2-aryl isoquinoline salt type compound and application thereof in preparation of plant pathogenic fungus resistant bactericide

Abstract

The invention relates to a 2-aryl isoquinoline salt type compound and application of the 2-aryl isoquinoline salt type compound in preparation of a bactericide for resisting plant pathogenic fungi. The structure of the compound is shown in formulas I-III: # imgabs0 #, wherein R1 and R2 are selected from hydrogen, halogen, hydroxyl, trifluoromethyl, C1-C6 alkyl and C1-C6 alkoxy; r3 is selected from C1-C6 alkyl groups; x is selected from F, Cl and Br; and m and n are integers from 1 to 4. The compound disclosed by the invention has obvious inhibitory activity on various plant pathogenic fungi, and can be used for preparing a bactericide for preventing and treating crop diseases.

Description

Technical Field

[0001] The invention relates to the field of pesticide fungicides, in particular to 2-aryl isoquinoline salt type compounds and applications thereof in preparing anti-plant pathogenic fungicide fungicides. Background Art

[0002] Isoquinoline alkaloids are common nitrogen-containing heterocyclic natural products in nature, mainly distributed in plants such as Papaveraceae, Amaryllidaceae, and Menispermaceae. Berberine, sanguinarine, and chelerythrine are very special types of isoquinoline alkaloids, containing quaternary ammonium salt structures (C=N + ), also known as quaternary ammonium isoquinoline alkaloids, have significant antibacterial, anti-inflammatory, antioxidant and other biological activities, and their development and application have received much attention. There are already natural insecticides-1% sanguinarine wettable powder, feed antibiotics-Meiyouzhuang and antibacterial and anti-inflammatory drugs berberine hydrochloride on the market. Earlier, the applicant reported that two types of 3-aryl isoquinoline compounds and their use as anti-plant pathogenic fungicides were invented with quaternary ammonium isoquinoline alkaloids: sanguinarine, chelerythrine and berberine as the lead. Studies have shown that the isoquinoline skeleton is a potential antibacterial parent nucleus, which has laid an experimental foundation for the creation of natural anti-plant pathogenic fungicides (CN115353488B).

[0003] Based on the previous research results, the applicant used quaternary ammonium isoquinoline alkaloids as the lead, adopted the biomimetic pesticide design strategy, simplified the lead structure, combined with the pharmacophore splicing principle, and designed and synthesized a series of novel 2-aryl isoquinoline salt compounds. The biological activity test results show that the isoquinoline salt derivatives involved in the present invention have antibacterial activity against a variety of plant pathogenic fungi.

[0004] The 2-aryl isoquinoline salt type compound involved in the present invention is a new compound not reported in the literature. Although similar molecules have been reported in the literature, the molecules protected by the present invention and their physical and chemical data have not been clearly listed. Summary of the invention

[0005] The present invention aims to provide 2-aryl isoquinoline salt type compounds and their application in preparing anti-plant pathogenic fungicide.

[0006] The 2-aryl isoquinoline salt type compound of the present invention has a structure as shown in Formula I-III,

[0007] In formula I-III, R1 and R2 are selected from hydrogen, halogen, hydroxyl, trifluoromethyl, C1-C6 alkyl and C1-C6 alkoxy; R3 is selected from C1-C6 alkyl; X is F, Cl and Br; m and n are integers of 1-4.

[0008] The present invention provides a general preparation method of the 2-aryl isoquinolate type compound I-III, and its typical synthesis route is as shown in Reaction Formula 1:

[0009] Reaction 1

[0010] Compounds I-III are used as drugs for preparing anti-plant pathogenic fungi, and have significant inhibitory activity against Rhizotonia cerealis, Physalospora piricola, Fusarium graminearum, Ustilago hordei, Ustilago nuda and Alternaria alternata.

