阅读说明：本技术 一种吴茱萸碱类似物及其在防治植物病原真菌中的用途 (Evodiamine analog and application thereof in preventing and treating plant pathogenic fungi ) 是由 刘映前 杨程杰 吴天琳 王璟汝 李海昕 罗雄飞 贺颖慧 杜莎莎 于 2020-12-03 设计创作，主要内容包括：本发明涉及药物化学领域,公开了一种吴茱萸碱类似物WZY01～WZY25及其在抗植物病原菌中的用途。生物活性测试发现,本发明所述化合物对立枯丝核菌,油菜菌核病菌,小麦赤霉病菌,番茄灰霉病菌,棉花枯萎病菌和稻瘟病菌等6种农业病害表现出潜在的抑制活性,尤其是化合物WZY-01对于立枯丝核菌和油菜菌核病菌的活性表现出显著的抑制作用。本化合物制备简单,原料廉价易得,有望开发为新型抑菌剂。(The invention relates to the field of medicinal chemistry, and discloses an evodiamine analog WZY 01-WZY 25 and application thereof in resisting phytopathogen. Biological activity tests show that the compound of the invention has potential inhibition activity on 6 agricultural diseases such as rhizoctonia solani, sclerotinia sclerotiorum, fusarium graminearum, botrytis cinerea, fusarium oxysporum and pyricularia oryzae, and particularly the compound WZY-01 has obvious inhibition effect on the activity of rhizoctonia solani and sclerotinia sclerotiorum. The compound is simple to prepare, the raw materials are cheap and easy to obtain, and the compound is expected to be developed into a novel bacteriostatic agent.)

1. The invention relates to application of evodiamine analogs WZY 01-WZY 25 in preparation of medicines for preventing and treating or resisting phytopathogens.

2. The evodiamine analog WZY 01-WZY 25 of claim 1, having the following molecular structural features:

3. the use of any one of the evodiamine analogs WZY 01-WZY 25 of claim 1 in the preparation of a medicament for the prevention or treatment of Rhizoctonia solani.

4. The use of the evodiamine analog WZY 01-WZY 25 according to claim 1 in the preparation of a medicament for the prevention or treatment of sclerotinia sclerotiorum.

5. The use of the evodiamine analog WZY 01-WZY 25 of claim 1 in the preparation of a medicament for the prevention or treatment of fusarium graminearum.

6. The use of the evodiamine analog WZY 01-WZY 25 according to claim 1 in the preparation of a medicament for the prevention or treatment of botrytis cinerea.

7. The use of the evodiamine analog WZY 01-WZY 25 according to claim 1 in the preparation of a medicament for the prevention or treatment of cotton blight.

8. The use of the evodiamine analog WZY 01-WZY 25 according to claim 1 in the preparation of a medicament for preventing or treating Pyricularia oryzae.

Technical Field

The invention belongs to the field of medicinal chemistry, and discloses an evodiamine analog WZY-01-WZY 25 and application thereof in preventing and treating rhizoctonia solani, sclerotinia sclerotiorum, fusarium graminearum, botrytis cinerea, fusarium oxysporum and pyricularia oryzae.

Background

The plant pathogenic fungi pose a serious threat to the healthy development of agriculture, the caused plant diseases account for about 70-80% of all plant diseases, and the yield and the quality of crops are seriously influenced while huge economic loss is brought to the agriculture. At present, chemical control is still the main means for controlling plant pathogenic fungal diseases, but the long-term single use of chemical pesticides not only enhances the drug resistance of plant pathogenic bacteria, but also causes chemical residues and soil pollution, and seriously threatens the environmental safety and human health. Therefore, the development of novel pesticides with high efficiency, low toxicity and low residue is an important target for the creation of pesticides at present. Plant-derived pesticides have gradually become a research hotspot of pesticide research and development due to the advantages of low toxicity, no residue, high selectivity, easy decomposition, difficult generation of drug resistance and the like. The natural product is used as inspiration, potential antibacterial active ingredients and active leaders are searched and screened from the natural product, and a novel bactericide with high efficiency and low toxicity is obtained through structure optimization design, so that the natural product becomes an important way for creating and developing novel agriculture.

