CN113980025B - Nicotine and indole hybrid compound, and synthesis method and application thereof - Google Patents

Nicotine and indole hybrid compound, and synthesis method and application thereof Download PDF

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CN113980025B
CN113980025B CN202111411993.8A CN202111411993A CN113980025B CN 113980025 B CN113980025 B CN 113980025B CN 202111411993 A CN202111411993 A CN 202111411993A CN 113980025 B CN113980025 B CN 113980025B
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indole
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杨亦谋
李晓倩
李吉
向毅
黄华
蔡雨田
周玉洁
郑绍军
陈磊
陈孝云
朱瑞
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Jiangsu University of Science and Technology
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
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Abstract

The invention relates to a nicotine and indole hybrid compound, a synthesis method and application thereof. The method comprises the steps of taking nicotine analogues as raw materials, adding a solvent, dissolving in anhydrous tetrahydrofuran, reacting with thionyl chloride under the condition of oil bath heating to prepare a corresponding acyl chloride substrate, carrying out amidation reaction with indole compounds, adding a quenching agent for quenching reaction, and carrying out reduced pressure concentration to remove tetrahydrofuran to obtain a hybrid compound. The plant pathogenic bacteria are sclerotinia sclerotiorum, early blight of tomato, verticillium dahliae of cotton, fusarium wilt of cucumber, pythium Juglandis or curvularia zeae. And the synthesis process is simple and the product purity is high.

