Alkaloid barakacin derivatives, synthesis thereof and use thereof for the control of plant virus and bacterial diseases

Abstract

The application relates to alkaloid barakacin derivatives I-1 to I-23, a preparation method thereof and application of the alkaloid barakacin derivatives I-1 to I-23 in preventing and treating plant virus and bacterial diseases. The application develops a high-efficiency synthesis method of alkaloid barakacin derivatives, lays a foundation for synthesis and biological activity research of alkaloid barakacin and derivatives thereof. The alkaloid barakacin derivatives I-1 to I-23 have the activity of resisting plant viruses, can inhibit tobacco mosaic virus, and meanwhile, the compounds have the broad-spectrum activity of resisting plant bacteria.

Description

Technical Field

[0001] This invention relates to alkaloid barakacin derivatives, their preparation, and their application in the prevention and control of plant viral and bacterial diseases, belonging to the field of agricultural protection technology. Background Technology

[0002] Crop diseases and pests have long been a major natural disaster affecting crops in my country. Once an outbreak occurs, its impact is widespread and significant, with numerous types of diseases and pests severely impacting the national economy and grain production. In some areas, there are even hundreds of species of diseases and pests, affecting millions of hectares each time. If pests and pests are not effectively controlled during the crop growth process, the loss rate of agricultural products can reach 30% or even 100%. Currently, many parts of China rely heavily on chemical pesticide spraying for crop disease and pest control. While this method is effective in the short term, long-term use of chemical pesticides seriously harms the agricultural ecosystem, leading to increased pesticide resistance in pests and even impacting rivers and drinking water, exacerbating rural ecological pollution. Therefore, there is an urgent need to find environmentally friendly and effective biopesticides. Biopesticide development involves various approaches, including random screening, analogue synthesis, natural product models, and biorhythmic design, with natural product models attracting the most attention.

[0003] Barakacin is a novel thiazole indole alkaloid characterized by a bisindole skeleton. It was first isolated from the bovine rumen bacterium *Pseudomonas aeruginosa* strain ZIO by the Zendah research group at the University of Ottingen, Germany (Z. Naturforsch. 2012, 67, 417-420.). To date, no applications of this compound or its derivatives in combating plant viral pathogens have been found.

[0004]

[0005] Structural Formula 1 Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides a barakacin alkaloid derivative, its preparation method, and its application in the prevention and control of plant viral and fungal diseases. The barakacin derivative of this patent exhibits excellent antiviral and antifungal activity against plant viruses and pathogens.

[0007] The alkaloid barakacin derivative I of the present invention is the compound shown in I-1 to I-23 below (structural formula II).

[0008]

[0009] Structural Form 2

[0010] The preparation method of I-1 to I-23 in claims 1:

[0011] Synthesis of barakacin derivative I-1: Prepared according to the method shown in Equation 1: First, using acetone as solvent and potassium carbonate as catalyst, iodomethane was added to o-hydroxybenzonitrile (1) and stirred at room temperature for 12 hours to generate 2-methoxybenzonitrile (2). Then, using N,N-dimethylformamide as solvent, sodium hydrosulfide and magnesium chloride hexahydrate were added and stirred at 40°C for 6 hours. After quenching with hydrochloric acid, 2-methoxybenzylthioamide (3) was obtained. Then, using ethanol as solvent, ethyl bromopyruvate was slowly added dropwise at 0°C. The mixture was then transferred to a 90°C oil bath and stirred for 3 hours to obtain 2-(2-methoxyphenyl)thiazole-4- Ethyl carboxylate (4), then with tetrahydrofuran as solvent, lithium aluminum hydride was slowly added to it, and the compound (4) dissolved in tetrahydrofuran was slowly added dropwise to the mixture and stirred at room temperature for 2.5 hours. After water quenching, (2-(2-methoxyphenyl)thiazol-4-yl)methanol (5) was obtained. Then, with dichloromethane as solvent, pyridine chlorochromate (PCC) was added and stirred at room temperature for 4 hours to obtain 2-(2-methoxyphenyl)thiazol-4-carboxaldehyde (6). Finally, with acetonitrile as solvent and iodine as catalyst, indole was added to obtain 4-(di(1H-indole-3-yl)methyl)-2-(2-methoxyphenyl)thiazolium (I-1);

[0012]

[0013] Equation 1

[0014] Synthesis of Barakacin derivatives I-2 to I-6: Prepared according to the method shown in Equation 2: First, using N,N-dimethylformamide as a solvent, sodium hydride was slowly added to the reaction solution containing I-1 at 0°C and stirred for 1 hour. Then, the corresponding halogenated derivative was added, and stirring continued for 12–24 hours. After quenching with ice water, I-2 to I-6 were obtained, where R... 1 These are the groups shown in the structures of compounds I-2 to I-6;

[0015]

[0016] Equation 2

[0017] Synthesis of Barakacin derivatives I-7 to I-8: Prepared according to the method shown in Equation 3: First, using dichloromethane as solvent, under argon protection, boron tribromide was slowly added dropwise to the reaction solution containing I-1 at -78℃, and then stirred at room temperature for 12 hours to obtain 2-(4-(bis(1H-indol-3-yl)methyl)thiazol-2-yl)phenol (7). Then, using N,N-dimethylformamide as solvent and potassium carbonate as catalyst, the corresponding halogens were added to obtain 4-(bis(1H-indol-3-yl)methyl)-2-(2-(prop-2-yn-1-propoxy)phenyl)thiazole (I-7) and 2-(2-(benzyloxy)phenyl)-4-(bis(1H-indol-3-yl)methyl)thiazole (I-8), where R is the group shown in the structure of compounds I-7 to I-8;

[0018]

[0019] Equation 3

[0020] Synthesis of Barakacin derivatives I-9 to I-12: Prepared according to the method shown in Equation 4: First, using ethanol as solvent, ethyl bromopyruvate was slowly added dropwise to benzyl thioamide (8) at 0°C, and then stirred in an oil bath at 90°C for 2 hours to obtain ethyl 2-phenylthiazol-4-carboxylate (9). Then, using tetrahydrofuran as solvent, lithium aluminum hydride was slowly added to it, and the compound (9) dissolved in tetrahydrofuran was slowly added dropwise to the mixture and stirred at room temperature for 4 hours. After water quenching reaction, (2-phenylthiazol-4-yl)methanol (10) was obtained. Then, using dichloromethane as solvent, pyridine chlorochromate was added. (PCC) After stirring at room temperature for 4 hours, 2-phenylthiazol-4-carboxaldehyde (11) was obtained. Finally, using acetonitrile as solvent and iodine as catalyst, the corresponding indole or monosubstituted indole was added to obtain 4-(di(1H-indol-3-yl)methyl)-2-phenylthiazolium (I-9), 4-(bis(5-methoxy-1H-indol-3-yl)methyl)-2-phenylthiazolium (I-10), 4-(bis(5-bromo-1H-indol-3-yl)methyl)-2-phenylthiazolium (I-11), and 4-(bis(6-bromo-1H-indol-3-yl)methyl)-2-phenylthiazolium (I-12), where R 2 R 3 The groups shown in the structures of compounds I-9 to I-12;

[0021]

[0022] Equation 4

[0023] Synthesis of Barakacin derivatives I-13 to I-19: Prepared according to the method shown in Equation 5: Using glacial acetic acid as solvent, add the corresponding aldehydes 12 to 18 and indole and stir at room temperature for 16 hours to obtain I-13 to I-19, where R is the group shown in the structure of compounds I-13 to I-19.

[0024]

[0025] Equation 5

[0026] Synthesis of Barakacin derivative I-20: Prepared according to the method shown in Equation 6: First, indole and sodium hydride were stirred at room temperature for 0.5 hours in tetrahydrofuran as solvent, followed by the addition of iodomethane and stirring for another 4.5 hours to obtain 1-methyl-1H-indole (19). Then, 1H-benzo[d]imidazol-2-carboxaldehyde (14) was added in glacial acetic acid as solvent and stirred at room temperature for 16 hours to obtain 2-(bis(1-methyl-1H-indole-3-yl)methyl)-1H-benzo[d]imidazolium (I-20);

[0027]

[0028] Equation 6

[0029] Synthesis of Barakacin derivative I-21: Prepared according to the method shown in Equation 7: First, I-20 and sodium hydride were added to N,N-dimethylformamide as solvent and stirred at room temperature for 0.5 hours. Then, iodomethane was added and stirring was continued for 16 hours to obtain 2-(bis(1-methyl-1H-indol-3-yl)methyl)-1-methyl-1H-benzo[d]imidazolium (I-21);

[0030]

[0031] Equation 7

[0032] Synthesis of Barakacin derivatives I-22 to I-23: prepared according to the method shown in Equation 8: first, using tetrahydrofuran as solvent, I-20 and sodium hydride were added and stirred at room temperature for 0.5 hours, then the corresponding halogenated product was added and stirred for another 16 hours to obtain I-22 to I-23.

