,J=7.3Hz,1H),8.12(s,1H),7.88(t,J=7.9Hz,1H),7.30-7.19(m,4H),6 .02(d,J=4.3Hz,1H),5.65-5.55(m,1H),3.72(s,2H),2.87(dd,J=12.6,4.3Hz,1H),2.77(dd,J=12.5,6.8Hz,1H).MS-ESIm / z:C 20 H 15 ClF6N2O: 448.9931 [M+H] + .

[0106] Example 3: Determination and Results of the Anti-Agricultural Pathogenic Bacteria Activity of 2,8-bis(trifluoromethyl)-4-hydroxyquinoline Derivatives

[0107] 1) Test reagents: 2,8-bis(trifluoromethyl)-4-hydroxyquinoline derivatives Q-1 to Q-39.

[0108] 2) Test strains: Xanthomonas oryzae ACCC 11602, the pathogen of rice bacterial blight, and Xanthomonas axonopodis pv. Citri, the pathogen of citrus canker, were provided by Guangxi Tianyuan Biochemical Co., Ltd.

[0109] 3) Antibacterial activity test:

[0110] The bacterial strains used in this experiment were cryopreserved in the laboratory at -80℃ with 30% glycerol. The cryopreserved strains were removed and streaked onto NB solid medium (beef extract: 3g, peptone: 5g, yeast extract: 1g, sucrose: 10g, agar: 15g, distilled water: 1L, pH 7.0; sterilized at 121℃ for 20min), and incubated at 28℃ until single colonies appeared. Single colonies from the solid medium were transferred to NB liquid medium (beef extract: 3g, peptone: 5g, yeast extract: 1g, sucrose: 10g, distilled water: 1L; sterilized at 121℃ for 20min) and cultured on a shaker at 28℃ and 180 rpm until the logarithmic growth phase. The strains in the logarithmic growth phase were diluted with NB liquid medium to approximately 10... 6 CFU / mL is prepared for use. Dissolve the compounds separately in DMSO, add them to the liquid culture medium, mix thoroughly, and prepare a drug-containing liquid culture medium with a concentration of 200 μg / mL. Take 50 μL of the drug-containing culture medium and the same volume of approximately 10... 6 CFU / mL bacterial culture was added to the wells of a 96-well plate, resulting in a final drug concentration of 100 μg / mL. A control of 100 μL of bacterial culture containing an equal amount of DMSO was used. The 96-well plates were incubated at 28°C for 24–48 h until bacterial growth was observed in the control group. The OD value (OD) of the bacterial culture in each well was then measured using a microplate reader. 600 In addition, the OD values ​​of 100 μL of liquid culture medium and a 100 μg / mL drug concentration were measured to correct for the OD values ​​caused by the culture medium and the drug itself. The formulas for calculating the corrected OD value and inhibition rate are as follows:

[0111] Corrected OD value = OD value of bacterial culture medium - OD value of sterile culture medium;

[0112] Inhibition rate = (OD value of bacterial suspension in the control medium after correction - OD value of bacterial suspension in the drug-containing medium after correction) / OD value of bacterial suspension in the control medium after correction × 100%

[0113] The drug-containing liquid culture medium was diluted in 96-well plates using a two-fold dilution method to obtain a series of 50 μL drug-containing media of different concentrations. The inhibition rates corresponding to these concentrations were then determined using the same experimental method described above. All experiments were performed in triplicate, and the MIC of the compound was determined. 90The minimum drug concentration required to inhibit 90% bacterial growth is shown in Table 1.

[0114] Table 1. In vitro MICs of 2,8-bis(trifluoromethyl)-4-hydroxyquinoline derivatives Q-1 to Q-39 against plant pathogenic bacteria. 90 (μg / mL)

[0115]

[0116]

[0117] As shown in Table 1, the 2,8-bis(trifluoromethyl)-4-hydroxyquinoline derivatives Q-1 to Q-39 prepared in this invention exhibited different degrees of inhibitory activity against two plant pathogenic bacteria. Among them, Q-29 showed the highest MIC against rice bacterial blight pathogen and citrus canker pathogen. 90 The values ​​all reached 1.56 μg / mL, significantly better than the control drugs thiabendazole and thiabendazole copper. These derivatives are readily available and easy to synthesize. Some of their compounds exhibit higher antibacterial activity than the control drugs thiabendazole and thiabendazole copper, making them worthy of further development and potentially promising as novel agricultural antibacterial agents.

Claims

1. A 2,8-bis(trifluoromethyl)-4-hydroxyquinoline derivative Q-38~Q-39 in the preparation of a fungicide for controlling or resisting rice bacterial blight (… Xanthomonas oryzae ACCC 11602) and / or citrus canker ( Xanthomonas axonopodis Use in pv. Citri); the structural formulas of the 2,8-bis(trifluoromethyl)-4-hydroxyquinoline derivatives Q-38 to Q-39 are as follows: ,in 。

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