Description

Nicotine and indole hybrid compound, and synthesis method and application thereof
Technical Field
The invention belongs to the field of pesticide synthesis, and particularly relates to a nicotine and indole hybrid compound, a synthesis method thereof and application thereof in inhibiting phytopathogens.
Background
The situation of agricultural production in China is more serious, and the guarantee of the production of agricultural crops is the most effective solution. With the planting of various crops, the crop yield reduction and the economic crop benefit reduction are inevitably caused by plant diseases and insect pests, weeds and other harmful organisms. The pesticide is an important agricultural production data for ensuring high yield and harvest of crops, and is always the key point of pesticide development. The use of a large amount of pesticides brings great economic benefits and other problems, and causes poisoning of people and livestock and phytotoxicity along with risks to human and environment and acute toxicity hazards; ecological balance is destroyed; environmental pollution and chronic toxicity, and the pesticide in the environment finally enters a human body to generate potential chronic toxicity to human bodies through biological enrichment; the control object generates drug resistance, the use amount of pesticides is promoted to be increased, the drug resistance is further improved, vicious circle is formed in the current society which highly attaches importance to ecological safety and food safety, the problems attract wide attention, and extremely negative influence is brought to the pesticides
Indole compounds are the most extensive heterocyclic species in nature, and many compounds containing indole structures have been shown to have significant biological activity. The indole compounds as natural products are used for developing new pesticides with low toxicity and environmental protection characteristics, but because the indole alkaloids are extracted from natural products in a small amount, people are difficult to obtain enough amount and wider variety from the nature so as to meet the requirements of further research, and the research on the chemical synthesis of the indole alkaloids and the analogues thereof is particularly important. Diversity-oriented synthesis (Diversity-oriented synthesis) is a rapidly developing field of drug synthesis research in recent years, which is a "high-throughput" way to produce "Natural product-like" compounds. The method starts from simple initial raw materials, flexibly constructs compound aggregates with complex and various structures by selecting proper construction modules, condition control factors and branch reaction paths, and then biologically screens the compound aggregates. The diversity synthesis strategy has important significance for finding and optimizing active drug leads by virtue of the characteristics of simplicity, rapidness, high efficiency and wide range.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a nicotine and indole hybrid compound which has good inhibitory activity on sclerotinia sclerotiorum, early blight of tomato, verticillium wilt of cotton, fusarium wilt of cucumber, pythium Juglandis and curvularia zeae.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
a nicotine and indole-hybridized compound having the general formula (I):
Figure BDA0003374465900000021
the synthetic route for nicotine and indole-hybrid compounds having formula (I) is as follows:
Figure BDA0003374465900000031
the nicotine analogue is any one of the following groups:
Figure BDA0003374465900000032
the nicotinic acid analogs corresponding to the above groups are 3-chloroisonicotinic acid, 5-chloropyrazine-2-carboxylic acid, 2-chloro-6-carboxylic pyridine, 2-pyrazine formate, p-methoxybenzoic acid, 1-naphthoic acid, 2-fluoronicotinic acid, 2-methylnicotinic acid, 2-picolinic acid, 2-chloroisonicotinic acid, 5-methylpyrazine-2-carboxylic acid, isonicotinic acid, 2-chloronicotinic acid, 6-chloronicotinic acid, 5, 6-dichloronicotinic acid, 5-methylnicotinic acid, 2-hydroxynicotinic acid, nicotinic acid, 2-aminonicotinic acid and o-aldehyde benzoic acid.
Specifically, the synthesis process of the nicotine and indole hybrid compound with the formula (I) comprises the following steps:
step one, preparing acyl chloride: the nicotine analogue is taken as a raw material, anhydrous tetrahydrofuran is added for dissolution, and the solution reacts with thionyl chloride under the condition of oil bath heating to prepare a corresponding acyl chloride substrate.
