Tetrahydro-beta-carboline bacteriostatic agent as well as synthesis method and application thereof

Abstract

The invention relates to a tetrahydro-beta-carboline bacteriostatic agent as well as a synthesis method and application thereof. The method comprises the following steps: by taking a nicotinic acid analogue as a raw material, adding a solvent anhydrous dichloromethane for dissolving, reacting with thionyl chloride under the condition of oil bath heating to prepare a corresponding acyl chloride substrate, then carrying out amidation reaction with a tetrahydro-beta-carboline compound, adding a quenching agent for quenching reaction, and carrying out vacuum concentration to remove dichloromethane to obtain the heterocyclic compound. The compound has the application of inhibiting phytopathogen. The phytopathogens are Dioscorea nipponica, Phytophthora parasitica var nicotianae, rhizoctonia solani, Colletotrichum gloeosporioides, Colletotrichum frutescens and Coriolus versicolor. The synthesis process is simple, and the product purity is high.

Description

Technical Field

[0001] The invention belongs to the field of pesticide synthesis, and specifically relates to a tetrahydro-β-carboline antibacterial agent, a synthesis method thereof, and use and application thereof for inhibiting plant pathogenic bacteria. Background Art

[0002] Plant diseases and insect pests are one of the direct factors leading to crop yield reduction and major economic losses. How to solve this problem is still a difficult task. With the large-scale and long-term use of traditional pesticides, the resistance of field pests to existing pesticides has increased, and the research work on creating new pesticides is in full swing. Green, efficient, and non-target biologically safe new pesticides are the mainstream direction of pesticide creation today. Among them, natural products are an important way to discover new pesticides. Therefore, taking natural products as the guide and using the principle of sub-active molecule splicing, a new class of antibacterial agents was designed, which has important research significance for the creation of new pesticides.

[0003] Tetrahydro-β-carboline compounds are indole alkaloids widely found in nature, mainly in plants and marine organisms. The tetrahydro-β-carboline nucleus is the basic nucleus showing biological activity. This class of compounds has a variety of biological activities, including anti-tumor, antibacterial, antiviral, antioxidant and antihypertensive activities. Therefore, the chemical synthesis and biological activity of tetrahydro-β-carboline compounds have attracted much attention from scientific researchers. Summary of the invention

[0004] In order to overcome the shortcomings of the prior art, the purpose of the present invention is to provide a tetrahydro-β-carboline antibacterial agent, a synthesis method and use thereof. The antibacterial agent is synthesized from nicotinyl chloride and tetrahydro-β-carboline, and has a good inhibitory effect on pine blight pathogen, tobacco black shank pathogen, rice sheath blight pathogen, oil tea anthracnose pathogen, oil tea fruit spiny Colletotrichum or colorful vesiculocarp.

[0005] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions:

[0006] Tetrahydro-β-carboline antibacterial agent having the general formula (I):

[0007]

[0008] The synthesis route of the tetrahydro-β-carboline antibacterial agent of formula (I) is as follows:

[0009]

[0010] The R is any one of the following groups:

[0011]

[0012] Specifically, the synthesis process of the tetrahydro-β-carboline antibacterial agent having formula (I) comprises the following steps:

[0013] Step 1, preparing acyl chloride: using nicotinic acid analog as raw material, adding anhydrous dichloromethane to dissolve, and reacting with thionyl chloride under heating in an oil bath to prepare the corresponding acyl chloride substrate.

[0014] The nicotinic acid analog is selected from any one of the following: 1-naphthoic acid, 2-amino-3-acetylpyridine, 2-fluoronicotinic acid, 6-chloropyridine-2-carboxylic acid, 2-chloronicotinic acid, 3-chlorobenzoic acid, 3-chloroisonicotinic acid, 5,6-dichloronicotinic acid, 5-methylpyrazine-2-carboxylic acid, 5-methylnicotinic acid, 5-chloropyridine-2-carboxylic acid, 6-methylpyridine-3-carboxylic acid, 6-chloronicotinic acid, 2-carboxylic acid pyridine, pyrazine-2-carboxylic acid, 4-methoxybenzoic acid, 3-fluorobenzoyl chloride, 3-methylbenzoic acid, nicotinic acid, isonicotinic acid.

[0015] Step 2: The acyl chloride substrate obtained in step 1 undergoes an amidation reaction with a tetrahydro-β-carboline compound (substrate a), and the reaction is followed by TLC detection. When the reaction is complete, water is added dropwise to the reaction solution to quench the reaction, and the dichloromethane is removed by concentration under reduced pressure. The organic phases are combined and concentrated under reduced pressure. The crude product is separated by column chromatography to obtain a tetrahydro-β-carboline compound.

[0016] Specifically, an anhydrous dichloromethane solution of an acyl chloride substrate is added to an anhydrous dichloromethane solution of tetrahydro-β-carboline to which Et3N has been added, to cause an amidation reaction.

[0017] The tetrahydro-β-carboline antibacterial agent is used to inhibit plant pathogens, which are pine blight pathogen, tobacco black shank pathogen, rice sheath blight pathogen, tea anthracnose pathogen, tea fruit spiny colleorhiza or colored coriolus.

[0018] Beneficial effects: The tetrahydro-β-carboline compounds provided by the present invention have the characteristics of simple structure, readily available raw materials, mild reaction conditions, simple process, and have the activity of inhibiting plant pathogens.