[0033]

[0034] Equation 8

[0035] The barakacin derivatives I-1 to I-23 of the present invention exhibit excellent antiviral and antifungal activity against plant viruses and pathogens, and can effectively inhibit seven plant pathogens, including tobacco mosaic virus (TMV), cucumber wilt, apple ring rot, wheat sheath blight, tomato early blight, rice blast, pepper phytosis, and rapeseed sclerotium. Detailed Implementation

[0036] The following examples and test results are intended to further illustrate the present invention, but do not imply limitation of the invention.

[0037] Example 1: Synthesis of barakacin derivative I-1

[0038] Step 1: Synthesis of compound 2-methoxybenzonitrile (2): o-hydroxybenzonitrile (1) (2 g, 16.8 mmol), potassium carbonate (2.32 g, 16.8 mmol), and iodomethane (2.38 mL, 7.55 mmol) were added to a 250 mL round-bottom flask. 100 mL of acetone was added, and the mixture was stirred at room temperature until the color of the solution in the flask became lighter. After the reaction was monitored by TLC, the solvent was removed, an appropriate amount of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate and the solvent was removed to obtain 2.13 g of a light yellow buttery liquid, with a yield of 95%. 1 HNMR (400MHz, CDCl3) δ7.54 (ddd, J=7.4, 4.4, 2.6Hz, 2H), 7.00 (ddd, J=12.2, 6.5, 2.7Hz, 2H), 3.93 (s, 3H). 13 C NMR (100MHz, CDCl3) δ161.2, 134.5, 133.7, 120.8, 116.6, 111.4, 101.6, 56.0.

[0039] Step 2: Synthesis of compound 2-methoxybenzylthionamide (3): 70% sodium hydrosulfide (1.5 g, 26.3 mmol) and magnesium chloride hexahydrate (2.67 g, 13.15 mmol) were added to 20 mL of DMF. Compound (2) (1 g, 7.51 mmol) dissolved in 10 mL of DMF was added dropwise under vigorous stirring. The mixture was stirred at 40 °C for 6 h. The reaction was monitored by TLC to ensure complete reaction. Part of the solvent was removed, and 100 mL of 1 M hydrochloric acid was added. The mixture was stirred for 0.5 h. The reaction solution was extracted with ethyl acetate (30 mL × 3), the organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed to obtain 3.82 g of a reddish-brown solid, yield 87%. Melting point: 139-141 °C. 1 H NMR (400MHz, CDCl3) δ9.05 (s, 1H), 8.63 (dd, J=8.0, 1.8Hz, 1H), 8.18 (s, 1H), 7.47 (ddd, J=8.4, 7.3, 1.8Hz, 1H), 7.20-6.87 (m, 2H), 3.97 (s, 3H). 13C NMR (100MHz, CDCl3) δ199.2, 156.3, 136.4, 133.7, 124.9, 121.3, 111.5, 56.1.

[0040] Step 3: Synthesis of compound 2-(2-methoxyphenyl)thiazole-4-carboxylic acid ethyl ester (4): Compound (3) (2 g, 12 mmol) was dissolved in 200 mL of ethanol. Ethyl 3-bromo-2-oxopropionate (3.5 g, 18 mmol) was gradually added dropwise to the system while stirring at 0 °C. After the addition was complete, the ice bath was removed, and the reaction system was heated to 90 °C under reflux. After TLC monitoring to confirm the completeness of the reaction, the solvent was evaporated under reduced pressure to obtain 2.91 g of a pale yellow solid, with a yield of 92%. Melting point: 137-139 °C. 1 H NMR (400MHz, CDCl3) δ8.45 (dd, J=7.9, 1.7Hz, 1H), 8.13 (s, 1H), 7.50-7.27 (m, 1H ), 7.09-6.86 (m, 2H), 4.37 (q, J=7.1Hz, 2H), 3.96 (s, 3H), 1.36 (t, J=7.1Hz, 3H). 13 C NMR (100MHz, CDCl3) δ163.0, 162.0, 156.5, 146.0, 131.4, 129.1, 127.9, 121.5, 121.1, 111.2, 61.3, 55.6, 14.4.

[0041] Step 4: Synthesis of compound (2-(2-methoxyphenyl)thiazol-4-yl)methanol (5): Lithium aluminum hydride (0.28 g, 7.6 mmol) was dissolved in 20 mL of tetrahydrofuran and slowly added dropwise to tetrahydrofuran containing compound (4) (2 g, 7.6 mmol) under stirring at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and dissolved to obtain 1.43 g of yellow solid, with a yield of 85%. Melting point: 116-118 °C. 1 H NMR (400MHz, CDCl3) δ8.40 (dd, J=7.8, 1.7Hz, 1H), 7.54-7.35 (m, 1H), 7.39 (s, 1H), 7.19-6.99 (m, 2H), 4.86 (s, 2H), 4.04 (s, 3H), 2.95 (s, 1H). 13 C NMR (100MHz, CDCl3) δ162.9, 156.4, 154.9, 130.9, 128.4, 121.9, 121.1, 115.5, 111.4, 61.1, 55.6.

[0042] Step 5: Synthesis of 2-(2-methoxyphenyl)thiazole-4-carboxaldehyde (6): Pyridinium chlorochromate (PCC) (2.92 g, 13.6 mmol) was dissolved in 90 mL of dichloromethane. Compound (5) (2 g, 9 mmol) dissolved in 40 mL of dichloromethane was added dropwise to the reaction system at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 4 h. After the reaction was complete, the mixture was washed with 10% hydrochloric acid (30 mL × 2) and extracted with ethyl acetate (50 mL × 3). The organic layer was washed successively with saturated brine and water, dried with anhydrous sodium sulfate, and dissolved to obtain 2.42 g of white solid, yield 81%. Melting point: 81-83 °C. 1 H NMR (400MHz, CDCl3) δ10.14 (s, 1H), 8.49 (dd, J=7.9, 1.7Hz, 1H), 8.22 (s, 1H), 7.63-7.44 (m, 1H), 7.11 (ddd, J=22.3, 14.6, 4.7Hz, 2H), 4.06 (s, 3H). 13 C NMR (100MHz, CDCl3) δ185.4, 163.7, 156.6, 153.7, 131.7, 128.8, 128.0, 121.3, 111.4, 77.3, 77.0, 76.7, 55.6.

[0043] Step 6: Synthesis of 4-(bis(1H-indol-3-yl)methyl)-2-(2-methoxyphenyl)thiazole (I-1): Indole (0.94 g, 8 mmol), iodine (0.25 g, 1 mmol), and compound (6) (0.44 g, 2 mmol) were added to 90 mL of acetonitrile. After stirring at room temperature for 30 min, 40 mL of 5% sodium thiosulfate solution was added and stirring was continued for 15 min. After the reaction was completed, the mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and dissolved to obtain the crude product. Finally, column chromatography (PE:EA = 5:1) was performed to obtain 0.62 g of a pale yellow solid, yield 71%. Melting point: 210-212 °C. 1 H NMR (400MHz, DMSO-d6) δ10.82 (d, J=1.8Hz, 2H), 8.24 (dd, J=7.9, 1.7Hz, 1H), 7.45 (d, J=8.2Hz, 2H), 7.44-7.40 (m, 1H), 7.33 (d , J=8.1Hz, 2H), 7.29 (s, 1H), 7.22 (d, J=8.0Hz, 1H), 7.09-7.00 (m, 5H), 6.88 (dd, J=11.0, 3.9Hz, 2H), 6.07 (s, 1H), 3.99 (s, 3H). 13C NMR (100MHz, DMSO-d6) δ160.7, 159.2, 156.4, 136.9, 131.2, 128.1, 127.0, 124.0, 12 2.1, 121.3, 119.6, 118.5, 117.5, 116.5, 112.7, 111.9, 56.3, 36.9.HRMS(ESI)calcd for C 27 H 22 N3OS[M+H] + 436.1478, found 436.1472.