And step two, carrying out amidation reaction on the acyl chloride substrate obtained in the step one and an indole compound (substrate a), tracking and detecting by TLC (thin layer chromatography), dropwise adding water into the reaction solution for quenching reaction when the reaction is complete, carrying out reduced pressure concentration to remove tetrahydrofuran, combining organic phases, carrying out reduced pressure concentration, and separating a crude product by using column chromatography to obtain the nicotine and indole hybrid compound.
Specifically, et is added to an anhydrous tetrahydrofuran solution of an acid chloride substrate 3 And carrying out amidation reaction on the substrate a of the N in an anhydrous tetrahydrofuran solution.
The application of the nicotine and indole hybrid compound in inhibiting phytopathogen. The plant pathogenic bacteria are sclerotinia sclerotiorum, early blight of tomato, verticillium dahliae of cotton, fusarium wilt of cucumber, pythium Juglandis or curvularia zeae.
Has the beneficial effects that: the nicotine and indole hybrid compound provided by the invention has the characteristics of simple structure, readily available raw materials, mild reaction conditions and simple process, and has the activity of inhibiting phytopathogens.
The activity test result shows that the compound T-2 has obvious bacteriostatic action on sclerotinia sclerotiorum, and MIC values are all 1.95 mu g/mL; the compound T-2 has excellent inhibition effect on tomato early blight bacteria, and MIC values are all 3.9 mu g/mL; the compound T-2 has the same obvious bacteriostatic activity on verticillium dahliae, and the minimum bacteriostatic concentration of the compound T-2 is 1.95 mu g/mL. The compound T-15 has excellent inhibition effect on pythium Juglandis, and MIC values of 3.9 mug/mL, and has excellent application prospect.
Detailed Description
The present invention will be described in detail with reference to examples.
Example 1
Figure BDA0003374465900000051
Synthesis of (2)
The first step is as follows: preparing acyl chloride. The preparation method comprises the following steps: first, 0.32g (2 mmol) of 3-chloronicotinic acid was accurately weighed into a 50mL round-bottomed flask, 10mL of anhydrous tetrahydrofuran was added, then 0.31mL (4 mmol) of thionyl chloride was injected into the reaction system with a 1mL syringe, refluxed for 2 hours in an oil bath set at 55 ℃, and thionyl chloride and methylene chloride were removed with a rotary evaporator to obtain an acid chloride substrate.
The second step is that: 0.29g of (A)0.77mmol, 1equiv) of the substrate a, dissolved in 10mL of anhydrous tetrahydrofuran, and added with 0.12mL (1.16mmol, 1.5equiv) of Et 3 N (triethylamine), the reaction was placed in an ice bath. 10mL of anhydrous tetrahydrofuran was uniformly mixed with the acid chloride prepared in the first step, and the mixture was slowly added dropwise to the reaction system with generation of white smoke, followed by reaction at room temperature for 2 hours, and TLC was used to monitor whether the starting material spot disappeared. The reaction was quenched by the addition of 3mL of saturated sodium bicarbonate solution, stirred for 10min, extracted with ethyl acetate (30 mL × 3), washed with saturated NaCl solution, dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to give T-1 as a white solid (0.35g, 89%).
And (3) character identification: a white solid, a solid which is, 1 H-NMR(400MHz,Acetone-d 6 ),δ8.65(s,1H),8.57(d,J＝4.8Hz,1H),7.30–6.89(m,11H),6.72(dt,J＝14.8,7.5Hz,1H),6.17(d,J＝7.8Hz,1H),5.97(d,J＝10.1Hz,1H),4.57(dd,J＝49.8,16.5Hz,2H),3.42–3.02(m,4H),2.40–2.20(m,2H). 13 C-NMR(100MHz,Acetone-d 6 ),δ164.58(C),163.00(C),162.89(C),160.58(C),160.48(C),150.66(C),149.58(CH),148.58(CH),143.54(C),135.18(C),133.76(C),131.75(CH),131.67(CH),131.29(C),128.78(CH),128.64(CH),128.58(CH),128.57(C),123.49(CH),121.83(CH),117.64(CH),114.87(CH),114.68(CH),114.66(CH),114.47(CH),105.94(CH),81.88(CH),57.25(CH 2 ),48.53(C),47.24(CH 2 ),43.38(CH 2 ),38.15(CH 2 ).MS(ESI(+))calcd for C 30 H 24 ClF 2 N 3 O[M+H] + :516.1；found:516.1。
examples 2-19 example 1 differs in the nicotine reagents used, as shown in table 1:
TABLE 1 physicochemical constants of hybrid Compounds of Nicotine and indoles
Figure BDA0003374465900000061
Figure BDA0003374465900000071
Example 2
Figure BDA0003374465900000072
The oil is a light yellow oil, 1 H-NMR(400MHz,Acetone-d 6 ),δ8.73(t,J＝1.2Hz,1H),8.69–8.66(m,1H),7.16–7.11(m,1H),7.08–7.02(m,3H),6.99–6.92(m,6H),6.71(td,J＝7.4,1.0Hz,1H),6.16(d,J＝7.8Hz,1H),6.02(s,1H),4.53(q,J＝16.3Hz,2H),3.93(ddd,J＝11.5,7.1,1.2Hz,1H),3.46–3.39(m,1H),3.21(d,J＝13.4Hz,1H),3.03(d,J＝13.5Hz,1H),2.34–2.25(m,2H). 13 C-NMR(100MHz,Acetone-d 6 ),δ164.69(C),162.90(C),160.49(C),150.57(C),147.71(C),145.99(C),145.02(CH),142.49(CH),141.50(C),135.27(C),133.82(C),131.75(CH),131.67(CH),131.55(CH),128.70(CH),128.62(CH),128.55(C),123.48(CH),117.66(CH),114.88(CH),114.81(CH),114.66(CH),114.44(CH),106.21(CH),82.83(CH),56.51(CH 2 ),48.80(C),48.63(CH 2 ),43.51(CH 2 ),37.98(CH 2 ).MS(ESI(+))calcd for C 30 H 23 ClF 2 N 4 O[M+H] + :517.1；found:517.1。