[0011] Compared with the prior art, the present invention has the following advantages and effects:

[0012] The present invention takes natural quaternary ammonium salt type isoquinoline alkaloids as the guide, adopts the strategy of bionic design, takes a unified bionic skeleton-isoquinoline as the mother nucleus, introduces the key pharmacophores of amides, succinate dehydrogenase inhibitors and biphenyl fungicides, and designs and synthesizes a series of novel 2-aryl isoquinoline salt compounds with novel structures. Through in vitro antibacterial activity tests, it is proved that the anti-plant pathogenic fungi activity of this type of compounds is significant, and some target compounds are equivalent to commercial fungicides chlorothalonil and carbendazim, providing basic data for the synthesis and biological activity research of 2-aryl isoquinoline salt derivatives. DETAILED DESCRIPTION

[0013] In the present invention, the structural formula of the 2-aryl isoquinoline salt type compound designed and synthesized is as follows:

[0014] In formula I-III, R1 and R2 are selected from hydrogen, halogen, hydroxyl, trifluoromethyl, C1-C6 alkyl and C1-C6 alkoxy; R3 is selected from C1-C6 alkyl; X is F, Cl and Br; m and n are integers of 1-4.

[0015] Application of 2-arylisoquinoline salt compounds as fungicides against plant pathogenic fungi. It is known that isoquinoline compounds have significant inhibitory activity against the following plant pathogenic fungi: Rhizotonia cerealis, Physalospora piricola, Fusarium graminearum, Ustilago hordei, Ustilago nuda, Alternaria alternata, etc.

[0016] The general synthesis method of the 2-aryl isoquinolate type compound I-III of the present invention is carried out according to Reaction Scheme 1. Compound I-1 is used for specific description.

[0017]

[0018] Example 1, Synthesis of Compound I-1.

[0019] The synthesis route of compound I-1 is shown in Reaction Scheme 2.

[0020] Reaction 2

[0021] Synthesis of intermediate 2a: Dissolve isochroman 1a (0.05 mol, 6.71 g) and copper bromide (0.06 mol, 13.4 g) in 80 mL of acetonitrile, heat to reflux, and monitor the reaction by TLC. After cooling, remove the solvent under reduced pressure, add 100 mL of ethyl acetate to the residue, wash with saturated brine until neutral, dry with anhydrous sodium sulfate, and separate by column chromatography to obtain a colorless liquid with a yield of 92.6%.

[0022] Synthesis method of target compound I-1: 1.0 mmol of 2-amino-5-methylbenzoate 3a was dissolved in 10 mL of acetonitrile, and a solution of intermediate 2a (1.2 mmol) in acetonitrile (5 mL) was added dropwise, and stirred overnight. The solvent was removed under reduced pressure, and 10 mL of ethyl acetate was added to the residue, stirred thoroughly, filtered, and the solid was washed with ethyl acetate and dried to obtain target compound I-1.

[0023] Compound I-1: yellow solid, yield 81.4%; mp 166–168°C. 1H NMR (400MHz, CDCl3) δ9.91 (s, 1H), 8.39 (d, J = 7.4Hz, 1H), 8.25 (d, J = 8.1Hz, 1H), 7.98 (d, J = 1.2Hz, 1H), 7.78 –7.70(m,1H),7.60–7.54(m,1H),7.50–7.37(m,2H),4.39(br,2H),3.88(s,3H),3.60(br,2H),2.45(s,3H). 13 C NMR (100MHz, CDCl3) δ168.60,164.45,142.21,140.10,138.77,136.65,136.52,135 .71,132.79,128.67,128.23,127.67,125.27,123.68,54.07,53.00,26.21,21.29.

[0024] The synthesis methods of the remaining target compounds I-III are the same as I-1, and the structural formulas of some representative compounds are shown in Appendix 1.

[0025] The physicochemical data of some representative compounds are as follows:

[0026] Compound I-2: yellow solid, yield 58.7%; mp 154-155°C. 1 H NMR (400MHz, CDCl3) δ9.99(s,1H),8.61(dd,J=8.7,4.7Hz,1H),8.33(d,J=7.5Hz,1H),7.86(dd,J=8.4, 2.8Hz,1H),7.77(t,J=7.5Hz,1H),7.52–7.40(m,3H),4.44(br,2H),3.92(s,3H),3.63(t,J=7.3Hz,2H). 13 C NMR(100MHz,CDCl3)δ169.26,163.21,162.98(d, 1 J CF =255.0Hz),138.98,138.42,138.39,136.64,130.56(d, 3 J CF =8.6Hz),128.63,128.29,126.43(d, 3 J CF =8.0Hz),125.19,122.04(d, 2 J CF =22.6Hz),119.31(d, 2 J CF=25.4Hz),54.11,53.39,26.15.