Evodia rutaecarpa (Juss.) Benth is a traditional Chinese medicine, has the effects of dispelling cold, relieving pain, calming adverse-rising energy, stopping vomiting, supporting yang and relieving diarrhea, and is commonly used for treating jueyang headache, cold disease abdominal pain, vomiting, acid regurgitation, morning diarrhea, hypertension and the like. The evodiamine is the main alkaloid component of the evodia rutaecarpa and has the effects of resisting tumors, resisting inflammation, relieving pain, reducing blood pressure, protecting cardiovascular system, improving immunity and the like. Because of various pharmacological activities and unique chemical structures, evodiamine becomes a hot spot for research of numerous scientific researchers. For example, by modifying and transforming the structure of evodiamine by Zhang Wan et al, the anti-tumor activity of the evodiamine is obviously improved ((1) J.Med.chem.2010,53, 7521-7531, (2) J.Med.chem.2012,55, 7593-7613); meanwhile, evodiamine is reported to have a good neuroprotective effect (europ.j.med.chem.2014,81, 15-21). Therefore, the subject group takes the evodiamine as a lead structure, designs and synthesizes various evodiamine analogs through various structural modification strategies such as skeleton transition, biological electron isostere and the like, finds that partial compounds of the evodiamine analogs can well inhibit the growth of various plant pathogenic fungi, and can be developed as a novel bactericide.

Disclosure of Invention

The invention provides the following technical method: a medicine for resisting Rhizoctonia solani, Sclerotinia sclerotiorum, Gibberella graminis, Botrytis cinerea, Fusarium oxysporum F.sp.gossypii and Magnaporthe grisea contains a therapeutically effective amount of one of evodiamine analogs WZY-01-WZY 25, and the structure of the compound is shown in chemical formula 1.

Chemical formula 1

The synthetic method of the evodiamine analog WZY-01-WZY 25 is shown in the embodiment, a pure product is obtained by separation of conventional methods such as silica gel column chromatography for many times, and the structures of the compounds WZY-01-WZY 25 are determined by spectrum technologies such as mass spectrum and nuclear magnetic resonance, and the structural formula is shown in chemical formula 1. The activity screening result shows that the compound of the invention has a certain degree of inhibition effect on rhizoctonia solani, sclerotinia sclerotiorum, fusarium graminearum, botrytis cinerea, fusarium oxysporum and pyricularia oryzae, and particularly the compound WZY-01 has a remarkable inhibition effect on the activity of rhizoctonia solani and sclerotinia sclerotiorum.

Detailed Description

The foregoing and other aspects of the present invention will become more apparent from the following detailed description, given by way of example only, for purposes of illustrating the invention. This is not to be construed as limiting the invention. The experimental procedures described in the following examples are conventional unless otherwise specified.

EXAMPLE 1 Synthesis of Compound WZY-01

The synthesis method of the compound WZY-01 is carried out according to the following reaction formula:

tryptamine (10mmol) was dissolved in a solvent of methanol/acetic acid (1:5), and then paraformaldehyde (12mmol) was added, and heated under reflux at 100 ℃ for 6 hours. Removing methanol by spin drying after the reaction is finished, adding a large amount of distilled water, adjusting the pH to be alkaline by using NaOH solution, separating out a large amount of solids, filtering, and drying a filter cake to obtain the 1,2,3, 4-tetrahydro-9H-pyridine [3,4-B ]]And indole intermediate products are ready for use. Then the intermediate 1,2,3, 4-tetrahydro-9H-pyridine [3,4-B ] is added]And indole (5mmol) was dissolved in DMF solution, 2-fluoronitrobenzene (2mmol) was added, followed by heating at 130 ℃ under reflux for 12 hours. After the reaction was complete, the DMF was removed by spin-drying, extracted with water and dichloromethane, the organic phases were combined, anhydrous MgSO₄Drying, filtering, spin-drying and purifying by column chromatography to obtain the target compound WZY-01.

Yield: 64 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:12.84(s,1H),7.68(d,J＝7.9Hz,1H),7.54(d,J＝7.5Hz,1H),7.35(d,J＝7.9Hz,1H),7.25(t,J＝7.5Hz,1H),7.18(m,2H),7.13-6.99(m,2H),4.40(t,J＝7.3Hz,2H),3.37(t,J＝7.3Hz,2H).¹³C NMR(100MHz,Chloroform-d)δ:144.82,142.30,137.24,133.86,125.03,124.06,122.72,121.83,121.37,118.94,118.21,118.03,112.58,111.68,108.12,40.91,19.68.MS-ESI m/z:C₁₇H₁₃N₃:258.1[M-H]-。