example 3
Figure BDA0003374465900000081
The oil is yellow and oily, 1 H-NMR(400MHz,Acetone-d 6 ),δ8.00–7.94(m,1H),7.71(dd,J＝7.6,0.8Hz,1H),7.57–7.54(m,1H),7.15–7.12(m,1H),7.01–6.90(m,8H),6.77–6.68(m,2H),6.14(d,J＝7.8Hz,1H),6.01(s,1H),4.53(q,J＝16.3Hz,2H),3.86(ddd,J＝11.5,7.1,1.1Hz,1H),3.48–3.39(m,1H),3.21(d,J＝13.4Hz,1H),3.04(t,J＝8.7Hz,1H),2.28(ddd,J＝9.6,8.7,5.1Hz,2H). 13 C-NMR(100MHz,Acetone-d 6 ),δ165.81(C),163.00(C),160.46(C),154.49(C),150.60(C),149.33(C),140.38(CH),135.32(C),133.93(C),131.74(CH),131.67(CH),131.59(CH),128.70(CH),128.63(CH),128.52(CH),125.77(C),123.47(CH),122.82(CH),117.55(CH),114.85(CH),114.64(CH),114.43(CH),106.155(CH),82.75(CH),56.48(CH 2 ),48.77(C),48.72(CH 2 ),43.56(CH 2 ),38.05(CH 2 ).MS(ESI(+))calcd for C 30 H 24 ClF 2 N 3 O[M+H] + :516.1；found:516.1。
example 4
Figure BDA0003374465900000091
Pale yellow oil, 1H-NMR (400mhz, acetone-d 6), δ 8.90 (s, 1H), 8.69 (d, J =2.4hz, 1h), 8.62-8.59 (M, 1H), 7.14 (d, J =7.3hz, 1h), 7.06-6.91 (M, 10H), 6.16 (d, J =7.9hz, 1h), 6.03 (s, 1H), 4.54 (q, J =16.3hz, 2h), 3.94-3.88 (M, 1H), 3.42 (dt, J =13.8,6.6hz, 1h), 3.22 (d, J = 13.13 hz, 1h), 3.03 (d, J =13.5hz, 1h), 2.29 (dd, J =10.7, 4.7hz, 2h), 13.13C-163 mhz, 163, 163.80C, 163.42 (d, 18H), 161.38 (C), 161.27 (C), 151.42 (C), 150.23 (CH), 146.69 (CH), 146.20 (CH), 143.54 (C), 136.09 (C), 134.67 (C), 132.54 (CH), 132.46 (CH), 132.39 (C), 129.50 (CH), 129.42 (CH), 129.32 (C), 124.27 (CH), 118.38 (CH), 115.65 (CH), 115.44 (CH), 115.44 (CH), 115.23 (CH), 106.95 (CH), 83.56 (CH), 57.28 (CH 2), 49.57 (C), 49.39 (CH 2), 44.35 (CH 2), 38.89 (CH 2). MS (ESI (+)) calcd for C29H24F2N4O [ M + H ] + ]: 483.1; found is 483.1.
Example 5
Figure BDA0003374465900000101
White solid, 1H-NMR (400MHz, acetone-d 6), δ 7.52 (d, J =7.7Hz, 2H), 7.17 (d, J =7.2Hz, 1H), 6.99 (ddd, J =18.0,8.3,3.3Hz, 11H), 6.73 (t, J =7.4Hz, 1H), 6.19-6.07 (M, 2H), 4.52 (dd, J =69.9,16.3Hz, 2H), 3.87 (s, 3H), 3.69 (d, J =7.3Hz, 1H), 3.42 (d, J =3.8Hz, 1H), 3.25 (d, J =13.4Hz, 1H), 3.06 (d, J =13.4Hz, 1H), 2.34-2.18 (M, 2H), 13C-NMR (100MHz, acetone-d 6), delta 169.54 (C), 162.95 (C), 162.79 (C), 161.33 (C), 160.54 (C), 160.38 (C), 150.84 (C), 135.34 (C), 134.03 (C), 134.00 (C), 131.68 (CH), 131.61 (CH), 129.69 (CH), 129.69 (CH), 128.48 (CH), 128.45 (CH), 128.45 (C), 128.41 (C), 123.47 (CH), 117.28 (CH), 114.77 (CH), 114.56 (2 CH), 114.34 (CH), 113.24 (CH), 113.24 (CH), 105.83 (CH), 82.02 (CH), 56.51 (CH 2), 54.85 (CH 3), 49.44 (C), 48.12 (CH 2), 43.65 (CH 2), 38.23 (CH 2). MS (ESI (+)) calcd for C32H28F2N2O2[ M + H ] +:511.2; found is 511.2.
Example 6
Figure BDA0003374465900000111
White solid, 1H-NMR (400MHz, acetone-d 6), δ 7.91 (d, J =8.3Hz, 2H), 7.63 (d, J =8.3Hz, 1H), 7.52-7.41 (M, 3H), 7.31 (d, J =6.9Hz, 1H), 7.14-7.08 (M, 3H), 7.06-6.92 (M, 7H), 6.69-6.63 (M, 1H), 6.23-6.13 (M, 2H), 4.65 (t, J =21.4Hz, 2H), 3.21 (d, J =13.4Hz, 1H), 3.16-2.99 (M, 3H), 2.14 (dd, J =6.1,1.8Hz, 2H), 13C-NMR (100MHz, acetone-d 6), δ (160.160), 163.85, 160.60, 60C (C) (C.85, 60), 135.23 (C), 133.96 (C), 133.56 (C), 131.92 (CH), 131.84 (CH), 131.76 (C), 129.42 (CH), 129.13 (CH), 128.76 (CH), 128.68 (CH), 128.56 (CH), 128.44 (C), 126.90 (CH), 126.39 (CH), 125.21 (CH), 124.86 (CH), 123.99 (CH), 123.52 (CH), 117.50 (CH), 114.96 (CH), 114.74 (2 CH), 114.53 (CH), 105.85 (CH), 81.91 (CH), 57.16 (CH 2), 48.76 (C), 48.03 (CH 2), 43.56 (CH 2), 38.17 (CH 2). MS ((+ ESI)) calc 35H28F2N2O [ M + H ] 531.2; found:531.2.
Example 7
Figure BDA0003374465900000121
A light yellow oily solid, 1H-NMR (400MHz, acetone-d 6), δ 8.31 (d, J =4.1Hz, 1H), 7.94 (t, J =8.3Hz, 1H), 7.45-7.37 (M, 1H), 7.15 (d, J =7.3Hz, 1H), 7.06-6.90 (M, 9H), 6.70 (t, J =7.4Hz, 1H), 6.14 (d, J =7.9Hz, 1H), 5.98 (s, 1H), 4.52 (q, J =16.4Hz, 2H), 3.47 (dd, J =11.2,5.8Hz, 1H), 3.32-3.19 (M, 2H), 3.05 (d, J =13.4Hz, 1H), 2.29 (Acetone, 11.3,4.7, 7H), 13.160, 13.163-13 Hz, 60 MHz, C.60C, 60C = 60C, 60 MHz, C =16, 13 Hz, 13 MHz, 13 MHz, 60C, C-15 MHz, 160.49 (C), 160.03 (C), 157.67 (C), 150.75 (CH), 149.17 (CH), 149.02 (CH), 140.50 (C), 140.47 (C), 135.24 (CH), 133.84 (CH), 131.70 (CH), 131.62 (CH), 131.31 (CH), 128.60 (C), 128.52 (C), 123.53 (CH), 122.11 (CH), 122.07 (CH), 119.74 (CH), 117.62 (C), 114.87 (CH), 114.65 (2 CH), 114.43 (CH), 106.04 (CH), 82.27 (CH), 57.12 (CH 2), 48.66 (C), 47.83 (CH 2), 43.66 (CH 2), 38.05 (CH 2). MS (ESI (+)) lccad for C30H24F3N3O [ M + H ] +:500.1; found is 500.1.
Example 8
Figure BDA0003374465900000131
A yellow oily solid, and a white solid, 1 H-NMR(400MHz,Acetone-d 6 ),δ8.54(s,1H),7.73(d,J＝7.7Hz,1H),7.26(d,J＝7.9Hz,1H),7.13(d,J＝7.1Hz,1H),7.04–6.90(m,9H),6.70(t,J＝7.4Hz,1H),6.14(d,J＝7.8Hz,1H),6.06(s,1H),4.50(dd,J＝46.0,16.5Hz,2H),3.62(dd,J＝15.8,8.9Hz,1H),3.41(d,J＝6.2Hz,1H),3.23(d,J＝13.4Hz,1H),3.03(d,J＝13.3Hz,1H),2.51(s,3H),2.31–2.22(m,2H). 13 C-NMR(100MHz,Acetone-d 6 ),δ167.97(C),163.00(C),162.86(C),160.58(C),160.45(C),160.27(C),150.80(CH),148.06(C),135.40(CH),133.94(C),131.71(C),131.64(CH),131.43(CH),129.31(CH),128.55(CH),128.48(C),123.54(2CH),122.29(CH),117.42(CH),114.84(CH),114.63(2CH),114.40(CH),105.93(CH),82.27(CH),56.71(CH 2 ),49.17(C),48.39(CH 2 ),43.69(CH 2 ),38.28(CH 2 ),23.65(CH 3 ).MS(ESI(+))calcd for C 31 H 27 F 2 N 3 O[M+H] + :496.2；found:496.2。