[0019] The results of activity test showed that compounds J-2, J-6 and J-17 had good activities. Compound J-2 showed good inhibitory activity against pine tip blight pathogen, rice sheath blight pathogen, tea anthracnose pathogen, tea fruit spiny Colletotrichum and Colletotrichum velveticum, with inhibition rates of 66.83%, 62.09%, 98.38%, 59.55% and 97.04%, respectively. Compound J-6 had an inhibition rate lower than 50% only against pine tip blight pathogen, while the others were higher than 50%. The inhibition rates against tobacco black shank pathogen, rice sheath blight pathogen and tea anthracnose pathogen were better than those of azoxystrobin and kresoxim-methyl, with inhibition rates of 63.41%, 75.82% and 94.05%, respectively. Compound J-17 had good inhibitory activity against tobacco black shank pathogen, rice sheath blight pathogen and tea fruit spiny Colletotrichum, with inhibition rates of 84.62%, 94.51% and 65.66%, respectively. Through longitudinal comparative analysis, it was found that most compounds showed good inhibitory activity against tea oil anthracnose, among which compounds J-1, J-2, J-3, J-4, J-5, J-6 and J-9 all exceeded 66% against tea oil anthracnose, which was better than azoxystrobin; only compounds J-7, J-8, J-14, J-15, J-16, and J-20 had an inhibition rate of less than 50% against tea oil anthracnose. DETAILED DESCRIPTION

[0020] The present invention is described in detail below in conjunction with embodiments.

[0021] Example 1 Synthesis

[0022] Step 1: Preparation of acyl chloride. The preparation method is as follows: First, accurately weigh 246.9 mg (1.8 mmol) of naphthoic acid into a dry 50 mL round-bottom flask, add 10 mL of anhydrous dichloromethane, add 0.20 mL (2.7 mmol, 2.3 eq.) of thionyl chloride dropwise therein during stirring, heat to 55°C and reflux for 2.5 h, remove dichloromethane and thionyl chloride by vacuum distillation, and the corresponding acyl chloride is set aside.

[0023] Step 2: Weigh 279 mg (1.5 mmol) of the reaction substrate a and place it in a 100 mL round-bottom flask, add 10 mL of anhydrous dichloromethane and stir to dissolve, add 0.32 mL (2.3 mmol, 2.3 eq.) of triethylamine dropwise thereto, stir and react at room temperature for 30 min, then move to an ice-water bath, dissolve the above-prepared acyl chloride in 5 mL of anhydrous dichloromethane with the aid of an ultrasonic instrument, and add dropwise to the reaction system, after the addition is complete, transfer to room temperature for reaction, stir for 4 h, track and detect the reaction by TLC, and perform post-treatment. Treatment method: Add saturated sodium bicarbonate solution to the reaction solution in an ice-water bath to quench the reaction, extract with dichloromethane, then wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to remove the solvent. The crude product obtained is separated by silica gel column chromatography (V乙酸乙酯 :V 石油醚 =1:2), and finally 250.22g of the target compound J-1 (1.1mmol, 73.5%) was obtained.

[0024] Property identification: white solid, 1 H NMR (400MHz, CDCl3) δ: 8.97 (s, 1H, H-1), 7.95 (d, J = 7.8Hz, 1H, H-18), 7.91 (d ,J=7.7Hz,1H,H-23),7.61-7.39(m,6H,H-21,22,24,25,26,4),7.19(d,J=7.5 Hz,1H,H-7),7.14-7.07(m,2H,H-5,6),6.22(dd,J=31.5,6.8Hz,1H,H-10),3 .74-3.38(m,2H,H-12),2.97-2.50(m,2H,H-13),1.76(d,J=6.7Hz,3H,H-14). 13 CNMR(101MHz, CDCl3)δ:170.10(C,C-15),136.37(C,C-8),134.85(C,C-2),133.68(C,C-20),129.87(C,C-17 ),129.43(C,C-19),128.71(CH,C-21),127.41(CH,C-23),126.72(CH,C-26),125.45(CH,C-18),124.96(CH, C-25),124.60(CH,C-24),123.76(C,C-6),123.36(CH,C-22),121.87(CH,C-6),119.53(CH,C-5),118.02(CH ,C-4),111.39(CH,C-7),107.16(C,C-3),45.93(CH,C-10),41.68(CH2,C-12),22.26(CH2,C-13),19.64(CH3 C-14).MS(ESI(+))calcd for C 23 H 21 N2O[M+H] + :340.2;found:340.8.

[0025] The difference between Examples 2 to 19 and Example 1 is that the reaction reagents used are different nicotinic acid analogs. The specific properties and yields of the obtained products and the information of the nicotinic acid analogs used are shown in Table 1:

[0026] Table 1

[0027]

[0028] Example 2

[0029]

[0030] White solid, 1 H NMR (400MHz, CDCl3) δ: 8.97 (s, 1H, H-1), 7.95 (d, J = 7.8Hz, 1H, H-18), 7.91 (d ,J=7.7Hz,1H,H-23),7.61-7.39(m,6H,H-21,22,24,25,26,4),7.19(d,J=7.5 Hz,1H,H-7),7.14-7.07(m,2H,H-5,6),6.22(dd,J=31.5,6.8Hz,1H,H-10),3 .74-3.38(m,2H,H-12),2.97-2.50(m,2H,H-13),1.76(d,J=6.7Hz,3H,H-14). 13 C NMR(101MHz, CDCl3)δ:170.10(C,C-15),136.37(C,C-8),134.85(C,C-2),133.68(C,C-20),129.8 7(C,C-17),129.43(C,C-19),128.71(CH,C-21),127.41(CH,C-23),126.72(CH,C-26),125.45(CH, C-18),124.96(CH,C-25),124.60(CH,C-24),123.76(C,C-6),123.36(CH,C-22),121.87(CH,C-6) ,119.53(CH,C-5),118.02(CH,C-4),111.39(CH,C-7),107.16(C,C-3),45.93(CH,C-10),41.68(CH 2, C-12),22.26(CH 2, C-13),19.64(CH3C-14).MS(ESI(+))calcd forC 23 H 21 N2O[M+H] + :340.2; found:340.8.