EXAMPLE 2 Synthesis of Compound WZY-02

The experimental procedure was the same as in example 1, except that 5-chloro-2-fluoronitrobenzene was used instead of 2-fluoronitrobenzene. Yield: 43 percent; yellow colourA colored solid;¹H NMR(400MHz,Chloroform-d)δ:11.95(s,1H),7.63(d,J＝1.8Hz,1H),7.55(d,J＝7.9Hz,1H),7.30-7.21(m,2H),7.19-7.17(m,2H),7.09(t,J＝7.4Hz,1H),4.38(t,J＝7.3Hz,2H),3.38(t,J＝7.3Hz,2H).¹³C NMR(100MHz,Chloroform-d)δ:145.64,142.82,137.20,132.44,127.05,124.90,123.40,123.22,122.34,119.35,118.25,117.74,113.28,111.50,108.80,41.08,19.58.MS-ESI m/z:C₁₇H₁₂ClN₃:292.1[M-H]^-。

EXAMPLE 3 Synthesis of Compound WZY-03

The experimental procedure was the same as in example 1 except that 2-nitro-4-trifluoromethylfluorobenzene was used instead of 2-fluoronitrobenzene. Yield: 40 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:12.22(s,1H),7.93(s,1H),7.57(d,J＝7.8Hz,1H),7.51(d,J＝8.4Hz,1H),7.41(d,J＝8.4Hz,1H),7.22-7.12(m,2H),7.09(m,1H),4.44(t,J＝7.3Hz,2H),3.40(t,J＝7.3Hz,2H).¹³C NMR(100MHz,Chloroform-d)δ:146.50,141.95,137.29,135.89,124.90,123.85(d,J＝32.3Hz),123.50,123.21,122.39,119.42,118.83(d,J＝3.6Hz),118.35,115.60(d,J＝4.3Hz),113.69,111.48,108.35,41.14,19.59.MS-ESI m/z:C₁₈H₁₂F₃N₃:326.1[M-H]^-。

example 4 Synthesis of Compound WZY-04

The experimental procedure was the same as in example 1, except that 4-fluoro-3-nitrobenzonitrile was used instead of 2-fluoronitrobenzene. Yield: 41 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:10.56(s,1H),7.65(d,J＝8.0Hz,1H),7.60(d,J＝8.2Hz,1H),7.41(d,J＝8.3Hz,1H),7.38-7.32(m,2H),7.22-7.17(m,1H),7.13(d,J＝7.5Hz,1H),4.51(t,J＝7.3Hz,2H),3.49(t,J＝7.2Hz,2H).¹³C NMR(100MHz,Chloroform-d)δ:145.64,142.82,138.28,126.83,125.35,123.29,122.14,120.93,119.82,119.63,117.97,112.44,110.95,110.12,44.10,42.21,20.48.MS-ESI m/z:C₁₈H₁₂N₄:283.1[M-H]^-。

EXAMPLE 5 Synthesis of Compound WZY-05

The experimental procedure was the same as in example 1, except that 5-chlorotryptamine was used instead of tryptamine and 4-chloro-2-fluoronitrobenzene was used instead of 2-fluoronitrobenzene. Yield: 36 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:11.56(s,1H),8.27(s,0H),7.63(d,J＝8.7Hz,1H),7.59(s,1H),7.44(s,1H),7.37-7.29(m,3H),4.47(t,J＝7.4Hz,2H),3.43(t,J＝7.4Hz,2H).¹³C NMR(100MHz,Chloroform-d)δ:145.64,142.82,137.20,132.44,127.05,124.90,123.40,123.22,122.34,119.35,118.25,117.74,113.28,111.50,108.80,41.08,19.58.MS-ESI m/z:C₁₇H₁₁C_l2N₃:326.0[M-H]^-。

EXAMPLE 6 Synthesis of Compound WZY-06

The experimental procedure was the same as in example 1, except that 4-fluoro-3-nitrotoluene was used instead of 2-fluoronitrobenzene. Yield: 51 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:12.64(s,1H),7.61(d,J＝7.7Hz,1H),7.55(s,1H),7.30(d,J＝8.1Hz,2H),7.21-7.07(m,3H),4.44(t,J＝7.3Hz,2H),3.43(t,J＝7.3Hz,2H),2.45(s,3H).¹³C NMR(100MHz,Chloroform-d)δ:145.59,143.27,138.19,132.90,132.23,126.05,125.01,124.35,123.72,120.00,119.03,113.45,112.73,108.65,41.98,21.58,20.70.MS-ESI m/z:C₁₈H₁₅N₃:272.1[M-H]^-。