[0044] Example 2: Synthesis of barakacin derivative I-2

[0045] Compound I-1 (1 g, 2.3 mmol) was added to a round-bottom flask, followed by 10 mL of DMF. Sodium hydride (0.17 g, 6.9 mmol) was slowly added at 0 °C, and the mixture was stirred in an ice bath for 1 h. Iodomethane (1.3 g, 9.2 mmol) was then slowly added, and the mixture was brought to room temperature and stirred for another 24 h. After the reaction was complete, cold water was added to quench the reaction, resulting in the precipitation of a solid. The crude product was obtained by filtration. Separation by column chromatography (PE:EA = 2:1) yielded 0.80 g of a light red solid, with a yield of 75%. Melting point: 272-274 °C. 1 H NMR (400MHz, DMSO-d6) δ8.35-8.25 (m, 1H), 7.53 (d, J=7.9Hz, 2H), 7.50-7.46 (m, 1H), 7.43 (d, J=8.2Hz, 2H), 7.37 (s, 1H), 7.28 (d, J=4.7Hz , 1H), 7.15 (dd, J=14.3, 7.1Hz, 3H), 7.08 (s, 2H), 6.99 (t, J=7.5Hz, 2H), 6.14 (s, 1H), 4.04 (s, 3H), 3.77 (s, 6H)., 4.04 (s, 3H), 3.77 (s, 6H). 13 CNMR (100MHz, DMSO-d6) δ160.9, 159.0, 156.5, 137.3, 131.2, 128.2, 127.3, 122.1, 1 21.4, 119.7, 118.8, 116.8, 116.5, 112.7, 110.1, 56.3, 36.6, 32.8.HRMS(ESI)calcd forC 29 H 26 N3OS[M+H] + 464.1791, found 464.1798

[0046] Example 3: Synthesis of barakacin derivative I-3

[0047] Compound I-1 (1 g, 2.3 mmol) was added to a round-bottom flask, followed by 10 mL of DMF. Sodium hydride (0.17 g, 6.9 mmol) was slowly added at 0 °C, and the mixture was stirred in an ice bath for 1 h. Benzyl bromide (1.6 g, 9.2 mmol) was then slowly added, and the mixture was brought to room temperature and stirred for another 24 h. After the reaction was complete, cold water was added to quench the reaction, resulting in the precipitation of a solid. The crude product was obtained by filtration. Separation by column chromatography (PE:EA = 2:1) yielded 0.68 g of a yellow solid, with a yield of 48%. Melting point: 170-172 °C. 1 H NMR (400MHz, DMSO-d6) δ8.22 (dd, J=7.8, 1.7Hz, 1H), 7.49 (d, J=7.9Hz, 2H), 7.46-7.40 (m, 1H), 7.36 (d, J=8.2Hz, 2H), 7.31 (s, 1H), 7.28-7.18 (m, 9H), 7.15-7.10 (m, 4H), 7.05 (dt, J=14.4, 7.2Hz, 3H), 6.91 (t, J=7.5Hz, 2H), 6.12 (s, 1H), 5.37 (s, 4H), 3.98 (s, 3H). 13 C NMR (100MHz, DMSO-d6) δ160.5, 158.1, 156.0, 138.5, 136.3, 130.7, 128.4, 127.6, 127.2, 126.8, 1 21.7, 121.1, 120.8, 119.6, 118.5, 116.8, 116.1, 112.2, 110.1, 55.8, 48.8, 36.4.HRMS(ESI)calcd forC 41 H 34 N3OS[M+H] + 616.2417, found 616.2413.

[0048] Example 4: Synthesis of the alkaloid barakacin derivative I-4

[0049] Compound I-1 (1 g, 2.3 mmol) was added to a round-bottom flask, followed by 10 mL of DMF. Sodium hydride (0.17 g, 6.9 mmol) was slowly added at 0 °C, and the mixture was stirred in an ice bath for 1 h. Then, p-toluenesulfonyl chloride (1.8 g, 9.2 mmol) was slowly added, and the mixture was brought to room temperature and stirred for another 24 h. After the reaction was complete, cold water was added to quench the reaction, resulting in the precipitation of a solid. The crude product was obtained by filtration. Separation by column chromatography (PE:EA = 2:1) yielded 0.87 g of a pale yellow solid, with a yield of 51% and a melting point of 164-166 °C.1 H NMR (400MHz, CDCl3) δ8.98 (d, J=7.8Hz, 1H), 7.97 (d, J=8.3Hz, 2H), 7.65-7.51 (m, 5H), 7.36-7.27 (m, 5H ), 7.25-7.21(m, 1H), 7.17(d, J=8.0Hz, 6H), 7.13-7.07(m, 3H), 7.05(s, 1H), 4.09(s, 3H), 2.34(s, 6H). 13 C NMR (100MHz, DMSO-d6) δ161.3, 156.1, 154.1, 145.4, 134.8, 133.8, 131.1, 130.9, 130.2, 129.6, 127.3, 126. 5, 124.9, 123.6, 123.3, 121.5-121.4, 121.2, 120.5, 117.6, 113.4, 112.4, 55.9, 35.5, 21.0.HRMS(ESI)calcd for C 41 H 34 N3O5S3[M+H] + 744.1655, found 744.1658.

[0050] Example 5: Synthesis of barakacin derivative I-5

[0051] Compound I-1 (1 g, 2.3 mmol) was added to a round-bottom flask, followed by 10 mL of DMF. Sodium hydride (0.17 g, 6.9 mmol) was slowly added at 0 °C, and the mixture was stirred in an ice bath for 1 h. Benzoyl chloride (1.3 g, 9.2 mmol) was then slowly added, and the mixture was brought to room temperature and stirred for another 24 h. After the reaction was complete, cold water was added to quench the reaction, resulting in the precipitation of a solid. The crude product was obtained by filtration. Separation by column chromatography (PE:EA = 2:1) yielded 0.62 g of a light red solid, with a yield of 42% and a melting point of 165-166 °C. 1 H NMR (400MHz, DMSO-d6) δ8.24 (d, J=8.0Hz, 2H), 8.04 (d, J=6.7Hz, 1H), 7.75 (d, J=7.6Hz, 2H), 7.66 (dd, J=16.6, 7.7Hz, 6H), 7.60 (s, 1H), 7.54-7.43 (m, 5H), 7.40-7.27 (m, 6H), 7.22 (d, J=8.3Hz, 1H), 7.10 (t, J=7.5Hz, 1H), 6.19 (s, 1H), 3.96 (s, 3H). 13C NMR (100MHz, DMSO-d6) δ168.5, 168.2, 167.9, 161.1, 156.0, 154.7, 136.8, 135.8, 134.0, 132.0, 131.0, 129.6, 128.9, 128.5, 127.3, 126.2, 124.8, 123 .6, 122.6, 122.0, 120.9, 120.6, 120.1, 117.4, 115.8, 113.5, 113.0, 112.2 ,55.8,54.9,51.7,50.9,48.6,35.1,32.4,30.3,26.4.HRMS(ESI)calcdfor C 41 H 30 N3O3S[M+H] + 644.2002, found 644.2004.

[0052] Example 6: Synthesis of barakacin derivative I-6

[0053] Compound I-1 (1 g, 2.3 mmol) was added to a round-bottom flask, followed by 10 mL of DMF. Sodium hydride (0.17 g, 6.9 mmol) was slowly added at 0 °C, and the mixture was stirred in an ice bath for 1 h. Ethylsulfonyl chloride (1.2 g, 9.2 mmol) was then slowly added, and the mixture was brought to room temperature and stirred for another 24 h. After the reaction was complete, cold water was added to quench the reaction, resulting in the precipitation of a solid. The crude product was obtained by filtration. Separation by column chromatography (PE:EA = 2:1) yielded 0.71 g of a yellow solid, with a yield of 50%. Melting point: 165-166 °C. 1 H NMR (400MHz, DMSO-d6) δ8.20 (dd, J=7.8, 1.6Hz, 1H), 7.82 (d, J=8.3Hz, 2H), 7.67 (d , J=7.8Hz, 2H), 7.54 (s, 1H), 7.49-7.41 (m, 1H), 7.39-7.30 (m, 4H), 7.25 (dd, J=8.3, 5.9Hz, 3H), 7.08 (t, J=7.6Hz, 1H), 6.25 (s, 1H), 4.00 (s, 3H), 3.58 (q, J=7.3Hz, 4H) , 1.00 (t, J=7.3Hz, 6H)., 4.00 (s, 3H), 3.58 (q, J=7.3Hz, 4H), 1.00 (t, J=7.3Hz, 6H). 13C NMR (100MHz, DMSO-d6) δ161.2, 156.1, 154.6, 135.0, 131.1, 129.2, 127.3, 125.1, 124.7, 1 22.9, 121.6, 121.3, 120.9, 120.5, 117.5, 113.1, 112.3, 55.9, 48.0, 35.4.HRMS(ESI)calcd for C 31 H 30 N3O5S3[M+H] + 620.1342, found 620.1347.

