Dihalogenated BODIPY photosensitizer as well as preparation method and application thereof

Abstract

The invention discloses a dihalogenated BODIPY photosensitizer as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The dihalogenated BODIPY photosensitizer disclosed by the invention has relatively strong absorption in a visible light region, can be relatively well excited by natural light to generate active oxygen, shows an excellent broad-spectrum antifungal effect, particularly shows remarkable bacteriostatic activity on valsa mali, sclerotinia sclerotiorum, rhizoctonia solani, trichoderma viride and the like, and has a good application prospect. Moreover, the compound is relatively safe to plants, and lays a foundation for preparing photosensitive bactericides taking BODIPY derivatives as main antifungal active ingredients.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a dihalogenated BODIPY photosensitizer and a preparation method and application thereof. Background Art

[0002] Plant diseases caused by plant pathogenic fungi seriously threaten crop production and food security. Currently, the use of chemical fungicides to control plant diseases is still of great significance in modern agriculture. However, most chemical fungicides have a single target. With their long-term and large-scale use, chemical control is facing the challenges of the emergence of fungal resistance and the reduction in the number of commercially available fungicides. It is difficult to truly solve the problem of resistance by developing conventional fungicides with new structures, and it can only be delayed. Therefore, there is an urgent need to find alternative strategies with high efficiency, low toxicity, and novel mechanisms of action to meet this challenge.

[0003] Antimicrobial photodynamic therapy (aPDT) is a clinical therapy based on light-activated photosensitizers (PS). The principle of aPDT is that PS is activated under light irradiation to produce reactive oxygen species (such as 1 O2), rapidly reacts with lipids, proteins, DNA and other biomacromolecules, causing irreversible damage to pathogenic microorganisms. This nonspecific mode of action of aPDT minimizes the occurrence of drug resistance and has attracted considerable clinical interest and research attention in the treatment of microbial infections, especially drug-resistant microorganisms.

[0004] aPDT has three main factors: light, photosensitizer and molecular oxygen. For agricultural applications, oxygen molecules and natural light are abundant in nature, so developing suitable PS is the primary task for applying aPDT to agriculture. In recent years, a variety of natural and semi-synthetic PSs have been used for aPDT, such as curcumin, psoralen, phthalocyanine, methylene blue, and porphyrin, but the active oxygen production rate of these PSs is low, which greatly affects the effect of aPDT and leads to unsatisfactory anti-pathogenic microorganisms. Summary of the invention

[0005] The purpose of the present invention is to provide a dihalogenated BODIPY photosensitizer and a preparation method and application thereof, so as to solve the problems existing in the above-mentioned prior art.

[0006] The present invention introduces halogen atoms (chlorine, bromine, iodine) into the β position of the BODIPY core to promote intersystem crossing efficiency and improve the singlet oxygen production capacity, thereby solving the problem of low active oxygen yield of existing PSs and preparing a compound with high antifungal activity.

[0007] To achieve the above object, the present invention provides the following solutions:

[0008] One of the technical solutions of the present invention: a dihalogenated BODIPY photosensitizer, the structural formula of which is shown in formula (1):

[0009]

[0010] Among them, R 1 is phenyl, substituted phenyl or heterocyclic aromatic group; R 2 is hydrogen or methyl; X is Cl, Br or I.

[0011] Further, the substituted phenyl group is selected from one of o-fluorophenyl, p-fluorophenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, m-methoxyphenyl, p-methoxyphenyl, 4-tert-butylphenyl, p-cyanophenyl, 2,4,6-trimethylphenyl and pentafluorophenyl;

[0012] The heterocyclic aromatic group is 4-pyridyl or 2-thienyl;

[0013] The halogen atom is chlorine, bromine or iodine.