example 9
Figure BDA0003374465900000141
A light-yellow oily solid which is, 1 H-NMR(400MHz,Acetone-d 6 ),δ8.56(d,J＝4.4Hz,1H),7.90(td,J＝7.7,1.1Hz,1H),7.72(d,J＝7.8Hz,1H),7.45(dd,J＝6.8,5.5Hz,1H),7.13(d,J＝7.3Hz,1H),7.07–6.91(m,10H),6.12(d,J＝7.9Hz,1H),6.03(s,1H),4.60(d,J＝16.3Hz,1H),4.48(d,J＝16.3Hz,1H),3.90(dd,J＝11.5,6.9Hz,1H),3.42(td,J＝11.4,5.7Hz,1H),3.22(d,J＝13.4Hz,1H),3.03(d,J＝13.4Hz,1H),2.25(dd,J＝14.1,5.4Hz,2H). 13 C-NMR NMR(100MHz,Acetone-d 6 ),δ167.41(C),162.99(C),162.86(C),160.58(C),160.46(C),154.36(C),150.73(C),148.09(CH),136.94(CH),135.39(C),133.98(C),131.75(CH),131.67(CH),128.71(CH),128.64(CH),128.46(CH),125.17(CH),125.05(C),123.89(CH),123.58(CH),123.45(CH),117.44(CH),114.84(CH),114.62(2CH),114.41(CH),106.05(CH),82.63(CH),56.45(CH 2 ),48.71(C),47.10(CH 2 ),43.65(CH 2 ),38.21(CH 2 ).MS(ESI(+))calcd for C 30 H 25 F 2 N 3 O[M+H] + :482.2；found:482.2。
example 10
Figure BDA0003374465900000151
A white solid, which is a solid, 1 H-NMR(400MHz,Acetone-d6),δ8.46(d,J＝5.0Hz,1H),7.50–7.35(m,2H),7.15(d,J＝7.3Hz,1H),7.05–6.91(m,9H),6.71(t,J＝7.4Hz,1H),6.17(d,J＝7.9Hz,1H),5.98(s,1H),4.52(dd,J＝39.4,16.5Hz,2H),3.61–3.51(m,1H),3.43–3.32(m,1H),3.24(d,J＝13.4Hz,1H),3.04(d,J＝13.4Hz,1H),2.30(dd,J＝9.4,5.0Hz,2H). 13 C-NMR(100MHz,Acetone-d6)δ166.27(C),162.98(C),162.85(C),160.57(C),160.45(C),151.27(C),150.68(C),150.26(C),147.26(CH),135.33(C),135.30(C),133.82(C),133.79(C),131.65(CH),131.58(CH),131.24(CH),128.55(CH),128.52(CH),128.44(C),123.49(CH),122.06(CH),120.64(CH),117.52(CH),114.84(CH),114.62(CH),114.60(CH),114.39(CH),105.95(CH),82.38(CH),56.83(CH 2 ),48.67(C),48.35(CH 2 ),43.51(CH 2 ),38.10(CH 2 ).MS(ESI(+))calcd for C 30 H 24 ClF 2 N 3 O[M+H] + :516.1；found:516.1。
example 11
Figure BDA0003374465900000161
A light-yellow solid, wherein the solid is, 1 H-NMR(400MHz,Acetone-d 6 ),δ8.78(s,1H),8.49(s,1H),7.14(d,J＝7.3Hz,1H),7.05–6.92(m,10H),6.14(d,J＝7.9Hz,1H),6.04(s,1H),4.53(dd,J＝36.9,16.3Hz,2H),3.92(dd,J＝11.4,6.8Hz,1H),3.16–3.08(m,2H),2.57(s,3H),2.48(s,1H),2.28(dd,J＝12.5,5.6Hz,2H). 13 C-NMR(100MHz,Acetone-d 6 ),δ165.90(C),162.94(C),162.82(C),160.53(C),160.41(C),155.49(C),150.57(CH),146.36(C),144.30(CH),142.23(C),135.27(C),135.24(C),133.88(C),133.85(C),131.71(CH),131.64(CH),131.55(CH),128.65(CH),128.57(CH),128.47(C),123.45(CH),117.52(CH),114.82(CH),114.60(2CH),114.38(CH),106.07(CH),82.64(CH),56.36(CH 2 ),48.66(C),48.60(CH 2 ),43.46(CH 2 ),38.01(CH 2 ),20.76(CH 3 ).MS(ESI(+))calcd for C 30 H 26 F 2 N 4 O[M+H] + :497.2；found:497.2。
example 12
Figure BDA0003374465900000171
A white solid, a solid which is, 1 H-NMR(400MHz,Acetone-d 6 ),δ8.64(d,J＝5.4Hz,2H),7.38(d,J＝5.5Hz,2H),7.13(d,J＝7.3Hz,1H),6.97(ddt,J＝20.5,17.7,5.7Hz,9H),6.70(t,J＝7.4Hz,1H),6.15(d,J＝7.8Hz,1H),6.00(s,1H),4.51(dd,J＝39.1,16.4Hz,2H),3.59–3.49(m,1H),3.35(td,J＝10.8,6.8Hz,1H),3.23(d,J＝13.4Hz,1H),3.03(d,J＝13.4Hz,1H),2.35–2.24(m,2H). 13 C-NMR(100MHz,Acetone-d 6 ),δ167.79(C),163.00(C),162.87(C),160.59(C),160.47(C),150.74(C),150.10(2CH),143.74(C),135.34(C),133.91(C),131.71(CH),131.63(CH),131.36(CH),128.58(C),128.47(CH),123.54(CH),121.46(2CH),117.52(CH),114.88(CH),114.67(CH),114.64(CH),114.43(CH),105.99(CH),82.33(CH),56.85(CH 2 ),48.87(C),48.47(CH 2 ),43.63(CH 2 ),38.15(CH 2 ).MS(ESI(+))calcd for C 30 H 25 F 2 N 3 O[M+H] + :482.2；found:482.2。
example 13
Figure BDA0003374465900000181
The oil is a light yellow oil, 1 H-NMR(400MHz,Acetone-d 6 ),δ8.44(dd,J＝4.7,1.9Hz,1H),7.72(s,1H),7.47(dd,J＝7.3,4.9Hz,1H),7.16(dd,J＝7.3,0.6Hz,1H),7.06–6.90(m,9H),6.71–6.63(m,1H),6.16(d,J＝7.6Hz,1H),5.96(s,1H),4.58(dd,J＝55.3,16.3Hz,2H),3.33(ddd,J＝10.9,6.5,1.8Hz,1H),3.21(dd,J＝37.5,13.3Hz,2H),3.05(d,J＝13.4Hz,1H),2.34–2.23(m,2H). 13 C-NMR(100MHz,Acetone-d 6 ),δ165.36(C),163.02(C),162.91(C),160.61(C),160.51(C),150.76(C),150.22(CH),146.36(C),137.16(CH),135.29(C),133.81(C),133.07(C),131.79(CH),131.71(CH),131.38(CH),128.71(CH),128.63(CH),128.60(C),123.51(CH),123.21(CH),117.62(CH),114.90(CH),114.71(2CH),114.50(CH),105.94(CH),81.94(CH),57.32(CH 2 ),48.56(C),47.44(CH 2 ),43.53(CH 2 ),38.26(CH 2 ).MS(ESI(+))calcd for C 30 H 24 ClF 2 N 3 O[M+H] + :516.1；found:516.1。
example 14
Figure BDA0003374465900000191
A light-yellow solid, wherein the solid is, 1 H-NMR(400MHz,Acetone-d 6 ),δ8.49(s,1H),7.93(d,J＝8.1Hz,1H),7.51(d,J＝8.2Hz,1H),7.28–6.83(m,11H),6.71(t,J＝7.4Hz,1H),6.16(d,J＝7.8Hz,1H),6.04(s,1H),4.51(dd,J＝42.1,16.5Hz,2H),3.71–3.61(m,1H),3.45(dt,J＝17.0,8.4Hz,1H),3.23(d,J＝13.4Hz,1H),3.04(d,J＝13.4Hz,1H),2.38–2.24(m,2H). 13 C-NMR(100MHz,Acetone-d 6 ),δ166.61(C),162.97(C),162.83(C),160.56(C),160.42(C),152.22(C),150.72(C),148.80(C),138.48(CH),135.32(C),133.84(C),131.66(CH),131.58(CH),131.45(CH),131.29(CH),128.54(C),128.50(CH),128.42(C),123.85(CH),123.50(CH),117.46(CH),114.82(CH),114.61(CH),114.58(CH),114.37(CH),105.93(CH),82.31(CH),56.71(CH 2 ),49.03(C),48.33(CH 2 ),43.57(CH 2 ),38.12(CH 2 ).MS(ESI(+))calcd for C 30 H 24 ClF 2 N 3 O[M+H] + :516.1；found:516.1。