[0054] Example 7: Synthesis of barakacin derivative I-7

[0055] Step 1: Synthesis of 2-(4-(bis(1H-indol-3-yl)methyl)thiazolyl-2-yl)phenol (7): Compound I-1 (1 g, 2.3 mmol) was dissolved in dichloromethane. Under argon protection, a 1 M boron tribromide solution in dichloromethane (28 mL, 27.6 mmol) was gradually added dropwise at -78 °C. The reaction was stirred overnight at room temperature. After the reaction was complete, the solvent was removed, an appropriate amount of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then separated by column chromatography (PE:EA = 2:1) to obtain 0.68 g of red solid, yield 70%. Melting point: 118-120 °C. 1 H NMR (400MHz, DMSO-d6) δ11.71 (s, 1H), 10.87 (s, 2H), 8.00-7.79 (m, 1H), 7.42 (dd, J=24.7, 5 .9Hz, 2H), 7.43-7.22(m, 4H), 7.15-6.98(m, 4H), 6.99-6.84(m, 4H), 6.09(d, J=11.8Hz, 1H). 13 C NMR (100MHz, DMSO-d6) δ165.0, 158.3, 155.4, 136.4, 131.1, 127.2, 126.5, 123.4 ,120.9,119.5,119.0,118.3,116.8,116.5,114.6,111.5,36.1.HRMS(ESI)calcd for C 26 H 18 N3OS[MH] - 420.1176, found 420.1179.

[0056] Step 2: Synthesis of 4-(bis(1H-indol-3-yl)methyl)-2-(2-(prop-2-yn-1-propoxy)phenyl)thiazole (I-7): Compound 7 (0.5 g, 1.19 mmol), potassium carbonate (0.33 g, 2.37 mmol), and 10 mL of N,N-dimethylformamide were added to a round-bottom flask. Then, 3-bromo-propyne (0.28 g, 2.37 mmol) was added, and the mixture was heated to 120 °C and stirred for 12 hours. After the reaction was complete, cold water was added to quench the reaction, and a solid precipitated. The solid was filtered to obtain the crude product. Separation by column chromatography (PE:EA = 2:1) yielded 0.19 g of a reddish-brown solid, with a yield of 35%. Melting point: 272-274 °C. 1 H NMR (400MHz, DMSO-d6) δ10.84 (s, 2H), 8.26 (dd, J=7.8, 1.5Hz, 1H), 7.47 (d, J=7.9Hz, 2H), 7.44-7.41 (m, 1H), 7.34 (d, J=8.7Hz, 3H), 7.28 (d, J=8 .5Hz, 1H), 7.11 (t, J=7.6Hz, 1H), 7.04 (dd, J=9.8, 5.0Hz, 4H), 6.89 (t, J=7.5Hz, 2H), 6.08 (s, 1H), 5.06 (d, J=2.3Hz, 2H), 3.64 (t, J=2.3Hz, 1H). 13 CNMR (100MHz, DMSO-d6) δ167.5, 160.5, 159.2, 154.4, 136.9, 132.0, 129.1, 127.0, 124.0, 12 1.3, 119.6, 118.6, 117.5, 111.9, 79.2, 65.5, 60.2, 56.7, 30.5, 19.1, 14.0.HRMS(ESI)calcd for C 29 H 22 N3OS[M+H] + 460.1478, found 460.1485.

[0057] Example 8: Synthesis of barakacin derivative I-8

[0058] Compound 7 (0.5 g, 1.19 mmol), potassium carbonate (0.33 g, 2.37 mmol), and 10 mL of N,N-dimethylformamide were added to a round-bottom flask. Then, benzyl bromide (0.41 g, 2.37 mmol) was added, and the mixture was heated to 120 °C and stirred for 12 hours. After the reaction was complete, cold water was added to quench the reaction, and a solid precipitated. The solid was filtered to obtain the crude product. Separation by column chromatography (PE:EA = 2:1) yielded 0.24 g of a pale yellow solid, with a yield of 40%. Melting point: 150-152 °C. 1 H NMR (400MHz, DMSO-d6) δ10.83 (s, 2H), 8.30-8.24 (m, 1H), 7.54 (d, J = 7.2Hz, 2H), 7.46 (d, J = 7.9Hz, 2H), 7.39 (t, J=7.3Hz, 3H), 7.32 (dd, J=13.0, 7.9Hz, 5H), 7.09-6.99 (m, 5H), 6.88 (t, J=7.5Hz, 2H), 6.06 (s, 1H), 5.37 (s, 2H). 13 C NMR (100MHz, DMSO-d6) δ169.5, 157.3, 154.0, 136.7, 136.5, 129.7, 128.9, 128.5, 127.6, 127.4, 127.1 ,123.0,122.1,121.7,121.5,119.8,118.8,116.6,115.6,112.1,111.1,71.1,53.6.HRMS(ESI)calcd for C 33 H 26 N3OS[M+H] + 512.1791, found 512.1797.

[0059] Example 9: Synthesis of barakacin derivative I-9

[0060] Step 1: Synthesis of ethyl 2-phenylthiazolium-4-carboxylate (9): Benzothiamide (8) (2 g, 14.6 mmol) was dissolved in 200 mL of ethanol. Ethyl 3-bromo-2-oxopropionate (5.25 g, 21.9 mmol) was gradually added dropwise to the system while stirring at 0 °C. After the addition was complete, the ice bath was removed, and the reaction system was heated to 90 °C under reflux. After TLC monitoring to confirm the completeness of the reaction, the solvent was evaporated under reduced pressure to obtain 2.89 g of a yellow solid, with a yield of 85%. 1H NMR (400MHz, CDCl3) δ8.16 (s, 1H), 8.06-7.98 (m, 2H), 7.52-7.42 (m, 3H), 4.45 (q, J=7.1Hz, 2H), 1.44 (t, J=7.1Hz, 3H). 13 C NMR (100MHz, CDCl3) δ168.8, 161.4, 148.0, 132.7, 130.7, 128.9, 127.1, 126.9, 61.4, 14.4.

[0061] Step 2: Synthesis of (2-phenylthiazol-4-yl)methanol (10): Lithium aluminum hydride (0.32 g, 8.6 mmol) was dissolved in 20 mL of tetrahydrofuran and slowly added dropwise to tetrahydrofuran containing compound 9 (2 g, 8.6 mmol) under stirring at 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and dissolved to obtain 1.46 g of a light yellow solid, with a yield of 90%. 1 H NMR (400MHz, DMSO-d6) δ7.96-7.89 (m, 2H), 7.56-7.44 (m, 4H), 5.40 (t, J=5.7Hz, 1H), 4.63 (dd, J=5.7, 0.9Hz, 2H). 13 C NMR (100MHz, DMSO-d6) δ166.8, 159.0, 133.2, 130.1, 129.2, 126.0, 114.9, 59.8.

[0062] Step 3: Synthesis of 2-phenylthiazol-4-carboxaldehyde (11): Pyridinium chlorochromate (PCC) (2.92 g, 13.6 mmol) was dissolved in 90 mL of dichloromethane. Compound 10 (1.7 g, 9 mmol) dissolved in 40 mL of dichloromethane was added dropwise to the reaction system at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 4 h. After the reaction was completed, the mixture was washed with 10% hydrochloric acid (30 mL × 2) and extracted with ethyl acetate (50 mL × 3). The organic layer was washed successively with saturated brine and water, dried with anhydrous sodium sulfate, and dissolved to obtain 1.58 g of reddish-brown solid, with a yield of 81%. 1 H NMR (400MHz, DMSO-d6) δ10.01 (s, 1H), 8.79 (s, 1H), 8.07-7.97 (m, 2H), 7.60-7.52 (m, 3H). 13 C NMR (100MHz, DMSO-d6) δ185.0, 168.6, 155.2, 132.2, 131.8, 131.0, 129.4, 126.6.

[0063] Step 4: Synthesis of 4-(bis(1H-indol-3-yl)methyl)-2-phenylthiazole (I-9): Compound 11 (1 g, 5.28 mmol) and indole (1.24 g, 10.56 mmol) were added to a round-bottom flask, followed by 50 mL of acetonitrile. After stirring at room temperature for 30 min, iodine (0.67 g, 5.28 mmol) was added to the flask. Stirring was continued for another 30 min. After the reaction was complete as monitored by TLC, sodium thiosulfate solution was added to the flask and stirred for 15 min to quench the reaction. After the reaction was complete, the solvent was removed, and the solution was extracted with ethyl acetate (50 mL × 3). The solution was concentrated under vacuum and recrystallized with dichloromethane and petroleum ether as solvents to give 1.93 g of a reddish-brown solid, with a yield of 91%. Melting point: 226-228 °C. 1 H NMR (400MHz, DMSO-d6) δ10.84 (s, 2H), 7.94-7.86 (m, 2H), 7.52-7.42 (m, 5H), 7.35 (d , J=8.1Hz, 2H), 7.29 (s, 1H), 7.09-7.00 (m, 4H), 6.90 (t, J=7.4Hz, 2H), 6.08 (s, 1H). 13 C NMR (100MHz, DMSO-d6) δ166.2, 160.7, 136.4, 133.3, 130.0, 129.2, 126.5, 126 .0, 123.5, 120.8, 119.1, 118.2, 116.7, 115.2, 111.5, 36.5.HRMS (ESI): Cacld forC 26 H 20 N3S[M+H] + 406.1372, found 406.1377.