[0027] Compound I-3: yellow solid, yield 75.2%; mp 180-182°C. 1 H NMR (400MHz, CDCl3) δ10.02(s,1H),8.62(d,J=8.5Hz,1H),8.34(d,J=7.5Hz,1H),8.15(d,J=2.4Hz,1H),7.76(dd,J=10.9,4.2Hz,1H) ,7.71(dd,J=8.5,2.4Hz,1H),7.47(t,J=7.6Hz,1H),7.41(d,J=7.6Hz,1H),4.43(t,J=7.7Hz,3H),3.92(s,3H),3.62(t,J=7.7Hz,2H). 13 C NMR (100MHz, CDCl3) δ169.14,163.33,140.74,139.02,137.63,136.82,136.65, 135.12,132.21,129.68,128.73,128.30,125.68,125.30,54.03,53.42,26.19.

[0028] Compound I-4: yellow solid, yield 74.6%; mp 179–181°C. 1 H NMR (400MHz, CDCl3) δ10.03(s,1H),8.54(d,J=8.5Hz,1H),8.34(d,J=7.6Hz,1H),8.31(d,J=2.2Hz,1H),7.86(dd,J=8.5,2.2H z,1H),7.77(t,J=7.6Hz,1H),7.47(t,J=7.6Hz,1H),7.41(d,J=7.6Hz,1H),4.44(br,2H),3.92(s,3H),3.62(t,J=7.8Hz,2H). 13 C NMR (100MHz, CDCl3) δ169.06,163.21,141.23,139.03,138.13,136.81,136.65, 135.13,129.76,128.72,128.30,125.76,125.59,125.28,53.97,53.42,26.18.

[0029] Compound I-5: yellow solid, yield 61.3%; mp 159-161°C. 1H NMR (400MHz, CDCl3) δ9.93(s,1H),8.47(dd,J=8.2,2.3Hz,1H),8.31(d,J=7.5Hz,1H),8.22(dd,J=8.9,5.7Hz,1H ),7.74(t,J=7.5Hz,1H),7.39(s,1H),7.36–7.30(m,1H),4.44(br,2H),3.87(s,3H),3.62(br,2H),2.62(s,3H). 13 C NMR (100MHz, CDCl3) δ168.96,165.28(d, 1 J CF =261.3Hz),163.52,144.14(d, 3 J CF =10.6Hz),138.93,136.78,136.56,134.57(d, 3 J CF =9.8Hz),128.67,128.26,125.31,120.63,118.63(d, 2 J CF =21.2Hz),116.25(d, 2 J CF =26.3Hz),53.87,53.11,26.15.

[0030] Compound I-6: yellow solid, yield 81.2%; mp 182-184°C. 1 H NMR (400MHz, CDCl3) δ9.98(s,1H),8.61(d,J=1.9Hz,1H),8.34(d,J=7.6Hz,1H),8.13(d,J=8.5Hz,1H) ,7.74(d,J=7.6Hz,1H),7.46(s,1H),7.39(d,J=7.6Hz,1H),4.40(br,2H),3.88(s,3H),3.61(br,2H). 13 C NMR (100MHz, CDCl3) δ169.01,163.62,143.10,141.23,138.98,136.87,136.53,133.26,131.75,128.74,128.26,128.06,125.32,124.67( 1 J CF =241.3Hz),122.73,53.88,53.22,26.16.

[0031] Compound II-1: yellow solid, yield 67.8%; mp 205-207°C. 1 H NMR (400MHz, CDCl3) δ9.94(s,1H),8.54(d,J=7.7Hz,1H),8.43(d,J=7.4Hz,1H),8.08(d,J=7.6Hz,1H),7.80(td,J =7.6,0.9Hz,1H),7.56–7.50(m,2H),7.45(d,J=7.6Hz,1H),4.39(br,2H),3.96(s,3H),3.59(br,2H),2.63(s,3H). 13 C NMR (100MHz, CDCl3) δ169.41,166.63,143.28,139.14,136.78,136.23,133.39,133 .06,132.35,129.42,128.86,128.41,127.88,125.30,53.26,52.56,25.90,15.94.