example 15
Figure BDA0003374465900000201
A white solid, which is a solid, 1 H-NMR(400MHz,Acetone-d 6 ),δ8.43(d,J＝1.9Hz,1H),8.06(d,J＝1.9Hz,1H),7.14(d,J＝7.3Hz,1H),7.03–6.92(m,9H),6.71(t,J＝7.4Hz,1H),6.17(d,J＝7.9Hz,1H),6.02(s,1H),4.50(dd,J＝42.6,16.5Hz,2H),3.73–3.66(m,1H),3.46(td,J＝10.8,6.7Hz,1H),3.23(d,J＝13.4Hz,1H),3.02(d,J＝13.4Hz,1H),2.34–2.26(m,2H). 13 C-NMR(100MHz,Acetone-d 6 ),δ165.29(C),163.01(C),162.88(C),160.60(C),160.47(C),150.74(CH),149.47(C),146.38(C),138.08(C),135.34(CH),133.83(C),132.91(C),131.69(CH),131.62(CH),131.28(C),129.71(CH),128.60(2CH),128.50(C),123.54(CH),117.55(CH),114.88(CH),114.66(2CH),114.43(CH),106.00(CH),82.45(CH),56.84(CH 2 ),48.99(C),48.39(CH 2 ),43.64(CH 2 ),38.22(CH 2 ).MS(ESI(+))calcd for C 30 H 23 Cl 2 F 2 N 3 O[M+H]+:550.1；found:550.1。
example 16
Figure BDA0003374465900000211
A light-yellow solid, wherein the solid is, 1 H-NMR(400MHz,Acetone-d 6 ),δ8.46(d,J＝9.7Hz,2H),7.62(s,1H),7.14(d,J＝7.2Hz,1H),7.08–6.90(m,9H),6.70(t,J＝7.3Hz,1H),6.16(d,J＝7.8Hz,1H),6.05(s,1H),4.51(dd,J＝49.1,16.5Hz,2H),3.63–3.54(m,1H),3.40(dt,J＝17.1,8.4Hz,1H),3.23(d,J＝13.4Hz,1H),3.04(d,J＝13.4Hz,1H),2.33(d,J＝11.6Hz,3H),2.30–2.22(m,2H). 13 C NMR(100MHz,Acetone-d 6 ),δ167.88(C),162.97(C),162.83(C),160.55(C),160.42(C),151.42(C),150.76(CH),145.61(CH),135.38(CH),135.08(C),133.92(C),132.77(C),131.70(CH),131.68(CH),131.60(2CH),131.38(C),128.52(CH),128.45(C),123.49(CH),117.39(CH),114.81(CH),114.59(2CH),114.37(CH),105.87(CH),82.17(CH),56.67(CH 2 ),49.03(C),48.30(CH 2 ),43.58(CH 2 ),38.18(CH 2 ),17.24(CH 3 ).MS(ESI(+))calcd for C 31 H 27 F 2 N 3 O[M+H] + :496.2；found:496.2。
example 17
Figure BDA0003374465900000221
The brown oil is a brown oil which, 1 H-NMR(600MHz,CDCl 3 ),δ8.63(s,2H),7.71(d,J＝7.9Hz,1H),7.29(dd,J＝7.6,4.9Hz,1H),7.03(td,J＝7.7,1.2Hz,1H),6.94–6.78(m,9H),6.70(t,J＝7.3Hz,1H),6.17(d,J＝7.8Hz,1H),5.96(s,1H),4.52(d,J＝16.3Hz,1H),4.38(d,J＝16.3Hz,1H),3.53(dd,J＝10.8,7.4Hz,1H),3.37(td,J＝11.5,5.4Hz,1H),3.10(d,J＝13.5Hz,1H),2.86(d,J＝13.5Hz,1H),2.21(dd,J＝12.2,5.3Hz,1H),2.09(td,J＝12.1,7.5Hz,1H). 13 C-NMR(150MHz,CDCl 3 ),δ168.08(C),162.68(C),161.06(C),151.37(C),150.61(CH),148.43(CH),135.30(CH),134.44(C),132.73(C),132.71(C),131.70(CH),131.36(CH),131.31(C),130.55(CH),128.97(CH),128.31(CH),128.26(C),123.48(CH),123.25(CH),117.65(CH),115.18(CH),115.04(CH),114.97(CH),114.83(CH),106.27(CH),82.31(CH),56.68(CH 2 ),49.34(C),48.67(CH 2 ),44.25(CH 2 ),38.37(CH 2 ).MS(ESI(+))calcd for C 30 H 25 F 2 N 3 O[M+H] + :482.2；found:482.2。
example 18
Figure BDA0003374465900000231
A white solid in the form of a needle, 1 H-NMR(400MHz,Acetone-d 6 ),δ8.03(dd,J＝4.8,1.6Hz,1H),7.46(d,J＝5.5Hz,1H),7.14(d,J＝7.2Hz,1H),7.05–6.87(m,9H),6.70(t,J＝7.4Hz,1H),6.56(dd,J＝7.4,4.9Hz,1H),6.08(dd,J＝36.5,26.1Hz,4H),4.43(t,J＝21.1Hz,2H),3.67(s,1H),3.48–3.17(m,2H),3.04(d,J＝13.4Hz,1H),2.34–2.19(m,2H). 13 C NMR(100MHz,Acetone-d 6 )δ169.11(C),162.98(C),162.86(C),160.57(C),160.45(C),157.98(C),150.84(CH),150.16(C),136.77(CH),135.24(C),133.95(C),133.92(CH),131.66(CH),131.58(CH),131.43(CH),128.48(CH),128.40(C),123.51(CH),117.43(CH),114.79(CH),114.57(CH),114.54(CH),114.33(CH),112.69(CH),111.71(CH),105.87(CH),82.12(CH),70.40(CH 2 ),56.75(C),48.17(CH 2 ),43.66(CH 2 ),38.37(CH 2 ).MS(ESI(+))calcd for C 30 H 26 F 2 N 4 O[M+H] + :497.2；found:497.2。
example 19
Figure BDA0003374465900000241
A brown solid which is a solid with a color of, 1 H-NMR(400MHz,Acetone-d 6 ),δ8.45(dd,J＝4.7,1.5Hz,1H),7.73(s,1H),7.47(dd,J＝7.1,5.1Hz,1H),7.17(d,J＝7.3Hz,1H),6.96(ddd,J＝45.0,25.2,17.9Hz,10H),6.70(t,J＝7.4Hz,1H),6.17(d,J＝7.6Hz,1H),5.96(s,1H),4.58(dd,J＝54.6,16.4Hz,2H),3.36–3.02(m,4H),2.37–2.25(m,2H). 13 C-NMR(100MHz,Acetone-d 6 ),δ165.34(C),162.99(C),162.88(C),160.58(C),160.48(C),150.73(C),150.18(CH),137.11(CH),135.26(C),133.80(C),133.04(CH),131.74(CH),131.66(C),131.34(CH),128.66(CH),128.59(CH),128.54(C),123.46(CH),123.15(CH),117.56(CH),114.84(CH),114.65(CH),114.63(CH),114.44(CH),105.89(CH),81.88(CH),57.25(CH 2 ),48.49(C),47.36(CH 2 ),43.45(CH 2 ),38.17(CH 2 ).MS(ESI(+))calcd for C 32 H 26 F 2 N 2 O 2 [M+H] + :509.2；found:509.2。
example 20
The inhibitory activity of the obtained compounds against phytopathogens was measured, and the results are shown in Table 2. Wherein T-1 to T-19 correspond to the compounds obtained in examples 1 to 19.
TABLE 2 MIC of Compounds against plant pathogenic fungi
Figure BDA0003374465900000242
Figure BDA0003374465900000251
Note: "-" indicates no activity. MIC: minimum inhibitory concentration, s.s.: sclerotinia sclerotiorum, a.s.: early blight of tomato, v.d.: verticillium dahliae, c.o.: cucumber fusarium wilt, c.j.: pythium Juglandis, C.l.: curvularia lunata (Fr.) Sing