[0064] Example 10: Synthesis of barakacin derivative I-10

[0065] Compound 11 (1 g, 5.28 mmol) and 5-methoxyindole (1.55 g, 10.56 mmol) were added to a round-bottom flask, followed by 50 mL of acetonitrile. After stirring at room temperature for 30 min, iodine (0.67 g, 5.28 mmol) was added to the flask. Stirring continued for another 30 min. After the reaction was complete (monitored by TLC), sodium thiosulfate solution was added to the flask, and the reaction was quenched by stirring for 15 min. After the reaction was complete, the solvent was removed, and the solution was extracted with ethyl acetate (50 mL × 3). The solution was then concentrated under vacuum and recrystallized using dichloromethane and petroleum ether as solvents to give 2.34 g of a brown solid, with a yield of 95%. Melting point: 192–194 °C. 1H NMR (400MHz, DMSO-d6) δ10.71 (d, J=2.0Hz, 2H), 7.97-7.89 (m, 2H), 7.51-7.42 (m, 3H), 7.36 (s, 1H), 7.25 (d, J=8 .7Hz, 2H), 7.08 (d, J=2.3Hz, 2H), 6.99 (d, J=2.4Hz, 2H), 6.71 (dd, J=8.7, 2.4Hz, 2H), 6.01 (s, 1H), 3.65 (s, 6H). 13 C NMR (100MHz, DMSO-d6) δ166.7, 161.2, 153.2, 133.8, 132.1, 130.5, 129.6, 127.3 ,126.4,124.7,116.9,115.7,112.5,111.2,101.7,55.7,36.9.HRMS(ESI):Cacld forC 28 H 24 N3O2S[M+H] + 466.1584, found 466.1588.

[0066] Example 11: Synthesis of the alkaloid barakacin derivative I-11

[0067] Compound 11 (1 g, 5.28 mmol) and 5-bromoindole (2.07 g, 10.56 mmol) were added to a round-bottom flask, followed by 50 mL of acetonitrile. After stirring at room temperature for 30 min, iodine (0.67 g, 5.28 mmol) was added to the flask. Stirring continued for another 30 min. After the reaction was complete (monitored by TLC), sodium thiosulfate solution was added to the flask, and the reaction was quenched by stirring for 15 min. After the reaction was complete, the solvent was removed, and the solution was extracted with ethyl acetate (50 mL × 3). The solution was then concentrated under vacuum and recrystallized from the solid using dichloromethane and petroleum ether as solvents to give 2.68 g of a red solid (90% yield). Melting point: 142-144 °C. 1 H NMR (400MHz, DMSO-d6) δ11.12 (s, 2H), 7.99-7.91 (m, 2H), 7.75 (s, 2H), 7.47 (d, J=6.6Hz, 3H), 7.4 1 (s, 1H), 7.34 (t, J=6.9Hz, 2H), 7.21 (d, J=1.7Hz, 2H), 7.16 (dd, J=8.6, 1.5Hz, 2H), 6.08 (s, 1H). 13C NMR (100MHz, DMSO-d6) δ167.1, 160.3, 135.6, 133.7, 130.6, 129.7, 128.7, 126 .5, 125.7, 123.8, 122.1, 116.7, 115.9, 114.0, 111.4, 36.6.HRMS (ESI): Cacld for C 26 H 18 Br2N3S[M+H] + 466.1584, found 466.1588.

[0068] Example 12: Synthesis of the alkaloid barakacin derivative I-12

[0069] Compound 11 (1 g, 5.28 mmol) and 6-bromoindole (2.07 g, 10.56 mmol) were added to a round-bottom flask, followed by 50 mL of acetonitrile. After stirring at room temperature for 30 min, iodine (0.67 g, 5.28 mmol) was added to the flask. Stirring continued for another 30 min. After the reaction was complete (monitored by TLC), sodium thiosulfate solution was added to the flask, and the reaction was quenched by stirring for 15 min. After the reaction was complete, the solvent was removed, and the solution was extracted with ethyl acetate (50 mL × 3). The solution was then concentrated under vacuum and recrystallized using dichloromethane and petroleum ether as solvents to give 2.53 g of a yellow solid, with a yield of 85%. Melting point: 238-240 °C. 1 H NMR (400MHz, DMSO-d6) δ11.03 (s, 2H), 7.90 (dd, J=7.6, 1.8Hz, 2H), 7.55 (d, J=1.2Hz, 2H), 7.48 (dd, J=10.3, 5. 1Hz, 3H), 7.40 (d, J=8.5Hz, 2H), 7.31 (s, 1H), 7.11 (d, J=1.8Hz, 2H), 7.04 (dd, J=8.5, 1.6Hz, 2H), 6.06 (s, 1H). 13 C NMR (100MHz, DMSO-d6) δ166.5, 160.0, 137.3, 133.2, 130.0, 129.2, 126.0, 125 .4, 124.6, 121.1, 120.8, 116.7, 115.5, 114.0, 113.7, 36.2.HRMS (ESI): Cacld for C 26 H 18 Br2N3S[M+H] + 466.1584, found 466.1578.

[0070] Example 13: Synthesis of the alkaloid barakacin derivative I-13

[0071] Indole (0.59 g, 5 mmol) and benzo[d]thiazol-2-carboxaldehyde (12) (0.4 g, 2.5 mmol) were added to 8 mL of acetic acid. The mixture was stirred at room temperature for 16 hours, and the reaction was observed on a TLC plate. After the reaction was complete, the pH was slowly adjusted with 3 M sodium hydroxide solution under ice bath conditions. The mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated brine, and separated by column chromatography (PE:EA = 4:1) to give 0.75 g of a brown solid, with a yield of 79%. Melting point: 143-145 °C. 1 H NMR (400MHz, DMSO-d6) δ11.03 (s, 2H), 7.94 (t, J=7.5Hz, 2H), 7.45 (dd, J=11.1, 4.1Hz, 3H), 7.42-7.32 (m, 3H), 7.22 (s, 2H), 7.07 (t, J=7.6Hz, 2H), 6.91 (t, J=7.5Hz, 2H), 6.38 (s, 1H). 13 C NMR (100MHz, DMSO-d6) δ176.3, 153.0, 141.5, 136.4, 135.0, 126.3, 125.8, 124.7, 12 4.0, 122.4, 122.0, 121.2, 118.9, 118.6, 115.2, 111.6, 56.0, 18.5.HRMS (ESI): Cacld for C 24 H 18 N3S[M+H] + 380.1216, found 380.1219.

[0072] Example 14: Synthesis of barakacin derivative I-14

[0073] Indole (0.59 g, 5 mmol) and pyrimidine-5-carboxaldehyde (13) (0.27 g, 2.5 mmol) were added to 8 mL of acetic acid. The mixture was stirred at room temperature for 16 hours, and the reaction was observed on a TLC plate. After the reaction was complete, the pH was slowly adjusted with 3 M sodium hydroxide solution under ice bath conditions. The mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated brine, and separated by column chromatography (PE:EA = 4:1) to give 0.85 g of a brown solid, with a yield of 71%. Melting point: 214-216 °C. 1H NMR (400MHz, DMSO-d6) δ11.00 (d, J=1.5Hz, 2H), 9.05 (s, 1H), 8.79 (s, 2H), 7.39 (d, J=8.1Hz, 2H), 7.34 (d, J=7.9Hz, 2H), 7.12-7.04 (m, 2H), 6.97 (d, J=2.2Hz, 2H), 6.91 (dd, J=11.1, 3.8Hz, 2H), 5.99 (s, 1H). 13 C NMR (100MHz, DMSO-d6) δ157.0, 156.9, 138.5, 137.0, 126.6, 124.4, 121.7, 119.3, 119.0, 116.6, 112.1, 35.4.HRMS (ESI): Cacld for C 21 H 17 N4[M+H] + 325.1448, found 325.1441.

[0074] Example 15: Synthesis of the alkaloid barakacin derivative I-15

[0075] Indole (0.59 g, 5 mmol) and 1H-benzo[d]imidazol-2-carboxaldehyde (14) (0.4 g, 2.5 mmol) were added to 8 mL of acetic acid. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the pH was slowly adjusted with 3M sodium hydroxide solution under ice bath conditions. The mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated brine, and separated by column chromatography (PE:EA = 4:1) to obtain 0.69 g of a light brown solid, with a yield of 71% and a melting point of 296-298 °C. 1 H NMR (400MHz, DMSO-d6) δ10.96 (d, J=1.7Hz, 2H), 7.51-7.33 (m, 7H), 7.16 (d, J=2.2Hz, 2 H), 7.10 (dd, J=6.0, 3.2Hz, 2H), 7.07-7.02 (m, 2H), 6.89 (t, J=7.5Hz, 2H), 6.11 (s, 1H). 13 C NMR (100MHz, DMSO-d6) δ157.3, 143.8, 137.2, 134.8, 128.6, 127.2, 121.9, 121.6 ,121.2,119.3,119.1,118.9,114.5,111.5,110.2,34.9,32.8.HRMS(ESI):Cacld for C 24 H 19 N4[M+H] +363.1604, dound 363.1609.