[0014] Technical solution 2 of the present invention: A method for preparing the above-mentioned dihalogenated BODIPY photosensitizer, comprising the following steps:

[0015] When R 2 When it is hydrogen, the preparation method comprises: mixing compound 1, pyrrole and hydrochloric acid for condensation reaction, then dissolving the obtained product in an organic solvent, and then sequentially adding an oxidant, a base and a ligand for reaction to obtain compound 2; mixing compound 2 with a halogenating agent for reaction to obtain the dihalogenated BODIPY photosensitizer;

[0016] The structural formula of the compound 1 is as follows:

[0017]

[0018] The structural formula of the compound 2 is as follows:

[0019]

[0020] When R 2 When it is methyl, the preparation method comprises: mixing compound 1, 2,4-dimethylpyrrole, an organic solvent and trifluoroacetic acid, performing a condensation reaction, and then sequentially adding an oxidant, a base and a ligand to react to obtain compound 3; mixing compound 3, glacial acetic acid and a halogenating agent to react to obtain the dihalogenated BODIPY photosensitizer;

[0021] The structural formula of the compound 3 is as follows:

[0022]

[0023] R in the compound 1, compound 2 and compound 3 1 All are phenyl, substituted phenyl or heterocyclic aryl.

[0024] In the compound, R 1 All are phenyl, substituted phenyl or heterocyclic aryl.

[0025] Further, the oxidant includes 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ);

[0026] The base includes triethylamine (Et3N);

[0027] The complexing agent includes boron trifluoride etherate (BF3·Et2O);

[0028] When X is bromine, the halogenating agent includes liquid bromine (Br2) or N-bromosuccinimide (NBS);

[0029] When X is chlorine, the halogenating agent includes N-chlorosuccinimide (NCS);

[0030] When X is iodine, the halogenating agent includes N-iodosuccinimide (NBS).

[0031] The organic solvent includes dichloromethane (DCM).

[0032] Further, the compound 1 is selected from one of benzaldehyde, o-fluorobenzaldehyde, p-fluorobenzaldehyde, o-chlorobenzaldehyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, o-bromobenzaldehyde, m-bromobenzaldehyde, p-bromobenzaldehyde, o-methylbenzaldehyde, m-methylbenzaldehyde, p-methylbenzaldehyde, m-methoxybenzaldehyde, p-methoxybenzaldehyde, 4-tert-butylbenzaldehyde, p-cyanobenzaldehyde, 2,4,6-trimethylbenzaldehyde, pentafluorobenzaldehyde, 4-pyridinecarboxaldehyde and 2-thiophenecarboxaldehyde.

[0033] The third technical solution of the present invention: an application of the above-mentioned dihalogenated BODIPY photosensitizer as an anti-plant pathogenic fungus drug.

[0034] Furthermore, the plant pathogenic fungi include apple rot pathogen, apple ring rot pathogen, sclerotinia pathogen, gray mold pathogen, Rhizoctonia solani, Fusarium graminearum, Trichoderma viride or Curvularia lunata.

[0035] The fourth technical solution of the present invention is a drug for resisting plant pathogenic fungi, which uses the above-mentioned dihalogenated BODIPY photosensitizer as an active ingredient.

[0036] The present invention discloses the following technical effects:

[0037] (1) The dihalogenated BODIPY photosensitizer of the present invention has strong absorption in the visible light region, can be well excited by natural light, produces active oxygen, and exhibits excellent broad-spectrum antifungal effect, especially against apple rot pathogen, rapeseed sclerotinia, Rhizoctonia solani and green Trichoderma, etc., and is relatively safe for plants, laying a foundation for the preparation of photosensitizers with BODIPY derivatives as the main antifungal active ingredients.

[0038] (2) The present invention has the advantages of a simple synthesis method and fewer route steps, and is of great significance for overcoming the drug resistance of plant pathogenic fungi.