[0031] Example 3

[0032]

[0033] Pale yellow solid, 1H NMR (400MHz, DMSO) δ10.89(s,1H,H-1),8.05(dd,J=4.9,1.8Hz,1H,H-20),7.42(dd,J=7.4,1.9 Hz,1H,H-22Z),7.39(d,J=7.7Hz,1H,H-4),7.31(d,J=8.0Hz,1H,H-7),7.08-7.03(m,1H,H-21) ,7.00-6.94(m,1H,H-6),6.63(dd,J=7.4,4.9Hz,1H,H-5),5.88(s,2H,H-23),5.62(d,J=5.4Hz ,1H,H-10),3.36(d,J=9.0Hz,2H,H-12),2.87-2.68(m,2H,H-13),1.53(d,J=6.6Hz,3H,H-14). 13 C NMR(101MHz, CDCl3)δ173.07(C,C-15),161.38(C,C-18),154.36(C,C-20),141.24(C,C-8 ,22),140.60(C,C-2),131.59(C,C-9),126.26(CH,C-6),123.86(CH,C-5),123.05(CH,C- 4),120.07(CH,C-21),117.20(C,C-17),116.35(CH,C-7),111.53(C,C-3),51.22(CH,C-1 0),47.18(CH2,C-12),26.98(CH2,C-13),24.24(CH3,C-14).MS(ESI(+))MS(ESI(+))calcd for C 18 H 19 N4O[M+H] + :306.2;found:306.8.

[0034] Example 4

[0035]

[0036] White solid, 1H NMR (400MHz, DMSO) δ11.02(s,1H,H-1),8.38(dd,J=4.5,1.5Hz,1H,H-20),8.09(ddd,J=9.4, 7.4,2.0Hz,1H,H-22),7.50(d,J=6.1Hz,1H,H-4),7.41(dd,J=14.5,7.8Hz,1H,H-21),7.31(d ,J=7.9Hz,1H,H-7),7.09-7.04(m,1H,H-6),7.01-6.95(m,1H,H-5),5.70(q,J=6.6Hz,1H,H-1 0),3.59(dd,J=12.8,4.9Hz,2H,H-12),2.81-2.70(m,2H,H-13),1.56(d,J=6.7Hz,3H,H-14). 13 CNMR(101MHz,DMSO)δ163.63(C,J=4.3Hz,C-15),158.69(C,J=243.6Hz,C-18),149.14(C,J=14.4Hz,C -20),136.54(C,C-8),135.20(C,C-22),126.69(C,C-2),123.14(C,C-9),121.62(CH,C-6),119.66(C, J=34.2Hz,C-17),119.17(CH,C-5),118.44(CH,C-4),118.32(CH,C-21),111.66(CH,C-7),106.48(C, C-3),45.94(CH,C-10),41.40(CH2,C-12),22.09(CH2,C-13),19.41(CH3,C-14).MS(ESI(+))calcdfor C 18 H 17 FN3O[M+H] + :309.1; found:309.7.

[0037] Example 5

[0038]

[0039] Pale yellow solid, 1H NMR(400MHz,DMSO)δ11.01(s,1H,H-1),8.04-7.99(m,1H,H-22),7.65-7.64 (m,1H,H-21),7.42-7.39(m,1H,H-4),7.34(d,J=8.1Hz,1H,H-7),7.09-6.9 5(m,3H,H-5,6,20),5.65(q,J=6.7Hz,1H,H-10),3.74(dddd,J=207,13.3,5 .3,3.0Hz,2H,H-12),,2.83-2.62(m,2H,H-13),1.56(d,J=6.7Hz,3H,H-14). 13 C NMR(101MHz,DMSO)δ166.25(C,C-15),155.16(C,C-19),149.83(C,C-17),141.69(CH,C-21 ),136.51(C,C-8),135.37(C,C-2),126.79(C,C-9),125.87(CH,C-20),122.40(CH,C-22), 121.57(CH,C-6),119.15(CH,C-5),118.33(CH,C-4),111.64(CH,C-7),106.64(C,C-3),46 .09(CH,C-10),41.62(CH2,C-12),22.12(CH2,C-13),19.36(CH3,C-14).MS(ESI(+))calcd for C 18 H 17 ClN3O[M+H] + :325.1;found:325.7.