[0076] Example 16: Synthesis of barakacin derivative I-16

[0077] Indole (0.59 g, 5 mmol) and bicyclo[2.2.1]hept-5-en-2-carboxaldehyde (15) (0.31 g, 2.5 mmol) were added to 8 mL of acetic acid. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the pH was slowly adjusted with 3 M sodium hydroxide solution under ice bath conditions. The mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated brine, and separated by column chromatography (PE:EA = 4:1) to obtain 0.92 g of pale yellow solid, yield 76%, melting point: 114-116 °C. 1 H NMR (400MHz, DMSO-d6) δ10.71 (dd, J=15.0, 1.5Hz, 2H), 7.58 (d, J=7.8Hz, 1H), 7.45 (d, J=7.9Hz, 1H), 7.3 9 (t, J=2.6Hz, 2H), 7.27 (d, J=7.9Hz, 1H), 7.23 (d, J=8.1Hz, 1H), 6.97-6.92 (m, 2H), 6.82 (dd, J=9.6, 8.0 Hz, 2H), 6.23 (dd, J=5.6, 2.9Hz, 1H), 6.06 (dd, J=5.7, 2.9Hz, 1H), 3.71 (d, J=12.0Hz, 1H), 3.27 (ddd, J=1 5.9, 8.1, 3.9Hz, 1H), 2.77 (s, 1H), 1.97-1.89 (m, 1H), 1.32 (t, J=8.0Hz, 3H), 0.59 (dd, J=6.9, 4.7Hz, 1H). 13 C NMR (100MHz, DMSO-d6) δ137.5, 136.9, 136.7, 133.1, 127.6, 126.8, 122.6, 122.3, 120.9, 120.8, 119. 7, 119.3, 119.1, 119.0, 118.2, 118.2, 111.7, 111.6, 49.3, 45.4, 43.5, 43.0, 33.0.HRMS (ESI): Cacld for C 24 H 23 N2[M+H] + 339.1856, found 339.1850.

[0078] Example 17: Synthesis of the alkaloid barakacin derivative I-17

[0079] Indole (0.59 g, 5 mmol) and 1H-pyrazole-4-carboxaldehyde (16) (0.24 g, 2.5 mmol) were added to 8 mL of acetic acid. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the pH was slowly adjusted with 3M sodium hydroxide solution under ice bath conditions. The mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated brine, and separated by column chromatography (PE:EA = 4:1) to obtain 1.07 g of brown solid, yield 82%, melting point: 270-272 °C. 1 H NMR (400MHz, DMSO-d6) δ12.49 (s, 1H), 10.76 (d, J=1.0Hz, 2H), 7.41 (s, 2H), 7.34 (dd, J=15.2, 8.0Hz, 4H), 7.05-6.94 (m, 4H), 6.85 (t, J=7.4Hz, 2H), 5.77 (s, 1H). 13 C NMR (100MHz, DMSO-d6) δ137.1, 127.0, 124.6, 123.4, 121.3, 119.7, 119.3, 118.5, 111.9, 30.3.HRMS (ESI): Cacld for C 20 H 17 N4[M+H] + 313.1448, found 313.1444.

[0080] Example 18: Synthesis of the alkaloid barakacin derivative I-18

[0081] Indole (0.59 g, 5 mmol) and 1H-imidazol-2-carboxaldehyde (17) (0.24 g, 2.5 mmol) were added to 8 mL of acetic acid. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the pH was slowly adjusted with 3M sodium hydroxide solution under ice bath conditions. The mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated brine, and separated by column chromatography (PE:EA = 4:1) to obtain 1.01 g of brown solid, with a yield of 77% and a melting point >300 °C. 1 H NMR (400MHz, DMSO-d6) δ11.90 (s, 1H), 10.87 (d, J=1.5Hz, 2H), 7.35 (dd, J=9.5, 8.8Hz, 4H), 7.06-7.00 (m, 4H), 6.91-6.85 (m, 4H), 5.91 (s, 1H). 13 C NMR (100MHz, DMSO-d6) δ150.5, 136.8, 127.0, 123.9, 121.3, 119.4, 118.7, 116.4, 111.9, 34.5.HRMS (ESI): Cacld for C20 H 17 N4[M+H] + 313.1448, found 313.1454.

[0082] Example 19: Synthesis of the alkaloid barakacin derivative I-19

[0083] Add indole (0.59 g, 5 mmol) and thiazol-2-carboxaldehyde (18) (0.28 g, 2.5 mmol) to 8 mL of acetic acid. Stir at room temperature for 16 hours. Spot the mixture onto a TLC plate. After the reaction is complete, adjust the pH slowly with 3 M sodium hydroxide solution under ice bath conditions. Extract with ethyl acetate (50 mL × 3). Wash with saturated brine. Separate by column chromatography (PE:EA = 4:1). 0.90 g of brown solid was obtained, yield 78%, melting point: 147-149 °C. 1 H NMR (400MHz, DMSO-d6) δ10.95 (s, 2H), 7.72 (d, J=3.3Hz, 1H), 7.51 (d, J=3.3Hz, 1H), 7.39 (t, J=8.8 Hz, 4H), 7.12 (d, J=1.7Hz, 2H), 7.06 (t, J=7.5Hz, 2H), 6.90 (t, J=7.5Hz, 2H), 6.28 (d, J=2.4Hz, 1H). 13 C NMR (100MHz, DMSO-d6) δ175.3, 142.5, 136.9, 126.7, 124.2, 121.5, 120.1, 119.4, 118.9, 116.6, 112.0, 30.8.HRMS (ESI): Cacld forC 20 H 16 N3S[M+H] + 330.1059, found 330.1062.

[0084] Example 20: Synthesis of the alkaloid barakacin derivative I-20

[0085] At room temperature, sodium hydride (1.96 g, 0.082 mol) was dissolved in 20 mL of tetrahydrofuran, and indole (8 g, 0.068 mol) was added and stirred for 30 min. Then, iodomethane (11.58 g, 0.082 mol) was added and stirred at room temperature for 8 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated brine, and separated by column chromatography to obtain (19). Indole (0.59 g, 5 mmol) and 1H-benzo[d]imidazolium-2-carboxaldehyde (14) (0.4 g, 2.5 mmol) were added to 8 mL of acetic acid and stirred at room temperature for 16 hours. After the reaction was complete, the pH was slowly adjusted with 3M sodium hydroxide solution under ice bath conditions. The mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated brine, and separated by column chromatography (PE∶EA=4∶1) to obtain 5.8 g of yellow solid, yield 84%, melting point: 247-249℃. 1 H NMR (400MHz, DMSO-d6) δ11.98 (s, 1H), 7.44 (ddd, J=19.2, 8.5, 5.7Hz, 6H), 7.18-7.07 (m, 6H), 6.94 (t, J=7.5Hz, 2H), 6.13 (s, 1H), 3.73 (s, 6H). 13 C NMR (100MHz, DMSO-d6) δ157.3, 137.2, 134.8, 128.6, 127.2, 121.9, 121.6, 121.2, 119.3, 119.1, 118.9, 114.5, 111.5, 110.2, 32.8.HRMS (ESI): Cacld for C 26 H 23 N4[M+H] + 391.1917, found 391.1911.

[0086] Example 21: Synthesis of the alkaloid barakacin derivative I-21

[0087] Compound I-20 (0.4 g, 1.02 mmol) was added to 20 mL of DMF, along with potassium hydroxide (0.12 g, 2.04 mmol) and methyl iodoform (0.145 g, 1.02 mmol). The mixture was stirred at room temperature for 8 h. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated brine, and separated by column chromatography (PE:EA = 4:1) to give 0.29 g of a brown solid, with a yield of 70%. Melting point: 241-243 °C. 1H NMR (400MHz, CDCl3) δ7.77 (d, J=7.2Hz, 1H), 7.43 (d, J=7.9Hz, 2H), 7.35-7.27 (m, 3H), 7.25 (s, 1H ), 7.25-7.17(m, 3H), 7.02(t, J=7.5Hz, 2H), 6.79(s, 2H), 6.24(s, 1H), 3.74(s, 3H), 3.68(s, 6H). 13 C NMR (100MHz, CDCl3) δ156.2, 137.3, 128.5, 127.1, 121.7, 119.9, 119.2, 119.1, 109.4, 109.0, 33.1, 32.8, 30.3.HRMS (ESI): Cacld for C 27 H 25 N4[M+H] + 405.2074, found 405.2079.