[0032] Compound II-2: yellow solid, yield 83.1%; mp 189–191°C. 1 H NMR (400MHz, CDCl3) δδ9.77(s,1H),8.63(d,J=6.0Hz,1H),8.26(s,1H),8.05(d,J=7.3Hz,1H),7.95(t,J=7.3Hz,1 H), 7.79 (t, J = 9.5Hz, 1H), 7.64 (dd, J = 15.8, 7.7Hz, 1H), 4.53 (t, J = 7.0Hz, 2H), 3.92 (s, 2H), 3.43 (t, J = 7.3Hz, 2H). 13 C NMR(150MHz,DMSO-d6)δ172.02,164.79,158.03( 1 J FC =260.0),139.69,138.16,135.80,134.36( 3 J FC =9.7),118.60( 3 J FC =11.3),128.82( 2 J FC =17.2),128.88,128.76,127.60,125.81,118.60( 2 J FC =20.1),53.28,52.11,25.35.

[0033] Compound II-3: yellow solid, yield 58.4%; mp 177–179°C. 1 H NMR (400MHz, CDCl3) δ10.14(s,1H),9.07(d,J=1.7Hz,1H),8.43(d,J=7.5Hz,1H),8.18(dd,J=8.4,1.7Hz,1H),7.81(t,J=7.3Hz,1 H), 7.71 (d, J = 8.4Hz, 1H), 7.54 (t, J = 7.6Hz, 1H), 7.47 (d, J = 7.6Hz, 1H), 4.45 (t, J = 7.3Hz, 2H), 3.92 (s, 3H), 3.60 (t, J = 7.7Hz, 2H). 13 C NMR (100MHz, CDCl3) δ169.95,164.63,140.24,139.44,137.28,136.53,133.25, 133.05,131.36,131.20,129.12,128.53,128.47,125.73,53.09,53.02,26.11.

[0034] Compound II-4: yellow solid, yield 68.1%; mp 191–193°C. 1 H NMR (400MHz, CDCl3) δ10.07(s,1H),9.04(d,J=1.8Hz,1H),8.40(d,J=7.6Hz,1H),8.08(dd,J=8.4,1.8Hz,1H),7.85(d,J=8.4H z,1H),7.78(t,J=7.5Hz,1H),7.52(t,J=7.6Hz,1H),7.44(d,J=7.6Hz,1H),4.41(br,2H),3.90(s,3H),3.60(t,J=7.8Hz,2H). 13 C NMR (100MHz, CDCl3) δ169.60,164.77,141.96,139.35,137.31,136.30,134.34, 133.37,132.18,129.19,128.50,128.44,125.83,122.95,53.15,53.08,26.22.

[0035] Compound II-5: yellow solid, yield 58.7%; mp 136-138°C. 1H NMR (400MHz, CDCl3) δ10.33(s,1H),8.43(d,J=7.4Hz,1H),8.36(dd,J=8.3,2.7Hz,1H),8.29(d,J=2.6Hz,1H),7.74(td,J=7.6,1.0Hz,1H),7.52–7. 36(m,3H),4.61(t,J=7.9Hz,2H),3.93(s,3H),3.57–3.54(m,4H),1.79(dt , J=14.4, 6.8Hz, 2H), 1.49 (dq, J=14.7, 7.4Hz, 2H), 0.99 (t, J=7.4Hz, 3H). 13 C NMR (100MHz, CDCl3) δ166.24,166.02,143.75,140.07,138.97,136.73,136.34,134.08,131.1 0,128.87,128.16,126.45,125.62,124.08,52.57,51.71,30.72,26.23,25.94,19.32,13.83.

[0036] Compound II-6: yellow solid, yield 84.7%; mp 178–180°C. 1 H NMR (400MHz, CDCl3) δ10.40(s,1H),8.44(dd,J=8.7,2.8Hz,1H),8.37(d,J=2.8Hz,1H),8.32(d,J=7.5Hz,1H),7.75(t,J=7.2Hz,1H), 7.56(d,J=8.7Hz,1H),7.48–7.37(m,2H),4.63(t,J=7.9Hz,2H),3.54(t,J=7.9Hz,2H),3.24(q,J=6.9Hz,2H),1.24(t,J=6.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ166.74,164.45,140.61,139.29,136.77,136.56,136.32,133 .15,131.44,128.89,128.23,127.52,125.61,125.49,60.91,53.14,51.82,14.92.