example 7 Synthesis of Compound WZY-07

The experimental procedure was the same as in example 1, except that 4-fluoro-3-nitrobenzyl ether was used instead of 2-fluoronitrobenzene. Yield: 36 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:12.99(s,1H),7.62(d,J＝7.7Hz,1H),7.32(m,2H),7.25(s,1H),7.21-7.09(m,2H),6.98(dd,J＝8.7,2.4Hz,1H),4.45(t,J＝7.3Hz,2H),3.76(s,3H),3.44(t,J＝7.3Hz,2H).¹³C NMR(100MHz,Chloroform-d)δ:155.38,144.92,142.85,137.15,128.41,125.07,124.13,122.58,118.99,118.02,112.04,111.95,111.77,108.50,100.49,54.82,41.08,19.68.MS-ESI m/z:C₁₈H₁₅N₃O:288.1[M-H]^-。

example 8 Synthesis of Compound WZY-08

The experimental procedure was the same as in example 1, except that 4-chloro-2-fluoronitrobenzene was used instead of 2-fluoronitrobenzene. Yield: 48 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:11.34(s,1H),7.57(dd,J＝8.3,5.2Hz,2H),7.35(d,J＝2.0Hz,1H),7.29(d,J＝8.2Hz,1H),7.19(m,2H),7.10(t,J＝7.5Hz,1H),4.38(t,J＝7.3Hz,2H),3.39(t,J＝7.4Hz,2H).¹³C NMR(100MHz,Chloroform-d)δ:144.85,139.76,137.17,134.18,128.02,124.85,123.64,122.63,122.40,119.51,118.43,118.34,113.64,111.51,108.53,41.10,19.52.MS-ESI m/z:C₁₇H₁₂ClN₃:292.1[M-H]^-。

example 9 Synthesis of Compound WZY-09

The experimental procedure was the same as in example 1, except that 3-fluoro-4-nitrobenzyl ether was used instead of 2-fluoronitrobenzene. Yield: 43 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:12.01(s,1H),7.60(d,J＝7.8Hz,1H),7.58-7.53(m,1H),7.46(d,J＝7.4Hz,1H),7.32(d,J＝8.0Hz,2H),7.23-7.15(m,2H),4.41(t,J＝7.3Hz,2H),3.91(s,3H),3.72(t,J＝5.7Hz,1H).¹³C NMR(100MHz,Chloroform-d)δ:156.99,138.05,128.70,126.05,123.84,122.03,120.11,119.71,119.39,119.01,117.91,113.22,112.53,111.39,111.00,93.32,55.94,41.92,20.60.MS-ESI m/z:C₁₈H₁₅N₃O:288.1[M-H]^-。

example 10 Synthesis of Compound WZY-10

The experimental procedure was the same as in example 1, except that 3-fluoro-4-nitrotoluene was used instead of 2-fluoronitrobenzene. Yield: 34 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:12.73(s,1H),7.62(t,J＝8.1Hz,2H),7.28(d,J＝8.0Hz,1H),7.22(s,1H),7.20-7.05(m,3H),4.45(t,J＝7.2Hz,2H),3.43(t,J＝7.3Hz,2H),2.54(s,3H).¹³C NMR(100MHz,Chloroform-d)δ:145.33,141.16,138.19,135.06,133.00,126.08,125.10,123.97,123.69,119.96,118.99,118.69,113.33,112.68,109.24,41.86,21.90,20.71.MS-ESI m/z:C₁₈H₁₅N₃:272.1[M-H]^-。

EXAMPLE 11 Synthesis of Compound WZY-11

The experimental procedure was the same as in example 1, except that 5-methoxytryptamine was used instead of tryptamine. Yield: 31 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:12.25(s,1H),7.74(d,J＝7.9Hz,1H),7.42(d,J＝7.9Hz,1H),7.33(t,J＝7.5Hz,1H),7.28(m,1H),7.20(d,J＝8.9Hz,1H),7.02(d,J＝2.4Hz,1H),6.87(dd,J＝8.9,2.5Hz,1H),4.48(t,J＝7.2Hz,2H),3.87(s,3H),3.42(t,J＝7.3Hz,2H).¹³C NMR(100MHz,Chloroform-d)δ:154.48,145.56,142.75,134.70,133.53,126.27,125.13,122.99,122.60,118.95,114.83,113.47,113.43,109.19,100.22,55.82,41.98,20.71.MS-ESI m/z:C₁₈H₁₅N₃O:288.1[M-H]-。