[0039] (3) The dihalogenated BODIPY photosensitizer of the present invention has a non-specific antibacterial principle, which is different from traditional chemical fungicides and is of great significance for overcoming the drug resistance of plant pathogenic fungi. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0041] Figure 1 The ultraviolet absorption spectra of compound B15 prepared in Example 15, compound B17 prepared in Example 17, compound B19 prepared in Example 19, and compound B20 prepared in Example 20 of the present invention;

[0042] Figure 2 This is the effect of compound B19 prepared in Example 19 of the present invention on the growth of wheat seedlings, wherein A is the blank control group and B is the compound B19 treatment group. DETAILED DESCRIPTION

[0043] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0044] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0045] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0046] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to the skilled artisan. The present invention description and examples are exemplary only.

[0047] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0048] The chemical reaction equations of Examples 1 to 18 of the present invention are as follows:

[0049]

[0050] Chemical reaction equations It is one of benzaldehyde, o-fluorobenzaldehyde, p-fluorobenzaldehyde, o-chlorobenzaldehyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, o-bromobenzaldehyde, m-bromobenzaldehyde, p-bromobenzaldehyde, o-methylbenzaldehyde, m-methylbenzaldehyde, p-methylbenzaldehyde, m-methoxybenzaldehyde, p-methoxybenzaldehyde, 4-tert-butylbenzaldehyde, p-cyanobenzaldehyde, 2,4,6-trimethylbenzaldehyde and pentafluorobenzaldehyde.

[0051] The chemical reaction equations of Examples 19 to 23 of the present invention are as follows:

[0052]

[0053] Chemical reaction equations It is 4-pyridinecarboxaldehyde, 2-thiophenecarboxaldehyde or 2,4,6-trimethylbenzaldehyde.

[0054] Example 1

[0055] A preparation method of a dibrominated BODIPY photosensitizer (Compound B1):

[0056] The synthetic route of compound B1 is as follows:

[0057]

[0058] (1) At room temperature, benzaldehyde (6.0 mmol) was dissolved in 250 mL of water, and 30 drops of hydrochloric acid and pyrrole (18.0 mmol, 3 equiv) were added in sequence to carry out condensation reaction. After 72 hours, the reaction mixture was crudely purified by simple filtration and dried. The obtained solid (3.0 mmol) was dissolved in 120 mL of dichloromethane, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (3.0 mmol, 1 equiv) was added for oxidation reaction for 40 minutes, and triethylamine (TEA) (30.0 mmol, 10 equiv) was added to continue the reaction for 40 minutes. BF3·Et2O (30.0 mmol, 10 equiv) was added in an ice bath for coordination reaction for 2 hours to stop the reaction. The mixture was separated and purified by silica gel column chromatography using a mixed solution of petroleum ether / dichloromethane (3:1 = v / v) as the eluent to obtain a yellow compound A1.

[0059] (2) At room temperature, compound A1 (0.1 mmol) was dissolved in 40 mL of dichloromethane, and liquid bromine (0.3 mmol, 3 equiv) was slowly added, and the reaction was monitored by TLC. After the reaction was completed, the mixture was washed with an aqueous sodium thiosulfate solution and a saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate and distilled to dryness under reduced pressure. Finally, the mixture was separated and purified by silica gel column chromatography using a mixed solution of petroleum ether / ethyl acetate (30:1 = v / v) as the eluent to obtain a reddish brown product B1.

[0060] Compound B1 was a reddish brown solid with a yield of 87%; 1 H NMR (600MHz, CDCl3) δ: 7.85 (s, 2H), 7.63 (s, 1H), 7.57-7.53 (m, 4H), 6.96 (s, 2H). 13 C NMR (151MHz, CDCl3) δ: 147.1, 144.3, 134.7, 132.9, 131.8, 131.5, 130.4, 128.8, 107.3.

[0061] Example 2

[0062] A preparation method of a dibrominated BODIPY photosensitizer (compound B2):

[0063] Same as Example 1, except that benzaldehyde is replaced by an equimolar amount of o-fluorobenzaldehyde.