As can be seen from the table, the indole pyrrole ring derivative T-2 has excellent bacteriostatic activity on Sclerotinia sclerotiorum (Sclerotinia sclerotiorum), and the minimum bacteriostatic concentration is 1.95 mu g/mL. In addition, the inhibition effect of the compounds T-4, T-11 and T-14 on sclerotinia sclerotiorum is also obvious, and the inhibition effect is equivalent to that of positive control amphotericin, and the inhibition effect is 3.9 mu g/mL; the inhibition effect of the compounds T-7, T-8, T-13 and T-15 on Sclerotinia sclerotiorum is identical to the effect of positive control carbendazim, and is 7.8 mug/mL.
The compounds T-2, T-4 and T-11 show high bacteriostatic activity on the tomato early blight (Alternaria solani) better than that of two groups of positive controls, and the minimum bacteriostatic activity of the compounds is 3.9 mu g/mL, 7.8 mu g/mL and 7.8 mu g/mL respectively. The compounds T-3, T-7, T-8, T-14, T-15 and T-16 show the bacteriostatic activity superior to that of positive control carbendazim, wherein the bacteriostatic activity of the T-15 and the T-16 on the tomato early blight bacteria is equivalent to that of the control amphotericin, and the minimum bacteriostatic concentration of the compounds is 15.16 mu g/mL.
The compound T-2 has obvious bacteriostatic activity on Verticillium dahliae (Verticillium dahliae), and the minimum bacteriostatic concentration of the compound T-2 is 1.95 mu g/mL. The bacteriostatic activity of the compounds T-11 and T-15 is also superior, which is higher than that of two groups of positive controls, and the minimum bacteriostatic concentration of the compounds is 3.9 mu g/mL and 7.8 mu g/mL respectively. The compounds T-4, T-7, T-13, T-14 and T-16 show better biological activity than the control amphotericin, and the minimum inhibitory concentrations thereof are 15.63 mug/mL, 15.63 mug/mL and 31.25 mug/mL respectively.
The compounds T-2, T-11 and T-15 show better bacteriostatic activity on cucumber fusarium wilt (Colletotrichum orbiculare) than two groups of positive controls, and the minimum bacteriostatic concentration of the compounds is 15.63 mu g/mL. The compounds T-3, T-4, T-7, T-8 and T-14 also show bacteriostatic activity superior to that of two groups of positive controls, and the minimum bacteriostatic concentration of the compounds is 31.3 mu g/mL.
The compounds T-4, T-15 and T-16 have obvious biological activity on the pythium Juglandis (Cytospora Juglans), which is higher than that of two positive control groups, and the T-15 has better bacteriostatic activity on the pythium Juglandis, and the minimum bacteriostatic concentration of the compounds is 3.9 mu g/mL. The bacteriostatic activity of the compounds T-2, T-7, T-13 and T-14 on pythium Juglandis compared with that of amphotericin in a control group is higher, and the minimum bacteriostatic concentrations are 31.3 mug/mL, 62.5 mug/mL and 31.3 mug/mL respectively.
The compounds T-1, T-2, T-3, T-4, T-7, T-14 and T-15 have excellent biological activity on Curvularia lunata (Curvularia lunata), are superior to two groups of positive control groups, and have the minimum inhibitory concentrations of 31.25 mu g/mL, 15.63 mu g/mL, 31.3 mu g/mL, 31.63 mu g/mL and 15.63 mu g/mL respectively. The biological activity of the compounds T-11 and T-12 is equivalent to that of positive control amphotericin, and the minimum inhibitory concentration is 62.5 mu g/mL.
By comparing the bacteriostatic activity of the compounds on different plant pathogenic fungi, the compound T-2 has stronger inhibitory action on sclerotinia sclerotiorum, early blight of tomato, verticillium dahliae of cotton, fusarium wilt of cucumber and curvularia zeae than two groups of positive controls, has the minimum inhibitory concentration of 1.95 mu g/mL on sclerotinia sclerotiorum and verticillium dahliae of cotton, has stronger inhibitory action on pythium Juglandis than the control amphotericin and is equivalent to carbendazim; the compound T-4 has stronger inhibiting effect on tomato early blight bacteria, cucumber wilt, walnut pythium and corn curvularia than two groups of controls, has inhibiting effect on other 2 plant pathogenic fungi and is stronger than or equal to one of the controls; the compound T-4 has better bacteriostatic effect on verticillium dahliae, fusarium wilt of cucumbers, pythium Juglandis and Curvularia zeae, is superior to two controls, also has inhibitory effect on other 2 plant pathogenic fungi, is stronger than or equal to one control, and has minimum inhibitory activity on pythium Juglandis of 3.9 mug/mL. However, the six plant pathogenic fungi of the compounds T-5, T-6, T-9, T-10, T-17 and T-18T-19 have poor inhibitory effect, and some of the compounds have no inhibitory effect.