EXAMPLE 12 Synthesis of Compound WZY-12

The experimental procedure was the same as in example 1, except that 5-methoxytryptamine was used instead of tryptamine and 2-nitro-4-trifluoromethylfluorobenzene was used instead of 2-fluoronitrobenzene. Yield: 32 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:11.49(s,1H),7.99(s,1H),7.58(d,J＝8.4Hz,1H),7.48(d,J＝8.4Hz,1H),7.23(d,J＝8.9Hz,1H),7.02(d,J＝2.4Hz,1H),6.93(dd,J＝8.9,2.4Hz,1H),4.51(t,J＝7.3Hz,2H),3.88(s,3H),3.45(t,J＝7.3Hz,2H).¹³C NMR(100MHz,Chloroform-d)δ:154.75,147.17,142.37,136.69,133.57,126.18,126.06,124.23,119.98,116.33,115.71,114.50,113.32,109.42,100.35,55.81,42.20,20.60.MS-ESI m/z:C₁₉H₁₄F₃N₃O:356.1[M-H]^-。

example 13 Synthesis of Compound WZY-13

The experimental procedure was the same as in example 1, except that 5-chlorotrimethylamine was used instead of tryptamine. Yield: 41 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:12.66(s,1H),7.72(d,J＝7.9Hz,1H),7.59(d,J＝2.0Hz,1H),7.45(d,J＝8.0Hz,1H),7.42-7.33(m,1H),7.33-7.29(m,1H),7.22(s,1H),7.14(dd,J＝8.7,2.0Hz,1H),4.51(t,J＝7.3Hz,2H),3.42(t,J＝7.3Hz,2H).¹³C NMR(100MHz,Chloroform-d)δ:144.96,142.30,136.56,134.57,126.99,125.95,125.76,124.40,123.44,122.95,118.90,118.59,113.70,113.34,109.43,41.92,20.53.MS-ESI m/z:C₁₇H₁₂ClN₃:292.1[M-H]^-。

example 14 Synthesis of Compound WZY-14

The experimental procedure was the same as in example 1 except that 5-chlorotryptamine was used instead of tryptamine and 2-nitro-4-trifluoromethylfluorobenzene was used instead of 2-fluoronitrobenzene. Yield: 36 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:11.66(s,1H),7.98(s,1H),7.60(dd,J＝6.8,1.8Hz,2H),7.50(d,J＝8.6Hz,1H),7.24(s,1H),7.20(dd,J＝8.7,1.9Hz,1H),4.53(t,J＝7.3Hz,2H),3.44(t,J＝7.3Hz,2H).¹³C NMR(100MHz,Chloroform-d)δ:146.06,142.39,136.66,136.49,126.90,126.41,125.48,125.14,125.06,120.32,120.29,118.89,116.54,114.23,113.45,109.64,42.12,20.44.MS-ESI m/z:C₁₈H₁₁ClF₃N₃:360.01[M-H]^-。

example 15 Synthesis of Compound WZY-15

The experimental procedure was the same as in example 1, except that 5-chlorotryptamine was used instead of tryptamine and 4-fluoro-3-nitrobenzyl ether was used instead of 2-fluoronitrobenzene. Yield: 28%; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:12.51(s,1H),7.58(s,1H),7.42(s,1H),7.31(d,J＝8.7Hz,1H),7.13(d,J＝8.4Hz,2H),7.04-6.94(m,1H),4.45(t,J＝7.4Hz,2H),3.79(s,3H),3.39(t,J＝7.4Hz,2H).¹³C NMR(100MHz,Chloroform-d)δ:161.99,156.68,136.42,134.64,129.24,125.91,124.07,122.28,118.55,117.60,113.65,113.39,111.93,109.78,101.28,55.88,42.04,20.52.MS-ESI m/z:C₁₈H₁₄ClN₃O:322.1[M-H]^-。

EXAMPLE 16 Synthesis of Compound WZY-16

The experimental procedure was the same as in example 1, except that 5-chlorotryptamine was used instead of tryptamine and 4-fluoro-3-nitrotoluene was used instead of 2-fluoronitrobenzene. Yield: 45 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:12.35(s,1H),7.58(d,J＝2.0Hz,1H),7.51(s,1H),7.31(d,J＝8.2Hz,1H),7.23(d,J＝8.7Hz,1H),7.20-7.12(m,2H),4.45(t,J＝7.3Hz,2H),3.39(t,J＝7.3Hz,2H),2.46(s,3H).¹³C NMR(100MHz,Chloroform-d)δ:145.64,143.37,138.51,136.38,132.46,127.12,126.38,125.84,124.65,124.02,119.04,118.49,113.57,112.75,108.81,41.90,21.60,20.56.MS-ESI m/z:C₁₈H₁₄ClN₃:306.1[M-H]^-。