[0064] The structural formula of compound B2 is as follows:

[0065]

[0066] Compound B2 was a reddish brown solid with a yield of 44%; 1H NMR (600MHz, CDCl3) δ: 7.84 (s, 2H), 7.59 (q, J = 7.1Hz, 1H), 7.44-7.41 (m, 1H), 7.36-7.27 (m, 2H), 6.88 (s, 2H). 13 C NMR(101MHz, CDCl3)δ:145.1,135.1,133.2,133.1,132.1,131.5,124.6,116.9,116.7,107.8,107.7.HRMS(ESI)m / z:calcd for C 15 H8BBr2F3N2Na[M+Na] + 466.89711, found 466.89716.

[0067] Example 3

[0068] A preparation method of a dibrominated BODIPY photosensitizer (compound B3):

[0069] Same as Example 1, except that benzaldehyde is replaced by an equimolar amount of p-fluorobenzaldehyde.

[0070] The structural formula of compound B3 is as follows:

[0071]

[0072] Compound B3 was a reddish brown solid with a yield of 53%; 1 H NMR (600MHz, CDCl3) δ: 7.86 (s, 2H), 7.56 (dd, J = 8.4, 5.2Hz, 2H), 7.28 (d, J = 8.2Hz, 2H), 6.93 (s, 2H). 13 CNMR(151MHz, CDCl3)δ:145.6,144.5,132.4,132.4,131.5,128.9,116.3,116.2,107.4.HRMS(ESI)m / z:calcd forC 15 H8BBr2F3N2Na[M+Na] + 466.89711, found 466.89713.

[0073] Example 4

[0074] A preparation method of a dibrominated BODIPY photosensitizer (compound B4):

[0075] Same as Example 1, except that benzaldehyde is replaced by an equimolar amount of o-chlorobenzaldehyde.

[0076] The structural formula of compound B4 is as follows:

[0077]

[0078] Compound B4 was a reddish brown solid with a yield of 46%; 1 H NMR (600MHz, CDCl3) δ: 7.85 (s, 2H), 7.56 (d, J = 7.9Hz, 1H), 7.52 (t, J = 7.3Hz, 1H), 7.43 (t, J = 7.1Hz, 1H), 7.37 (d, J = 7.6Hz, 1H), 6.75 (s, 2H). 13 C NMR(101MHz, CDCl3)δ:145.3,135.2,133.2,131.9,131.5,131.4,131.2,130.6,126.9,107.9.HRMS(ESI)m / z:calcd for C 15 H8BBr2ClF2N2Na[M+Na] + 482.86756, found 482.86780.

[0079] Example 5

[0080] A preparation method of a dibrominated BODIPY photosensitizer (compound B5):

[0081] Same as Example 1, except that benzaldehyde is replaced by an equimolar amount of m-chlorobenzaldehyde.

[0082] The structural formula of compound B5 is as follows:

[0083]

[0084] Compound B5 was a reddish brown solid with a yield of 41%; 1 H NMR (600MHz, CDCl3) δ: 7.87 (s, 2H), 7.61 (d, J = 8.2Hz, 1H), 7.54-7.48 (m, 2H), 7.42 (d, J = 7.9Hz, 1H), 6.94 (s, 2H). 13 C NMR(151MHz, CDCl3)δ:145.0,144.7,135.1,134.6,134.4,131.5,130.2,130.0,128.4.HRMS(ESI)m / z:calcd for C 15 H8BBr2ClF2N2Na[M+Na] + 482.86756, found 482.86795.

[0085] Example 6

[0086] A preparation method of a dibrominated BODIPY photosensitizer (compound B6):

[0087] Same as Example 1, except that benzaldehyde is replaced by an equimolar amount of p-chlorobenzaldehyde.