[0037] Compound II-7: yellow solid, yield 81.4%; mp 176-178°C. 1H NMR (400MHz, DMSO-d6) δ9.77(s,1H),8.32(s,1H),8.16–7.96(m,3H),7.91(t,J=7.3H z,1H),7.65–7.60(m,2H),4.58(t,J=7.0Hz,2H),3.93(s,3H),3.43(t,J=7.0Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ168.61,165.65,142.54,139.22,139.20,137.75,135.86 ,135.57,134.12,128.80,127.70,125.96,125.85,122.62,53.57,51.17,25.30.

[0038] Compound III-1: yellow solid, yield 61.2%; mp 185-187°C. 1 H NMR (400MHz, CDCl3) δ10.15(s,1H),8.42(d,J=7.5Hz,1H),8.19(d,J=8.3Hz,1H),8.03(s,1H),7.96(d,J=8.2Hz,1H),7 .78(t,J=7.2Hz,1H),7.49–7.49(m,7.6Hz,2H),4.43(t,J=7.8Hz,2H),3.95(s,3H),3.58(t,J=7.8Hz,2H),2.52(s,3H). 13 C NMR (100MHz, CDCl3) δ169.26,165.53,145.11,139.29,136.88,136.40,133.31,132 .43,132.32,129.26,128.91,128.43,125.80,125.25,52.89,52.68,26.01,18.30.

[0039] Compound III-2: yellow solid, yield 79.3%; mp 162–164°C. 1 H NMR (400MHz, CDCl3) δ10.27(s,1H),8.80(t,J=7.8Hz,1H),8.44(d,J=7.5Hz,1H),8.01(d,J=8.1Hz,1H),7.94(d, 3 J HF=11.1Hz,1H),7.81(t,J=7.5Hz,1H),7.57–7.42(m,2H),4.51(t,J=7.3Hz,2H),3.98(s,3H),3.56(t,J=7.5Hz,2H). 13 C NMR (100MHz, CDCl3) δ169.31,164.47,154.67(d, 1 J CF =254.1Hz),139.43,137.26,136.79,134.17(d, 2 J CF =61.4Hz),129.10,128.34,127.71,127.36,125.98,118.31,118.11,53.08,52.79,26.04.

[0040] Compound III-3: yellow solid, yield 64.1%; mp 192–194°C. 1 H NMR (400MHz, CDCl3) δ10.06(s,1H),8.87(d,J=8.3Hz,1H),8.41(d,J=7.5Hz,1H),8.23(d,J=1.6Hz,1H),8.12(dd,J=8.3,1.6Hz,1 H), 7.81 (t, J = 7.5Hz, 1H), 7.52 (t, J = 7.6Hz, 1H), 7.45 (d, J = 7.6Hz, 1H), 4.48 (t, J = 7.4Hz, 2H), 3.98 (s, 3H), 3.60 (t, J = 7.8Hz, 2H). 13 C NMR (100MHz, CDCl3) δ169.78,164.41,143.20,139.43,137.31,136.64,133 .96,131.77,130.30,129.01,128.46,128.43,125.66,53.08,52.94,26.05.

[0041] Compound III-4: yellow solid, yield 65.0%; mp 206-208°C. 1H NMR (600MHz, DMSO-d6) δ9.78(s,1H),8.41(d,J=1.3Hz,1H),8.25(dd,J=8.2,1.4Hz,1H),8.16(d,J=8.2Hz,1H),8.06(d ,J=7.4Hz,1H),7.98(t,J=7.4Hz,1H),7.67(t,J=7.4Hz,2H),4.47(t,J=7.5Hz,2H),3.93(s,3H),3.51(t,J=7.8Hz,2H). 13 C NMR(151MHz,DMSO)δ172.24,164.55,145.42,140.14,137.93,136.02,134.59, 133.74,130.57,129.24,129.08,128.60,125.34,118.68,53.51,52.45,25.44.