example 17 Synthesis of Compounds WZY-17

The experimental procedure was the same as in example 1, except that 5-chlorotryptamine was used instead of tryptamine and 3-fluoro-4-nitrobenzyl ether was used instead of 2-fluoronitrobenzene. Yield: 32 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:12.04(s,1H),7.57-7.46(m,2H),7.08(dd,J＝8.7,2.0Hz,1H),6.86(dd,J＝8.8,2.3Hz,1H),6.82(d,J＝2.3Hz,1H),4.37(t,J＝7.3Hz,2H),3.85(s,3H),3.33(t,J＝7.3Hz,2H).¹³C NMR(100MHz,Chloroform-d)δ:156.40,142.87,135.43,134.56,134.05,125.89,125.02,124.21,123.46,118.00,117.50,112.61,112.00,111.15,92.43,54.94,40.92,28.69,19.40.MS-ESI m/z:C₁₈H₁₄ClN₃O:322.1[M-H]^-。

EXAMPLE 18 Synthesis of Compound WZY-18

The synthesis method of the compound WZY-18 is carried out according to the following reaction formula:

dissolving rutaecarpine (6mmol) in 1, 4-dioxane, adding DDQ (12mmol), and reacting at 100 deg.C under reflux for 6 hr. After the reaction is finished, spin-drying to remove 1, 4-dioxane, extracting with water and dichloromethane, combining organic phases, anhydrous MgSO₄Drying, filtering, spin-drying and purifying by column chromatography to obtain the target compound WZY-19.

Yield: 60 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:12.69(s,1H),8.62(d,J＝7.5Hz,1H),8.46-8.30(m,1H),8.16(d,J＝8.0Hz,1H),7.92(d,J＝7.51H),7.83(dd,J＝10.0,7.8Hz,2H),7.70(d,J＝8.3Hz,1H),7.56-7.43(m,2H),7.29(t,J＝7.5Hz,1H).¹³C NMR(100MHz,Chloroform-d)δ:159.07,148.07,140.59,140.42,135.28,129.85,127.54,127.12,126.67,124.98,122.29,121.35,120.98,120.37,118.18,116.45,113.25,108.50.MS-ESI m/z:C₁₈H₁₁N₃O:286.1[M+H]⁺。

EXAMPLE 19 Synthesis of Compounds WZY-19

The synthesis method of the compound WZY-19 is carried out according to the following reaction formula:

rutaecarpine (6mmol) was dissolved in toluene, lawson's reagent (7.2mmol) was added, and the reaction was refluxed at 110 ℃ for 6 hours. After the reaction was complete, toluene was removed by spin-drying, extracted with water and dichloromethane, the organic phases were combined, anhydrous MgSO₄Drying, filtering, spin-drying, and purifying by column chromatography to obtain target compound WZY-20.

Yield: 60 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:9.25(s,1H),8.81(dd,J＝8.3,1.4Hz,1H),7.70(d,J＝7.5Hz,1H),7.63(d,J＝8.0Hz,2H),7.47-7.40(m,1H),7.36-7.29(m,1H),7.18(t,J＝7.4Hz,1H),5.20(t,J＝6.9Hz,2H),3.28(t,J＝6.9Hz,2H).¹³C NMR(100MHz,Chloroform-d)δ:188.72,144.00,142.47,138.55,134.55,131.97,128.91,127.49,127.28,127.20,125.85,125.44,120.78,120.25,118.45,112.10,49.14,19.90.MS-ESI m/z:C₁₈H₁₃N₃S:304.1[M+H]⁺。

EXAMPLE 20 Synthesis of Compound WZY-20

The experimental procedure was the same as in example 19, except that evodiamine was used instead of rutaecarpine.