[0040] Example 6

[0041]

[0042] Pale yellow solid, 1H NMR (400MHz, DMSO) δ11.02(s,1H,H-1),8.52(dd,J=4.8,1.9Hz,1H,H-20),7.96(ddd,J=15 .3,7.6,1.9Hz,1H,H-22),7.56(dd,J=7.5,4.7Hz,1H,H-4),7.38(d,J=7.9Hz,1H,H-21),7. 34(d,J=8.1Hz,1H,H-7),7.10-7.04(m,1H,H-6),7.01-6.95(m,1H,H-5),5.70(q,J=6.6Hz ,1H,H-10),3.52-3.39(m,2H,H-12),2.83-2.62(m,2H,H-13),1.57(d,J=6.6Hz,3H,H-14). 13 C NMR (101MHz, CDCl3) δ165.60(C,C-15),150.32(C,C-20),147.51(C,C-18),136.61(C,C-2 2),136.33(C,C-8),134.32(C,C-2),132.61(C,C-17),126.53(C,C-9),123.02(CH,C-21), 122.17(CH,C-6),119.77(CH,C-5),118.14(CH,C-4),111.29(CH,C-7),106.94(C,C-3),45 .94(CH,C-10),41.35(CH2,C-12),22.13(CH2,C-13),18.91(CH3,C-14).MS(ESI(+))calcd for C 18 H 17 ClN3O[M+H] + :325.1;found:325.7.

[0043] Example 7

[0044]

[0045] Pale yellow oily solid, 1H NMR(400MHz,DMSO)δ11.00(s,1H,H-7),7.56(s,1H,H-18),7.53-7.49(s,2 H,H-20,22),7.41-7.39(m,2H,H-21,1),7.34(d,J=8.1Hz,1H,H-4),7.09- 6.96(m,2H,H-2,3),5.64(q,J=6.6Hz,1H,H-10),3.68(dddd,J=90,13.1,6 .1,4.0Hz,2H,H-12),2.80-2.63(m,2H,H-13),1.55(d,J=6.7Hz,3H,H-14). 13 C NMR(101MHz,DMSO)δ168.34(C,C-15),139.22(C,C-5),136.51(C,C-17),135.61(C,C-8),133.9 2(C,C-19),131.17(CH,C-20),129.98(CH,C-21),126.81(CH,C-18),125.57(C,C-6),121.45(C H,C-22),119.24(CH,C-3),119.04(CH,C-2),118.43(CH,C-1),111.75(CH,C-4),106.55(C,C-9 ),46.01(CH,C-10),42.00(CH2,C-12),22.21(CH2,C-13),19.29(CH3,C-14).MS(ESI(+))calcd for C 19 H 18 ClN2O[M+H] + :324.1;found:324.7.

[0046] Example 8

[0047]

[0048] Yellow oily solid, 1H NMR (400MHz, DMSO) δ11.04(s,1H,H-1),8.79(s,1H,H-19),8.65(dd,J=6.7,4.8Hz,1H ,H-21),7.53(dd,J=14.8,4.8Hz,1H,H-22),7.40(dd,J=17.4,7.7Hz,1H,H-4),7.36-7 .26(m,1H,H-7),7.11-7.04(m,1H,H-6),7.01-6.94(m,1H,H-5),5.70(q,J=6.7Hz,1H, H-10),3.55-3.39(m,2H,H-12),2.85-2.62(m,2H,H-13),1.57(d,J=7.0Hz,3H,H-14). 13 C NMR(101MHz,DMSO)δ164.40(C,C-15),149.84(CH,C-19),149.36(CH,C-21),143.60(C,C-1 7),136.53(C,C-8),134.95(C,C-2),127.65(C,C-18),126.69(C,C-9),122.33(CH,C-22), 121.65(CH,C-6),119.19(CH,C-5),118.33(CH,C-4),111.68(CH,C-7),106.55(C,C-3),45 .73(CH,C-10),41.19(CH2,C-12),21.95(CH2,C-13),19.26(CH3,C-14).MS(ESI(+))calcd for C 18 H 17 ClN3O[M+H] + :325.1;found:325.7.

[0049] Example 9

[0050]

[0051] Pale yellow oily solid, 1H NMR (400MHz, DMSO) δ11.00(s,1H,H-1),8.52(d,J=2.0Hz,1H,H-17),8.31(d,J=2.5 Hz,1H,H-21),7.40(d,J=7.8Hz,1H,H-4),7.34(d,J=8.1Hz,1H,H-7),7.07(t,J=7.5 Hz,1H,H-6),7.00-6.95(m,1H,H-5),5.64(q,J=6.7Hz,1H,H-10),3.68(dd,J=240.1 ,13.9,6.2,4.9Hz,2H,H-12),2.83-2.62(m,2H,H-13),1.56(d,J=6.7Hz,3H,H-14). 13 C NMR(101MHz,DMSO)δ165.23(C,C-15),148.81(C,C-20),146.08(C,C-18),138.35(C,C-8) ,136.52(CH,C-22),135.25(C,C-2),133.70(C,C-17),130.06(C,C-21),126.78(C,C-9),1 21.57(CH,C-6),119.14(CH,C-5),118.33(CH,C-4),111.64(CH,C-7),106.63(C,C-3),46 .23(CH,C-10),42.19(CH2,C-12),22.18(CH2,C-13),19.40(CH3,C-14).MS(ESI(+))calcd for C 18 H 16 Cl2N3O[M+H] + :359.1;found:359.8.