[0088] Example 22: Synthesis of the alkaloid barakacin derivative I-22

[0089] Compound I-20 (0.4 g, 1.02 mmol) was added to 20 mL of DMF, along with potassium hydroxide (0.12 g, 2.04 mmol) and p-toluenesulfonyl chloride (0.19 g, 1.02 mmol). The mixture was stirred at room temperature for 8 h. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated brine, and separated by column chromatography (PE:EA = 4:1) to give 0.43 g of a white solid, with a yield of 75%. Melting point: 135-137 °C. 1 H NMR (400MHz, CDCl3) δ8.19 (d, J=8.2Hz, 1H), 7.69 (d, J=7.9Hz, 1H), 7.47 (d, J=7.9Hz, 2H), 7.34 (dd, J=18.0, 9.3Hz, 4H), 7.23 (s, 1H), 7.2 2-7.17 (m, 2H), 7.03 (t, J=7.3Hz, 2H), 6.96 (s, 1H), 6.71 (d, J=8.2Hz, 2H), 6.53 (s, 2H), 3.67 (d, J=2.6Hz, 1H), 3.55 (s, 6H), 2.20 (s, 3H). 13C NMR (100MHz, DMSO-d6) δ155.9, 145.9, 141.3, 136.8, 134.0, 129.7, 128.4, 126.5, 125.1, 12 4.7, 121.2, 120.0, 118.7, 118.5, 113.8, 113.4, 109.7, 32.8, 32.2, 21.0.HRMS (ESI): Cacld for C 33 H 29 N4O2S[M+H] + 545.2006, found 545.2001.

[0090] Example 23: Synthesis of the alkaloid barakacin derivative I-23

[0091] Compound (I-20) (0.4 g, 1.02 mmol) was added to 20 mL of DMF, along with potassium hydroxide (0.12 g, 2.04 mmol) and p-benzyl bromide (0.17 g, 1.02 mmol). The mixture was stirred at room temperature for 8 h. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated brine, and separated by column chromatography (PE:EA = 4:1) to give 0.32 g of a brownish-red liquid, with a yield of 65%. 1 H NMR (400MHz, DMSO-d6) δ7.61-7.56 (m, 1H), 7.44-7.39 (m, 1H), 7.34 (d, J = 8.2Hz, 2H), 7.28 (d, J = 7.9Hz, 3H), 7.20 (d, J = 6.6Hz, 3 H), 7.14 (dd, J=5.9, 3.2Hz, 2H), 7.08 (s, 3H), 6.98-6.93 (m, 2H), 6.87 (t, J=7.5Hz, 2H), 6.14 (s, 1H), 5.52 (s, 2H), 3.66 (s, 6H). 13 C NMR (100MHz, DMSO-d6) δ156.0, 142.1, 137.0, 136.7, 135.5, 128.4, 128.3, 127.3, 126.7, 126.5, 122 .6, 121.9, 121.3, 121.0, 119.0, 118.9-118.8, 118.4, 113.4, 110.2, 109.6, 32.2.HRMS (ESI): Cacld for C 33 H 29 N4[M+H] + 481.2387, found 481.2384.

[0092] Example 24: Determination of activity against tobacco mosaic virus, the procedure is as follows:

[0093] 1. Virus purification and concentration determination:

[0094] Virus purification and concentration determination were performed in accordance with the SOP (Standard Operating Procedure) for tobacco mosaic virus prepared by the Bioassay Laboratory of the Institute of Elementochemistry, Nankai University. The crude virus extract was centrifuged twice with polyethylene glycol, and the concentration was determined. It was then stored at 4°C for later use.

[0095] 2. Preparation of compound solutions:

[0096] After weighing, the original drug was dissolved in DMF to obtain 1×10 5 The stock solution was diluted to μg / mL with an aqueous solution containing 1‰ Tween 80 to the required concentration; the ribavirin preparation was diluted directly with water.

[0097] 3. In vivo protection:

[0098] Select uniformly growing *Nicotiana santalinus* plants at the 3-5 leaf stage and spray the entire plant with the pesticide. Each treatment was repeated three times, with a 1‰ Tween 80 aqueous solution as a control. 24 hours later, sprinkle emery (500 mesh) on the leaves. Using a brush dipped in the virus solution, gently rub the entire leaf surface along the veins twice, supporting the underside of the leaf with the palm of your hand. The virus concentration was 10 μg / mL. Rinse with running water after inoculation. Record the number of lesions after 3 days and calculate the control efficacy.

[0099] 4. In vivo therapeutic effects:

[0100] Select uniformly growing *Nicotiana sambac* plants at the 3-5 leaf stage. Inoculate the entire leaf with the virus using a paintbrush at a concentration of 10 μg / mL. Rinse with running water after inoculation. After the leaves have dried, spray the entire plant with the pesticide. Each treatment is replicated three times, with a 1‰ Tween 80 aqueous solution as a control. Record the number of lesions after 3 days and calculate the control efficacy.

[0101] 5. In vivo passivation effect:

[0102] Select uniformly growing 3-5 leaf stage *Nicotiana sambac* plants. Mix the pesticide with an equal volume of virus sap, inactivate for 30 minutes, and then inoculate by friction. The virus concentration is 20 μg / mL. Rinse immediately with running water after inoculation. Repeat 3 times. Include a 1‰ Tween 80 aqueous solution as a control. Count the number of lesions after 3 days and calculate the results.

[0103] Inhibition rate (%) = [(Number of control necrotic spots - Number of treated necrotic spots) / Number of control necrotic spots] × 100%

[0104] First, the in vivo inactivation activity against tobacco mosaic virus (TMV) of all compounds was tested at a treatment dose of 500 μg / mL. Compounds with a relative inhibition rate greater than 40% were further tested for in vivo therapeutic and protective activity at a treatment dose of 500 μg / mL, and for in vivo inactivation, therapeutic, and protective activity against TMV at a treatment dose of 100 μg / mL. The positive control was the commercially available antiviral agent ribavirin.

[0105] Table 1. Results of anti-Tobacco Mosaic Virus (TMV) activity tests of barakacin derivatives I-1 to I-23:

[0106]

[0107]

[0108] The data in the table show that the barakacin alkaloid derivatives I-1 to I-23 all exhibited good anti-TMV activity at a treatment concentration of 500 μg / mL. The antiviral activity of compounds I-4, I-5, I-7, I-9 to I-13, I-15, I-16, and I-19 was comparable to that of the commercially available ribavirin. Compounds I-8 and I-14 showed anti-TMV activity comparable to that of ningnanmycin, demonstrating great development value and application prospects.

[0109] Example 25: Antibacterial activity test, the determination procedure is as follows:

[0110] In vitro sterilization test, bacterial growth rate determination method (plate method):

[0111] A certain amount of the drug was dissolved in an appropriate amount of acetone, and then diluted to the required concentration with an aqueous solution containing 200 μg / mL emulsifier. 1 mL of the drug solution was then injected into each petri dish, followed by 9 mL of culture medium. After mixing, a 50 μg / mL drug-containing plate was prepared. A plate with 1 mL of sterile water added served as a blank control. Mycelial discs were cut along the outer edge of the hyphae using a 4 mm diameter punch and transferred to the drug-containing plate. Each treatment was repeated three times. The petri dishes were incubated in a constant temperature incubator at 24 ± 1℃. After 48 hours, the diameter of the mycelial discs in each treatment was observed, and the average value was calculated. The relative inhibition rate was then compared with the blank control.

[0112]

[0113] Table 2. Results of the anti-plant pathogen activity tests of barakacin derivatives I-1 to I-23:

[0114]

[0115] The alkaloid barakacin derivatives exhibited broad-spectrum inhibitory activity against all seven tested bacteria at a test concentration of 50 μg / mL. Among them, the inhibitory activity against rapeseed sclerotia was particularly good, with compounds I-2–I-7, I-14, I-22, and I-23 all showing inhibition rates exceeding 60%, superior to the inhibitory activities of commercial fungicides such as carbendazim and chlorothalonil. Compound I-14 achieved a 97% inhibition rate against apple ring rot, and some compounds showed superior inhibitory activity against certain strains compared to commercial fungicides such as carbendazim and chlorothalonil.