[0042] Compound III-5: yellow solid, yield 73.3%; mp 192–194°C. 1 H NMR(600MHz,DMSO-d6)δ9.78(s,1H),8.07(d,J=8.2Hz,2H),7.94–7.90(m,2H),7.84(d,J=8.1Hz ,1H),7.65–7.61(m,2H),4.61(t,J=7.8Hz,2H),3.89(s,3H),3.43(t,J=7.8Hz,2H),3.63(s,3H). 13 C NMR(151MHz,DMSO-d6)δ168.14,166.78,145.31,141.58,139.19,137.85,135.6 1,132.02,131.80,128.79,126.09,125.97,120.75,52.89,50.93,36.14,25.30.

[0043] Compound III-6: yellow solid, yield 67.2%; mp 181-182°C. 1 H NMR(600MHz,DMSO-d6)δ9.81(s,1H),8.25(s,1H),8.11(d,J=8.1Hz,1H),8.06(d,J=6.7Hz,1H), 8.00(d,J=7.2Hz,1H),7.93(s,1H),7.69–7.58(m,2H),4.60(br,2H),3.92(s,3H),3.43(br,2H). 13CNMR(151MHz,DMSO-d6)δ169.16,165.08,145.81,139.48,137.98,135.82,133.23,132.72,132.19,128.84,125.87,122.41,53.50,51.04,25.27.

[0044] Compound III-7: yellow solid, yield 82.5%; mp 182–184°C. 1 H NMR(600MHz,DMSO-d6)δ9.78(s,1H),8.38(s,1H),7.95–7.92(m,2H),6.82( s,1H),6.72(s,1H),4.59(br,2H),3.91(s,6H),3.51(s,3H),3.42(br,2H). 13 C NMR(151MHz,DMSO-d6)δ169.17,165.83,145.61,139.47,137.94,135.78,135.71,13 4.61,132.35,128.83,128.67,125.87,122.83,121.31,56.10,53.51,51.07,25.27.

[0047] Example 2, experimental methods and results of the anti-plant pathogenic fungi activity of target compounds I-III.

[0048] The present invention uses the hyphae growth rate method to test the in vitro activity of some target compounds I-III against six common crop pathogens, including wheat sheath blight (Rhizotonia cerealis; RC), apple ring rot (Physalospora piricola; PP), wheat head blight (Fusarium graminearum; FG), barley smut (Ustilago hordei; UH), naked smut (Ustilagonuda; UN) and pear black spot (Alternaria alternata; AA), with thiophanate-methyl and carbendazim as positive control drugs. The compound was dissolved in dimethyl sulfoxide to a concentration of 10 mg·L -1 The mother solution was diluted with Tween solution to a concentration of 50 mg·L -1 of the test solution. Take 1mL of the above solution and add it to 9mL of potato dextrose agar (PDA) medium. After the medium is completely solidified, inoculate the test bacteria. Use dimethyl sulfoxide as a blank control. Repeat the experiment 3 times. After culturing at 25℃ in the dark for 3-4 days, take out the culture dish and measure the colony diameter by the cross method. The test results of anti-plant pathogenic fungi are shown in Appendix 2.

[0049] The results show that the 2-aryl isoquinoline salt type compounds have moderate to significant in vitro antibacterial activity against 6 plant pathogenic fungi, which is comparable to the commercial drugs chlorothalonil and boscalid. Therefore, the 2-aryl isoquinoline salt type compounds of the present invention can be used to prepare anti-plant pathogenic fungicides. Appendix 1 Structural formula of target compounds I-III Table 2 Anti-plant pathogenic fungi activity of target compounds I-III (50 mg·L -1 , %)

Claims

1. 2-Aryl isoquinoline salt type compound, the structure of which is as shown in Formula I-III:

2. According to claim 1, in formula I-III, R1 and R2 are selected from hydrogen, halogen, hydroxyl, trifluoromethyl, C1-C6 alkyl and C1-C6 alkoxy; R3 is selected from C1-C6 alkyl; X is F, Cl and Br; m and n are integers of 1-4.

3. Use of the 2-aryl isoquinoline type compound according to claim 1 in the preparation of anti-plant pathogenic fungi drugs.

4. According to claim 3, the plant pathogenic fungi are selected from the group consisting of Rhizotonia cerealis, Physalospora piricola, Fusarium graminearum, Ustilago hordei, Ustilago nuda and Alternaria alternata.

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