[0052] Example 10

[0053]

[0054] White solid, 1H NMR (400MHz, CDCl3) δ8.87(d,J=1.5Hz,1H,H-22),8.60(s,1H,H-1),8.46(d,J=23.7Hz,1H,H -19),7.47(d,J=8.8Hz,1H,H-4),7.31(d,J=8.0Hz,1H,H-7),7.18-7.14(m,1H,H-6),7.10(t d,J=7.5,1.1Hz,1H,H-5),5.90(q,J=5.6Hz,1H,H-10),3.83(dddd,J=214.5,14.3,4.6,3.9H z,2H,H-12),3.01(ddd,J=13.3,5.2,3.9Hz,2H,H-13),2.66(s,3H,H),1.63(d,J=6.7Hz,3H). 13 CNMR(101MHz,CDCl3)δ166.18(C,C-15),155.15(C,C-20),146.87(C,C-17),144.23(CH,C- 19),142.77(CH,C-22),136.32(C,C-8),134.48(C,C-2),126.74(C,C-9),121.96(CH,C-6), 119.62(CH,C-5),118.17(CH,C-4),111.21(CH,C-7),107.55(C,C-3),46.61(CH,C-10),41 .80(CH2,C-12),22.38(CH2,C-13),21.81(CH3,C-23),19.32(CH3,C-14).MS(ESI(+))calcd for C 18 H 20 N4O[M+H] + :306.2;found:306.8.

[0055] Embodiment 11

[0056]

[0057] White solid, 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H,H-1),8.53(d,J=1.4Hz,1H,H-18),8.46(d,J=2.1Hz,1H,H -20),7.71(s,1H,H-22),7.40(d,J=7.7Hz,1H,H-4),7.34(d,J=8.0Hz,1H,H-7),7.07(t,J=7.4H z,1H,H-6),6.98(t,J=6.9Hz,1H,H-5),5.66(q,J=6.9Hz,1H,H-10),3.59(dddd,J=241.1,12.4, 6.3,4.7Hz,2H,H-12),2.81-2.63(m,2H,H-13),2.36(s,3H,H-23),1.55(d,J=6.8Hz,3H,H-14). 13 C NMR(101MHz,DMSO-d6)δ167.85(C,C-15),151.34(C,C-20),144.82(C,C-18),136.53(C,C-8),1 35.57(C,C-2),135.12(CH,C-22),133.68(C,C-21),132.52(C,C-17),126.81(C,C-9),121.56( CH,C-6),119.14(CH,C-5),118.33(CH,C-4),111.64(CH,C-7),106.57(C,C-3),46.01(CH,C-10 ),42.09(CH2,C-12),22.31(CH2,C-13),19.40(CH3,C-23),18.27(CH3,C-14).MS(ESI(+))calcd forC 19 H 20 N3O[M+H] + :305.2;found:305.7.

[0058] Example 12

[0059]

[0060] Pale yellow oily solid, 1H NMR (400MHz, DMSO) δ11.00(s,1H,H-1),8.87(dd,J=4.1,1.4Hz,1H,H-19),8.79(dd,J=4.9,1.4H z,1H,H-22),7.40(d,J=7.5Hz,1H,H-21),7.34(d,J=8.0Hz,1H,H-4),7.27(d,J=8.0Hz,1H,H-7)7 .10-7.04(m,1H,H-6),6.98(td,J=7.5,7.1,1.1Hz,1H,H-5),5.67(q,J=6.7Hz,1H,H-10),3.68(d ddd,J=203.3,13.3,5.3,3.8Hz,2H,H-12),2.84-2.66(m,2H,H-13),1.58(d,J=6.7Hz,3H,H-14). 13 C NMR(101MHz,DMSO)δ165.02(C,C-15),149.30(C,C-17),148.65(CH,C-19),144.40(C,C-8 ),143.75(CH,C-21),136.51(C,C-2),135.46(C,C-20)135.18(C,C-9),126.78(CH,C-22), 121.42(CH,C-6),118.41(CH,C-5),111.77(CH,C-4),107.08(CH,C-7),106.69(C,C-3),46 .29(CH,C-10),41.69(CH2,C-12),22.31(CH2,C-13),19.48(CH3,C-14).MS(ESI(+))calcd for C 18 H 17 ClN3O[M+H] + :325.1;found:325.6.

[0061] Embodiment 13

[0062]

[0063] Pale yellow oily solid, 1H NMR (400MHz, DMSO) δ11.00(s,1H,H-1),8.53(d,J=2.5,Hz,1H,H-18),7.97(dd,J=8.2,2.4Hz, 1H,H-22),7.64(d,J=8.2,Hz,1H,H-4),7.40(d,J=7.7Hz,1H,H-21),7.34(d,J=8.0Hz,1H,H-7 ),7.07(d,J=7.4Hz,1H,H-6),6.98(d,J=8.0Hz,1H,H-5),5.64(q,J=6.6Hz,1H,H-10),3.58(d ddd,J=240.1,13.9,5.6,4.8Hz,2H,H-12),2.82-63(m,2H,H-13),1.55(d,J=6.8Hz,3H,H-14). 13 C NMR (101MHz, CDCl3) δ167.14(C,C-15),152.82(C,C-20),147.83(CH,C-18),137.71(CH,C- 22),136.23(C,C-8),134.38(C,C-2),131.14(C,C-17),126.58(C,C-9),124.59(CH,C-21), 122.30(CH,C-6),119.93(CH,C-5),118.22(CH,C-4),111.18(CH,C-7),107.12(CH,C-3),4 6.47(CH,C-10),42.19(CH2,C-12),22.48(CH2,C-13),19.34(CH3,C-14).MS(ESI(+))calcd for C 18 H 17 ClN3O[M+H] + :325.1;found:325.8.