Claims

1. Barakacin alkaloid derivatives with the following structures: I-1 to I-13, I-15 to I-17, I-20 to I-23:

2. The method for preparing the barakacin alkaloid derivatives I-1 to I-13, I-15 to I-17, and I-20 to I-23 of claim 1, characterized in that... Compounds I-1 to I-13, I-15 to I-17, and I-20 to I-23 can be prepared according to the following method: Synthesis of barakacin derivative I-1: Prepared according to Equation 1: In a 250 mL round-bottom flask, add 2 g of o-hydroxybenzonitrile 1, 2.32 g of potassium carbonate, and 2.38 mL of iodomethane. Add 100 mL of acetone, stir at room temperature, and monitor the reaction on a TLC plate until complete. Remove the solvent, add an appropriate amount of water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and remove the solvent to obtain a light yellow, buttery liquid 2. Add 1.5 g of 70% sodium hydrosulfide and 2.67 g of magnesium chloride hexahydrate to 20 mL of DMF. Under vigorous stirring, add dropwise a solution of 10 mL of... 1g of compound 2 in DMF was stirred at 40℃ for 6 hours. The reaction was monitored by TLC to ensure complete reaction. After removing part of the solvent, 100mL of 1M hydrochloric acid was added, and the mixture was stirred for 0.5 hours. The reaction solution was extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed to obtain a reddish-brown solid 3. 2g of compound 3 was dissolved in 200mL of ethanol, and 3.5g of the solution was gradually added dropwise to the system while stirring at 0℃. Ethyl 3-bromo-2-oxopropionate was added dropwise. After the ice bath was removed, the reaction system was heated to 90°C and refluxed. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain a pale yellow solid 4. 0.28 g of lithium aluminum hydride was dissolved in 20 mL of tetrahydrofuran. While stirring at 0°C, the solution was slowly added dropwise to tetrahydrofuran containing 2 g of compound 4. After the addition was complete, the reaction was allowed to proceed at room temperature. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed to obtain a yellow solid 5. 2.92 g of pyridinium chlorochromate was dissolved in 90 mL of dichloromethane. 2 g of compound 5, dissolved in 40 mL of dichloromethane, was added dropwise to the reaction system at 0°C. After the addition was complete, the mixture was stirred at room temperature for 4 hours. After the reaction was complete, 30 mL of the solution was used to extract the solution. The organic phase was washed with 10% hydrochloric acid, extracted with ethyl acetate, washed successively with saturated brine and water, dried with anhydrous sodium sulfate, and dissolved to obtain a white solid 6. 0.94 g indole, 0.25 g iodine, and 0.44 g compound 6 were added to 90 mL acetonitrile. After stirring at room temperature for 30 min, 40 mL of 5% sodium thiosulfate solution was added and stirring continued for 15 min. After the reaction was complete, the organic phase was extracted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, and dissolved to obtain the crude product. Finally, column chromatography was used to separate the crude product, yielding a light yellow solid I-1. Synthesis of Barakacin derivatives I-2 to I-6: Prepared according to the method shown in Equation 2: 1 g of compound I-1 was added to a round-bottom flask, followed by 10 mL of DMF. 0.17 g of sodium hydride was slowly added at 0 °C. After stirring in an ice bath for 1 h, 9.2 mmol of the corresponding halide was slowly added. The mixture was then transferred to room temperature and stirred for another 24 h. After the reaction was complete, cold water was added to quench the reaction. The crude product was obtained by filtration and then separated by column chromatography to obtain I-2 to I-6, where R1 is the group shown in the structure of compounds I-2 to I-6. Synthesis of Barakacin derivatives I-7 to I-8: 1 g of compound I-1 was dissolved in dichloromethane. Under argon protection, 28 mL of a 1 M boron tribromide solution in dichloromethane was gradually added dropwise at -78 °C. The reaction was stirred overnight at room temperature. After solvent removal, an appropriate amount of water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a red solid 7. 0.5 g of compound 7 and 0.33 g of potassium carbonate were added to a round-bottom flask, followed by 10 mL of N,N-dimethylformamide. Then, 2.37 mmol of the corresponding halogenated product was added. The mixture was heated to 120 °C and stirred for 12 hours. After the reaction was complete, cold water was added to quench the reaction, and a solid precipitated. The solid was filtered to obtain the crude product, which was then separated by column chromatography to obtain I-7 to I-8, where R is the group shown in the structure of compounds I-7 to I-8. Synthesis of Barakacin derivatives I-9 to I-12: Prepared according to the method shown in Equation 4: 2 g of benzylthioamide 8 was dissolved in 200 mL of ethanol. 5.25 g of ethyl 3-bromo-2-oxopropionate was gradually added dropwise to the system under stirring at 0 °C. After the addition was complete, the ice bath was removed, and the reaction system was heated to 90 °C. After TLC monitoring to confirm the complete reaction, the solution was removed under reduced pressure to obtain a yellow solid 9. 0.32 g of lithium aluminum hydride was dissolved in 20 mL of tetrahydrofuran. Under stirring at 0 °C, this solution was slowly added dropwise to the tetrahydrofuran containing 2 g of compound 9. After the addition was complete, the reaction was allowed to proceed at room temperature. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solution was removed to obtain a pale yellow solid 10. 2.92 g of pyridinium chlorochromate was dissolved in 90 mL of dichloromethane. 1.7 g of compound 10, dissolved in 40 mL of dichloromethane, was added dropwise to the reaction system at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 4 minutes. h. After the reaction was complete, the mixture was washed with 10% hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed successively with saturated brine and water. It was dried with anhydrous sodium sulfate and dissolved to obtain a reddish-brown solid 11. 1 g of compound 11 and 10.56 mmol of substituted or unsubstituted indole were added to a round-bottom flask, followed by 50 mL of acetonitrile. After stirring at room temperature for 30 min, 0.67 g of iodine was added to the flask, and stirring was continued for another 30 min. After TLC monitoring to confirm the completeness of the reaction, sodium thiosulfate solution was added to the flask and stirred for 15 min to quench the reaction. After the reaction was complete, the mixture was dissolved, extracted with ethyl acetate, concentrated under vacuum, and recrystallized with dichloromethane and petroleum ether as solvents to obtain I-9 to I-12, where R... 2 R 3 The groups shown in the structures of compounds I-9 to I-12; Synthesis of Barakacin derivatives I-13, I-15 to I-17: Prepared according to the method shown in Equation 5: Add 0.59 g indole and 2.5 mmol of the corresponding substituted aldehydes 12, 14 to 16 to 8 mL of acetic acid, stir at room temperature for 16 hours, spot the reaction on a TLC plate, and after the reaction is complete, slowly adjust the pH with 3 M sodium hydroxide solution under ice bath, extract with ethyl acetate, wash with saturated brine, and separate by column chromatography to obtain I-13, I-15 to I-17, where R' is the group shown in the structure of compounds I-13, I-15 to I-17; Synthesis of Barakacin derivative I-20: Prepared according to the method shown in Equation 6: At room temperature, 1.96 g of sodium hydride was dissolved in 20 mL of tetrahydrofuran, 8 g of indole was added and stirred for 30 min, then 11.58 g of iodomethane was added and stirred at room temperature for 8 h. After the reaction was completed, it was extracted with ethyl acetate, washed with saturated brine, and separated by column chromatography to obtain 19. Then, 5 mmol of 19 and 2.5 mmol of 1H-benzo[d]imidazole-2-carboxaldehyde 14 were added to 8 mL of acetic acid and stirred at room temperature for 16 h. After the reaction was completed, the pH was slowly adjusted with 3 M sodium hydroxide solution under ice bath, extracted with ethyl acetate, washed with saturated brine, and separated by column chromatography to obtain yellow solid I-20. Synthesis of Barakacin derivative I-21: Prepared according to the method shown in Equation 7: Add 0.4 g of compound I-20, 0.12 g of potassium hydroxide and 0.145 g of iodomethane to 20 mL of DMF, stir at room temperature for 8 h, and after the reaction is complete, extract with ethyl acetate, wash with saturated brine, and separate by column chromatography to obtain brown solid I-21. Synthesis of Barakacin derivatives I-22 to I-23: prepared according to the method shown in Equation 8: 0.4 g of compound I-20, 0.12 g of potassium hydroxide and 1.02 mmol of the corresponding halide were added to 20 mL of DMF and stirred at room temperature for 8 h. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with saturated brine, and separated by column chromatography to obtain I-22 to I-23.

3. The use of I-1 to I-13, I-15 to I-17, I-20 to I-23 in claim 1 in the treatment of tobacco mosaic virus disease.

4. The application of I-1 to I-13, I-15 to I-17, and I-20 to I-23 in claim 1 for the treatment of plant pathogenic diseases, characterized in that... The plant pathogens mentioned are Fusarium wilt of cucumber, Rhizoctonia solani of apple, Rhizoctonia solani of wheat, Phytophthora indicum of tomato, Pythium oryzae of rice, Phytophthora capsici, or Sclerotinia sclerotiorum of rapeseed.

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