Yield: 45 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:8.56(d,J＝8.1Hz,1H),8.30(s,1H),7.63(d,J＝7.8Hz,1H),7.42-7.49(m,2H),7.29(d,J＝7.5Hz,1H),7.16-7.23(m,2H),7.10(d,J＝8.1Hz,1H),5.75(s,1H),5.56-5.62(m,1H),3.81-3.90(m,1H),3.03-3.09(m,2H),2.45(s,3H).¹³C NMR(100MHz,Chloroform-d)δ:190.71,145.52,136.64,132.85,132.41,127.81,126.40,122.51,121.76,120.05,119.44,118.31,115.45,112.51,111.32,69.71,47.55,35.31,19.62.MS-ESI m/z:C₁₉H₁₇N₃S:320.1[M+H]⁺。

EXAMPLE 21 Synthesis of Compounds WZY-21

The synthesis method of the compound WZY-21 is carried out according to the following reaction formula:

4, 9-dihydro-3H-pyrido (3,4-B) indole (6mmol) and thiosalicylic acid (6mmol) were dissolved in dichloromethane, appropriate amount of EDCI (12mmol) was added and the reaction stirred at ambient temperature for 6 hours. After the reaction, the mixture was extracted with water and dichloromethane, and the organic phases were combined over anhydrous MgSO₄Drying, filtering, spin-drying and purifying by column chromatography to obtain the target compound WZY-22.

Yield: 81 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:8.22(d,J＝8.0Hz,1H),8.10(s,1H),7.59(d,J＝8.0Hz,1H),7.44-7.34(m,2H),7.34(m,2H),7.28-7.26(m,1H),7.19-7.17(m,1H),6.35(s,1H),4.85-4.82(m,1H),3.49-3.47(m,1H),3.04(s,2H).¹³C NMR(100MHz,Chloroform-d)δ:164.83,137.25,136.07,132.58,131.12,129.42,128.25,127.57,126.86,126.04,122.70,119.59,118.96,112.11,110.57,56.82,40.43,20.58.MS-ESI m/z:C₁₈H₁₄N₂OS:307.1[M+H]⁺。

EXAMPLE 22 Synthesis of Compound WZY-22

The experimental procedure was the same as in example 21, substituting salicylic acid for thiosalicylic acid only.

Yield: 81 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:8.00(d,J＝8.0Hz,1H),7.59(d,J＝4.0Hz,1H),7.51-7.43(m,2H),7.25(t,J＝8.0Hz,1H),7.18-7.12(m,2H),7.06(d,J＝8.0Hz,1H),6.47(s,1H),4.90-4.87(m,1H),3.31-3.26(m,1H),3.06-2.94(m,2H)；¹³C NMR(100MHz,Chloroform-d)δ:167.51,160.90,141.28,138.30,132.39,130.80,129.55,127.12,126.84,123.58,122.96,122.27,120.31,116.68,115.64,85.21,43.26,24.06.MS-ESI m/z:C₁₈H₁₄N₂OS:307.1[M+H]⁺。

EXAMPLE 23 Synthesis of Compound WZY-23

The experimental procedure was the same as in example 18, except that evodiamine was used instead of rutaecarpine.

Yield: 61%; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:12.61(s,1H),8.57(d,J＝7.5Hz,1H),8.36-8.21(m,1H),8.12(d,J＝8.0Hz,1H),7.88(d,J＝7.51H),7.12(dd,J＝10.0,7.8Hz,2H),7.61(d,J＝8.3Hz,1H),7.46-7.33(m,2H),7.28(t,J＝7.5Hz,1H),5.77(s,1H),2.51(s,3H).¹³C NMR(100MHz,Chloroform-d)δ:159.01,147.07,140.36,140.32,135.15,129.75,127.24,127.08,126.59,124.93,122.21,121.33,120.95,120.32,118.14,116.41,113.22,108.34,19.91.MS-ESI m/z:C₁₉H₁₅N₃O:3020.1[M+H]⁺。

EXAMPLE 24 Synthesis of Compound WZY-24

The synthesis method of the compound WZY-24 is carried out according to the following reaction formula:

evocarpidine (6mmol) was dissolved in an appropriate amount of acetic acid, and then an excess of zinc powder (30mmol) and a 6N solution of hydrochloric acid (10mL) were added to the reaction, and the reaction was stirred at 60 ℃ for 6 hours. After the reaction was complete, the acetic acid was removed by rotary drying, extracted with water and dichloromethane, the organic phases were combined, anhydrous MgSO₄Drying, filtering, spin-drying and purifying by column chromatography to obtain the target compound WZY-25.

Yield: 52 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:7.54(d,J＝8.4Hz,1H),7.34(d,J＝8.4,1H),7.24-7.22(m,2H),7.18(t,J＝7.6Hz,1H),7.11(t,J＝7.6Hz,1H),7.04(t,J＝7.6Hz,1H),6.98(d,J＝6.8Hz,1H),4.59(s,2H),4.57(t,J＝6.8Hz,2H),3.15(t,J＝6.8Hz,2H).¹³C NMR(100MHz,Chloroform-d)δ:137.81,128.72,125.51,125.43,124.85,123.10,120.01,119.57,116.42,112.31,50.51,49.95,20.22.MS-ESI m/z:C₁₈H₁₅N₃:274.1[M+H]⁺。

EXAMPLE 25 Synthesis of Compounds WZY-25

The experimental procedure was the same as in example 24, except that evodiamine was used instead of rutaecarpine.