[0064] Embodiment 14

[0065]

[0066] White solid, 1H NMR (400MHz, DMSO) δ11.01 (s, 1H, H-1), 8.64 (d, J = 3.4, Hz, 1H, H-19), 7.97-7.92 (m, 1H, H-21), 7. 60(d,J=7.8Hz,1H,H-22),7.53-7.48(m,1H,H-20),7.39(d,J=8.2Hz,1H,H-4),7.34(d,J=8.2Hz,1 H,H-7),7.07(d,J=7.5Hz,1H,H-6),7.00-6.95(m,1H,H-5),5.69(q,J=6.6Hz,1H,H-10),3.62(ddd d,J=239.4,13.1,5.4,3.6Hz,2H,H-12),2.85-2.59(m,2H,H-13),1.56(d,J=6.7Hz,3H,H-14).13C NMR(101MHz,DMSO)δ167.86(C,C-15),155.01(C,C-17),149.16(CH,C-19),138.01(CH,C-2 1),136.51(C,C-8),135.57(C,C-2),126.83(C,C-9),125.21(CH,C-20),123.35(CH,C-22), 121.56(CH,C-6),119.14(CH,C-5),118.32(CH,C-4),111.61(CH,C-7),106.72(CH,C-3),4 5.87(CH,C-10),41.50(CH2,C-12),22.26(CH2,C-13),19.40(CH3,C-14).MS(ESI(+))calcd for C 18 H 18 N3O[M+H] + :291.1;found:291.8.

[0067] Embodiment 15

[0068]

[0069] White solid, 1H NMR (400MHz, CDCl3) δ8.98 (s, 1H, H-1), 8.68 (d, J = 2.5Hz, 1H, H-22), 8.63-8.52 (m, 2 H,H-19,20),7.47(d,J=7.7Hz,1H,H-4),7.32(d,J=8.0Hz,1H,H-7),7.20-7.15(m,1H ,H-6),7.13-7.09(m,1H,H-5),5.90(q,J=7.3,6.7Hz,1H,H-10),3.69(dddd,J=241. 3,13.6,5.3,3.6Hz,2H,H-12),3.08-2.74(m,2H,H-13),1.64(d,J=6.7Hz,3H,H-14). 13 C NMR(101MHz, CDCl3)δ165.86(C,C-15),149.92(C,C-17),145.29(CH,C-20),142.99(C H,C-19),136.31(CH,C-22),134.32(C,C-8),126.72(C,C-2),121.88(C,C-9),119.50( CH,C-6),118.23(CH,C-5),111.14(CH,C-4),108.91(CH,C-7),107.58(CH,C-3),46.60 (CH,C-10),41.85(CH2,C-12),22.32(CH2,C-13),19.20(CH3,C-14).MS(ESI(+))calcd forC 17 H 17 N4O[M+H] + :292.1;found:292.8.

[0070] Example 16

[0071]

[0072] White solid, 1H NMR (400MHz, DMSO) δ10.97(s,1H,H-1),7.41(d,J=4.0Hz,1H,H-18),7.39(d,J=2.8Hz,1H, H-22),7.34-7.30(m,1H,H-4),7.06(t,J=7.5Hz,1H,H-7),7.03-6.99(m,3H,H-5,6,21),6 .97(d,J=6.9Hz,1H,H-19),5.60(q,J=5.5Hz,1H,H-10),3.81(s,3H,H-24),3.60(dddd,J= 239.1,12.1,5.5,3.1Hz,2H,H-12),2.85-2.63(m,2H,H-13),1.53(d,J=6.7Hz,3H,H-14). 13 C NMR(101MHz,DMSO)δ169.86(C,C-15),160.69(C,C-20),136.47(C,C-8),135.97(C,C-2),1 29.19(C,C-17),129.02(CH,C-22),126.86(CH,C-18),121.50(C,C-9),119.10(CH,C-6),1 18.28(CH,C-5),114.32(CH,C-4),111.60(CH,C-7),106.66(CH,C-3),55.77(CH3,C-24),4 6.09(CH,C-10),42.02(CH2,C-12),22.33(CH2,C-13),19.35(CH3,C-14).MS(ESI(+))calcd for C 20 H 21 N2O2[M+H] + :320.1;found:320.8.

[0073] Embodiment 17

[0074]

[0075] Yellow oily solid, 1H NMR (400MHz, CDCl3) δ8.77(s,1H),7.46(dd,J=16.1,7.7Hz,2H),7.30-7.26(m,2H),7.21(d,J=4.9Hz,1H),7.19-7.15(m,2H),7.14-7.10(m,1H),5. 88(q,J=6.7Hz,1H),3.91(dd,J=13.8,4.9Hz,1H),3.49(td,J=13.7,13.0, 4.0Hz,1H),2.93-2.84(m,1H),2.75(dd,J=15.2,3.9Hz,1H),1.61(s,3H). 13 C NMR(101MHz, CDCl3) δ169.46(C,C-15),162.75(C,J=248.5Hz,C-19),138.55(C,J=7.0Hz,C-17),136.33(C,C -8),134.84(C,C-2),130.70(CH,J=8.2Hz,C-21),126.64(C,C-9),122.41(CH,C-22),121.98(CH,C-6),119.6 4(CH,C-5),118.10(CH,C-4),117.08(CH,J=21.0Hz,C-20),114.13(CH,J=23.1Hz,C-18),111.30(CH,C-7),1 06.99(CH,C-3),46.29(CH,C-10),41.99(CH2,C-12),22.38(CH2,C-13),19.30(CH3,C-14).MS(ESI(+))calcd for C 19 H 18 FN2O[M+H] + :308.1; found:308.7.