Claims (5)

1. A nicotine and indole hybrid compound represented by the general formula (I):
Figure 562283DEST_PATH_IMAGE001
formula (I);
the nicotine analogue is any one of the following groups:
Figure 417106DEST_PATH_IMAGE002
。
2. the process for synthesizing a nicotine/indole hybrid compound according to claim 1, wherein the reaction formula is as follows:
Figure 400106DEST_PATH_IMAGE003
the nicotinic acid analogue is selected from any one of the following: 3-chloroisonicotinic acid, 5-chloropyrazine-2-carboxylic acid, 2-chloro-6-carboxylic acid pyridine, 2-formic acid pyrazine, 1-naphthoic acid, 2-fluoronicotinic acid, 2-methylnicotinic acid, 2-picolinic acid, 2-chloroisonicotinic acid, 5-methylpyrazine-2-carboxylic acid, isonicotinic acid, 2-chloronicotinic acid, 6-chloronicotinic acid, 5, 6-dichloronicotinic acid, 5-methylnicotinic acid, nicotinic acid, 2-aminonicotinic acid, anthranilic acid.
3. A process for the synthesis of a nicotine and indole hybrid compound of general formula (I) according to claim 1, characterized by the following steps:
step one, preparing acyl chloride: taking a nicotinic acid analogue as a raw material, adding anhydrous tetrahydrofuran for dissolving, and reacting with thionyl chloride under the condition of oil bath heating to prepare a corresponding acyl chloride substrate;
and step two, carrying out amidation reaction on the acyl chloride substrate obtained in the step one and a substrate indole compound, tracking and detecting by TLC (thin layer chromatography), dropwise adding water into the reaction liquid to quench the reaction after the reaction is complete, carrying out reduced pressure concentration to remove tetrahydrofuran, combining organic phases, carrying out reduced pressure concentration, and separating a crude product by column chromatography to obtain the nicotine and indole hybrid compound.
4. The process of claim 3, wherein the amidation reaction in step two is carried out by reacting anhydrous tetrahydrofuran solution of acyl chloride substrate with anhydrous tetrahydrofuran solution of indole substrate to which Et is added 3 N。
5. Use of the nicotine and indole hybrid compound of the general formula (I) according to claim 1 for inhibiting phytopathogens, which are sclerotinia sclerotiorum, phytophthora solani, verticillium dahliae, fusarium oxysporum, pythium Juglandis or curvularia zeae.
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CN109438442A (en) * 2018-12-03 2019-03-08 江苏科技大学 A kind of Benzazole compounds, its synthetic method and its application
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Inventor before: Yang Yimou

Inventor before: Chen Xiaoyun

Inventor before: Zhu Rui

Inventor before: Li Xiaoqian

Inventor before: Li Ji

Inventor before: Xiang Yi

Inventor before: Huang Hua

Inventor before: Cai Yutian

Inventor before: Zhou Yujie

Inventor before: Zheng Shaojun

Inventor before: Chen Lei

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