[0088] The structural formula of compound B6 is as follows:

[0089]

[0090] Compound B6 was a reddish brown solid with a yield of 47%; 1 H NMR (600MHz, CDCl3) δ: 7.86 (s, 2H), 7.55 (dd, J = 8.4, 1.7Hz, 2H), 7.49 (dd, J = 8.4, 1.7Hz, 2H), 6.93 (s, 2H). 13 C NMR(151MHz, CDCl3)δ:145.3,144.7,138.2,134.5,131.5,131.4,131.2,129.2,107.5.HRMS(ESI)m / z:calcdfor C 15 H8BBr2ClF2N2Na[M+Na] + 482.86756, found 482.86761.

[0091] Example 7

[0092] A preparation method of a dibrominated BODIPY photosensitizer (compound B7):

[0093] Same as Example 1, except that benzaldehyde is replaced by an equimolar amount of o-bromobenzaldehyde.

[0094] The structural formula of compound B7 is as follows:

[0095]

[0096] Compound B7 was a reddish brown solid with a yield of 54%; 1 H NMR (600MHz, CDCl3) δ: 7.85 (s, 2H), 7.74 (d, J = 8.0Hz, 1H), 7.48 (t, J = 7.2Hz, 1H), 7.44 (t, J = 7.3Hz, 1H), 7.36 (d, J = 7.6Hz, 1H), 6.74 (s, 2H). 13C NMR(101MHz, CDCl3)δ:145.4,135.2,133.7,133.5,131.9,131.2,127.4,122.4,107.8.HRMS(ESI)m / z:calcd for C 15 H8BBr3F2N2Na[M+Na] + 526.81705, found 526.81726.

[0097] Example 8

[0098] A preparation method of a dibrominated BODIPY photosensitizer (compound B8):

[0099] Same as Example 1, except that benzaldehyde is replaced by an equimolar amount of m-bromobenzaldehyde.

[0100] The structural formula of compound B8 is as follows:

[0101]

[0102] Compound B8 was a reddish brown solid with a yield of 59%; 1 H NMR (600MHz, CDCl3) δ: 7.86 (s, 2H), 7.76 (d, J = 8.0Hz, 1H), 7.68 (s, 1H), 7.44 (m, 2H), 6.93 (s, 2H). 13 C NMR(151MHz, CDCl3)δ:145.1,134.7,134.7,134.5,131.6,130.5,129.0,123.1,107.8.HRMS(ESI)m / z:calcd forC 15 H8BBr3F2N2Na[M+Na] + 526.81705, found 526.81726.

[0103] Example 9

[0104] A preparation method of a dibrominated BODIPY photosensitizer (compound B9):

[0105] Same as Example 1, except that benzaldehyde is replaced by an equimolar amount of p-bromobenzaldehyde.

[0106] The structural formula of compound B9 is as follows:

[0107]

[0108] Compound B9 was a reddish brown solid with a yield of 62%; 1H NMR (600MHz, CDCl3) δ: 7.86 (s, 2H), 7.71 (d, J = 8.4Hz, 2H), 7.42 (d, J = 8.4Hz, 2H), 6.93 (s, 2H). 13 C NMR(151MHz, CDCl3)δ:145.4,144.8,134.5,132.3,132.3,131.7,131.7,131.7,131.5,126.5,107.6.HRMS(ESI)m / z:calcd for C 15 H8BBr3F2N2Na[M+Na] + 526.81705, found 526.81750.

[0109] Example 10

[0110] A preparation method of a dibrominated BODIPY photosensitizer (compound B10):

[0111] Same as Example 1, except that benzaldehyde is replaced by an equimolar amount of o-methylbenzaldehyde.

[0112] The structural formula of compound B10 is as follows:

[0113]

[0114] Compound B10 was a reddish brown solid with a yield of 71%; 1 H NMR (600MHz, CDCl3) δ: 7.84 (d, J = 8.4Hz, 2H), 7.46-7.43 (m, 1H), 7.35-7.30 (m, 2H), 7.23 (t, J = 8.6Hz, 1H), 6.72 (d, J = 11.3Hz, 2H), 2.24 (s, 3H). 13 C NMR(151MHz, CDCl3)δ:144.9,144.7,136.3,135.3,132.0,131.3,131.1,130.8 ,130.4,130.4,129.7,129.7,125.7,125.6,107.3,20.1.HRMS(ESI)m / z:calcd for C 16 H 11 BBr2F2N2Na[M+Na] + 462.92219, found 462.92218.