[0076] Embodiment 18

[0077]

[0078] White solid, 1H NMR (400MHz, CDCl3) δ8.74(s,1H,H-1),7.47(d,J=7.7Hz,1H,H-18),7.34(d,J=7.3 Hz,1H,H-22),7.31-7.27(m,4H,H-4,7,20,21),7.18-7.13(m,1H,H-6),7.12-7.08 (m,1H,H-5),5.92(d,J=6.6Hz,1H,H-10),3.62(dddd,J=238.1,13.6,5.1,3.1Hz,2 H,H-12),2.93-2.69(m,2H,H-13),2.42(s,3H,H-23),1.62(d,J=6.7Hz,3H,H-14). 13 C NMR(101MHz,DMSO)δ170.06(C,C-15),138.53(C,C-19),137.23(C,C-8),136.51(C,C-17),135.85(C ,C-2),130.58(CH,C-20),128.97(CH,C-21),127.48(CH,C-18),126.85(C,C-9),123.96(CH,C-22), 121.52(CH,C-6),119.11(CH,C-5),118.30(CH,C-4),111.61(CH,C-7),106.56(CH,C-3),45.78(CH, C-10),41.89(CH2,C-12),22.29(CH3,C-23),21.41(CH2,C-13),19.37(CH3,C-14).MS(ESI(+))calcd for C 20 H 21 N2O[M+H] + :304.1; found:304.7.

[0079] Embodiment 19

[0080]

[0081] White solid, 1H NMR (400MHz, DMSO) δ11.01(s,1H,H-1),8.69(d,J=4.9Hz,1H,H-18),8.67(d,J=2.1Hz,1H,H-20),7 .89(d,J=7.8Hz,1H,H-22),7.53-7.49(m,1H,H-4),7.40(d,J=7.7Hz,1H,H-21),7.35(d,J=8.0Hz, 1H,H-7),7.07(d,J=7.5Hz,1H,H-6),6.99(d,J=7.5Hz,1H,H-5),5.67(q,J=6.5Hz,1H,H-10),3.58 (dddd,J=239.5,13.6,4.7,2.9Hz,2H,H-12),2.86-2.67(m,2H,H-13),1.57(d,J=6.7Hz,3H,H-14). 13 C NMR(101MHz,DMSO)δ167.74(C,C-15),151.02(CH,C-20),147.78(CH,C-18),136.53(C,C-8 ),135.55(CH,C-22),134.96(C,C-2),132.96(C,C-17),126.81(C,C-9),124.20(CH,C-21), 121.57(CH,C-6),119.15(CH,C-5),118.32(CH,C-4),111.64(CH,C-7),106.56(CH,C-3),4 6.08(CH,C-10),42.11(CH2,C-12),22.28(CH2,C-13),19.40(CH3,C-14).MS(ESI(+))calcd forC 18 H 18 N3O[M+H] + :291.1;found:291.7.

[0082] Embodiment 20

[0083]

[0084] White solid, 1H NMR (400MHz, DMSO) δ11.02(s,1H,H-1),8.71(d,J=5.3Hz,2H,H-19,21),7.46(d,J=5.5 Hz,2H,H-18,22),7.39(d,J=8.0Hz,1H,H-4),7.34(d,J=8.1Hz,1H,H-7),7.07(t,J=7.6 Hz,1H,H-6),6.98(t,J=7.4Hz,1H,H-5),5.65(q,J=6.6Hz,1H,H-10),3.52(dddd,J=24 0.2,13.8,5.0,3.1Hz,2H,H-12),2.82-2.62(m,2H,H-13),1.55(d,J=6.7Hz,3H,H-14). 13 C NMR(101MHz,DMSO)δ167.73(C,C-15),150.59(CH,C-19,21),144.71(CH,C-17),136 .51(C,C-8),135.36(C,C-2),126.76(C,C-9),121.59(CH,C-18,22),121.53(CH,C- 6),119.17(CH,C-5),118.30(CH,C-4),111.65(CH,C-7),106.52(CH,C-3),45.86(C H,C-10),41.87(CH2,C-12),22.16(CH2,C-13),19.41(CH3,C-14).MS(ESI(+))calcd forC 18 H 18 N3O[M+H] + :291.1;found:291.7.

[0085] Embodiment 20

[0086] The inhibitory activity of the obtained compounds against plant pathogens was measured, and the results are shown in Table 2. Among them, J-1 to J-20 correspond to the compounds obtained in Examples 1 to 20.

[0087] Table 2 MIC of compounds against plant pathogenic fungi

[0088]

[0089] Note: SS: Sphaeropsis sapinea is the pathogen of pine blight; PN: Phytophthora nicotianae is the pathogen of tobacco black shank; RS: Rhizoctonia solan is the pathogen of rice sheath blight; CG: Colletotrichum gloeosporioides is the pathogen of rice sheath blight; CF: Camellia oleifera colletotrichum fructicola is the pathogen of tea fruit spiny spores; CV: Coriolus versicolor is the pathogen of colorful vellus. Azoxystrobin and kresoxim-methyl are positive controls. Each treatment was repeated three times and the average value was taken.