Yield: 58 percent; a yellow solid;¹H NMR(400MHz,Chloroform-d)δ:8.24(s,1H),7.55(d,J＝7.5Hz,1H),7.36(d,J＝7.8Hz,1H),7.10-7.23(m,3H),6.99-7.07(m,2H),6.95(d,J＝7.2Hz,1H),4.82(s,1H),4.07(d,J＝14.1Hz,1H),3.86(d,J＝13.1Hz,1H),3.34(m,1H),3.05(m,1H),2.81(m,2H),2.66(s,3H).¹³C NMR(100MHz,Chloroform-d)δ:148.01,136.03,130.42,126.78,126.45,121.84,121.55,119.12,118.12,111.41,110.75,73.61,55.72,50.14,39.12,20.61.MS-ESI m/z:C₁₉H₁₉N₃:290.1[M+H]⁺。

example 27 antifungal Activity of Evodia rutaecarpa analogs WZY-01-WZY-25 test methods and results

1) The test agent evodiamine analog WZY-01-WZY-25.

2) Test strains: rhizoctonia solani, sclerotinia sclerotiorum, fusarium graminearum, botrytis cinerea, fusarium wilt and rice blast.

3) And (3) testing antibacterial activity:

the test method comprises the following steps: the antibacterial activity was measured using potato dextrose agar medium (PDA medium). The preparation method comprises the following steps: firstly, cleaning and peeling potatoes, weighing 200g of potatoes, cutting the potatoes into small pieces, adding water, boiling the potatoes thoroughly (boiling for 20-30 minutes, the potato pieces can be punctured by a glass rod), filtering the potatoes by eight layers of gauze, heating the potatoes, adding 15g of agar, continuously heating, stirring the mixture evenly, adding glucose after the agar is dissolved, stirring the mixture evenly, slightly cooling the mixture, then supplementing the water to 1000 ml, subpackaging the mixture in conical bottles, plugging and binding the conical bottles, and sterilizing the mixture for 2 hours at 115 ℃ for later use. Respectively dissolving compounds WZY-01-WZY-25 in DMSO, adding the DMSO solutions into a culture medium, uniformly mixing to ensure that the concentrations of the compounds in the culture medium are respectively 100 mu g/mL or 50 mu g/mL, taking DMSO with equal concentration as a blank control, and taking the azoxystrobin which is a commercial drug as a positive control. And (3) pouring the plates, cooling, inoculating bacteria respectively, culturing in an incubator at 23 ℃, and determining the bacteriostasis rate of each compound by taking blank control hypha to overgrow the culture dish as a limit. All experiments were performed in triplicate or in triplicate. The calculation of the bacteriostasis rate is carried out according to the following calculation formula:

the bacteriostasis rate is (blank control hypha growth diameter-hypha growth diameter)/(blank control hypha growth diameter-fungus cake diameter) x 100%

The results of the activity test of the evodiamine analog WZY-01-WZY-25 on 6 plant pathogenic fungi are shown in Table 1.

TABLE 1 Evodia rutaecarpa alkali analog WZY-01-WZY-25 inhibition ratio to pathogenic fungi (%)

As can be seen from Table 1, the compounds have certain inhibition effect on 6 plant fungal diseases, wherein the compounds WZY-01 and WZY-09 have good antibacterial activity and broad spectrum, and the inhibition rate of the compounds WZY-01 and WZY-09 on various plant pathogenic fungi is more than 50% at the concentration of 50ppm, so that the compounds WZY-01 and WZY-09 are further subjected to activity tests, and the test results are shown in Table 2.

TABLE 2 Activity test results of Compounds WZY-01 and WZY-09 against 6 phytopathogenic fungi

As can be seen from Table 2, compounds WZY-01 and WZY-09 both have better inhibitory effects on 6 plant fungi, especially compound WZY-01 has EC against Rhizoctonia solani and Sclerotium sclerotiorum₅₀2.179 μ g/mL and 2.869 μ g/mL, respectively, showed good antifungal activity. The compound has simple synthesis method and cheap and easily obtained raw materials, and is expected to be developed into a novel antibacterial agent for plant pathogenic fungi.