[0090] As shown in the table, at a concentration of 100 mg / L, most of the compounds showed good antibacterial activity, among which compounds J-2, J-6 and J-17 had better activity. Compound J-2 showed good inhibitory activity against pine tip blight pathogen, rice sheath blight pathogen, tea anthracnose pathogen, tea fruit spiny colletotrichum and colored vesicular fungus, with inhibition rates of 66.83%, 62.09%, 98.38%, 59.55% and 97.04%, respectively; compound J-17 showed good inhibitory activity against pine tip blight pathogen, rice sheath blight pathogen, tea anthracnose pathogen, tea fruit spiny colletotrichum and colored vesicular fungus, with inhibition rates of 66.83%, 62.09%, 98.38%, 59.55% and 97.04%, respectively; -6 had an inhibition rate lower than 50% against pine blight pathogen, while the others were higher than 50%. The inhibition rates against tobacco black shank pathogen, rice sheath blight pathogen and oil-tea anthracnose pathogen were better than those of azoxystrobin and kresoxim-methyl, with inhibition rates of 63.41%, 75.82% and 94.05% respectively; compound J-17 had good inhibitory activity against tobacco black shank pathogen, rice sheath blight pathogen and oil-tea anthracnose pathogen, with inhibition rates of 84.62%, 94.51% and 65.66% respectively. Through longitudinal comparative analysis, it was found that most compounds showed good inhibitory activity against oil-tea anthracnose pathogen, among which compounds J-1, J-2, J-3, J-4, J-5, J-6 and J-9 all exceeded 66% against oil-tea anthracnose pathogen, which was better than kresoxim-methyl; only compounds J-7, J-8, J-14, J-15, J-16 and J-20 had an inhibition rate lower than 50% against oil-tea anthracnose pathogen.

[0091] By comparing the antibacterial activities of these compounds against different plant pathogenic fungi, it was found that compounds J-2, J-6 and J-17 had better antibacterial activities, among which compound J-2 had an inhibition rate of 98.38% and 97.04% against Colletotrichum oleifera and Coriolus versicolor; compound J-6 had an inhibition rate of more than 50% against tobacco black shank pathogen, rice sheath blight pathogen, Colletotrichum oleifera, Colletotrichum oleifera and Coriolus versicolor. Structure-activity relationship studies have found that for benzene ring substituents, the introduction of electron-withdrawing groups at the C-3 position has better activity than electron-donating groups; when nitrogen-containing heterocyclic substituents are introduced, the following rules apply:

[0092] (1) When the nitrogen atom is at the 3rd position, the introduction of a substituent at the para position will increase the antibacterial activity of the compound; the introduction of an electron-donating group at the ortho position will increase the antibacterial activity of the compound, whereas the introduction of an electron-withdrawing group will reduce the antibacterial activity.

[0093] (2) Increasing the number of N atoms will increase the antibacterial activity; adding a single Cl atom will increase the antibacterial activity, but adding two Cl atoms will reduce the antibacterial activity.

[0094] (3) When the N atom is at the meta position and has no substituent, the antibacterial activity is better than that at the ortho and para positions. In addition, when the C-3 substituents are the same, the antibacterial activity of the compounds substituted with benzene rings is better than that of the compounds substituted with heterocycles.

[0095] The present invention is further described above in conjunction with the embodiments, but the present invention is not limited to the above-mentioned implementation modes, and various changes can be made within the knowledge scope of ordinary technicians in this field without departing from the purpose of the present invention.

Claims

1. Tetrahydro- β -Carboline antibacterial agents: Formula (I); The R is any one of the following groups: 。 2. The tetrahydro- β - A synthesis process of a carboline antibacterial agent, characterized in that: The reaction formula is as follows: 。 3. The tetrahydro- β - A synthesis process of a carboline antibacterial agent, characterized in that: Here are the steps: Step 1, preparing acyl chloride: using nicotinic acid analog as raw material and anhydrous dichloromethane as solvent, adding thionyl chloride dropwise and heating to 55°C for reflux, removing dichloromethane and thionyl chloride by vacuum distillation, and obtaining the corresponding acyl chloride for standby use; Step 2: The reaction substrate tetrahydro- β -Carboline compound was placed in another round-bottom flask, anhydrous dichloromethane was added and stirred to dissolve, triethylamine was added dropwise thereto, the reaction was stirred at room temperature for 30 min and then moved to an ice water bath; Step 3: Add the dichloromethane solution of the acyl chloride substrate obtained in step 1 to the reaction system in step 2 and react with tetrahydro- β -Carboline compound undergoes amidation reaction, followed by TLC detection. After the reaction is complete, saturated sodium bicarbonate solution is added dropwise to the reaction solution to quench the reaction, and the dichloromethane is removed by concentration under reduced pressure. The organic phases are combined and concentrated under reduced pressure. The crude product is separated by column chromatography to obtain tetrahydro- β -Carboline antibacterial agent.

4. The tetrahydro- β -The synthesis process of carboline antibacterial agent is characterized in that: In step 2, the addition ratio of triethylamine is 2.3 equivalents.

5. The tetrahydro- β -The synthesis process of carboline antibacterial agent is characterized in that: In step 3, the crude product is separated by silica gel column chromatography ( V 乙酸乙酯 : V 石油醚 =1:2).

6. The tetrahydro- β -Use of carboline antibacterial agents to inhibit plant pathogens.

7. The use according to claim 6, characterized in that The plant pathogenic bacteria are pine tip blight pathogen, tobacco black shank pathogen, rice sheath blight pathogen, oil-tea camellia anthracnose pathogen, oil-tea camellia fruit thorny Colletotrichum or colorful vesiculocarp.

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