[0115] Embodiment 11

[0116] A preparation method of a dibrominated BODIPY photosensitizer (Compound B11):

[0117] Same as Example 1, except that benzaldehyde is replaced by an equimolar amount of m-tolualdehyde.

[0118] The structural formula of compound B11 is as follows:

[0119]

[0120] Compound B11 was a reddish brown solid with a yield of 69%; 1 H NMR(600MHz, CDCl3)δ:7.84(s,2H),7.44-7.42(m,2H),7.34(s,2H),6.96(s,2H),2.47(s,3H). 13 C NMR(151MHz, CDCl3)δ:147.4,144.1,138.8,134.7,132.9,132.3,131.8,130.9,128.7,127.7,107.1,21.4.HRMS(ESI)m / z:calcd for C 16 H 11 BBr2F2N2Na[M+Na] + 462.92219, found 462.92227.

[0121] Example 12

[0122] A preparation method of a dibrominated BODIPY photosensitizer (compound B12):

[0123] Same as Example 1, except that benzaldehyde is replaced by an equimolar amount of p-tolualdehyde.

[0124] The structural formula of compound B12 is as follows:

[0125]

[0126] Compound B12 was a reddish brown solid with a yield of 77%; 1 H NMR (600MHz, CDCl3) δ: 7.83 (s, 2H), 7.45 (d, J = 7.7Hz, 2H), 7.36 (d, J = 7.7Hz, 2H), 6.98 (s, 2H), 2.48 (s, 3H). 13 C NMR (151MHz, CDCl3) δ: 165.0, 144.0, 142.6, 134.8, 131.9, 130.7, 130.3, 129.7, 21.7.

[0127] Example 13

[0128] A preparation method of a dibrominated BODIPY photosensitizer (compound B13):

[0129] Same as Example 1, except that benzaldehyde is replaced by an equimolar amount of m-methoxybenzaldehyde.

[0130] The structural formula of compound B13 is as follows:

[0131]

[0132] Compound B13 was a reddish brown solid with a yield of 42%; 1 H NMR (600MHz, CDCl3) δ: 7.85 (s, 2H), 7.46 (t, J = 7.9Hz, 1H), 7.15 (d, J = 8.3Hz, 1H), 7.11 (d, J = 7.5Hz, 1H), 7.06 (s, 1H), 6.99 (s, 2H), 3.88 (s, 3H). 13 C NMR(101MHz, CDCl3)δ:159.7,146.9,144.4,134.8,134.1,131.9,130.1,123.0,117.0,116.3,107.4,55.7.HRMS(ESI)m / z:calcd for C 16 H 11 BBr2F2N2ONa[M+Na] + 504.96914, found 504.96918.

[0133] Embodiment 14

[0134] A preparation method of a dibrominated BODIPY photosensitizer (compound B14):

[0135] Same as Example 1, except that benzaldehyde is replaced by an equimolar amount of p-methoxybenzaldehyde.

[0136] The structural formula of compound B14 is as follows:

[0137]

[0138] Compound B14 was a reddish brown solid with a yield of 69%; 1 H NMR (600MHz, CDCl3) δ: 7.82 (s, 2H), 7.53 (d, J = 8.6Hz, 2H), 7.07 (d, J = 8.8Hz, 2H), 6.99 (s, 2H), 3.93 (s, 3H). 13C NMR (151MHz, CDCl3) δ: 162.9, 143.4, 132.6, 132.5, 131.5, 125.4, 114.6, 114.5, 55.7.

[0139] Embodiment 15

[0140] A preparation method of a dibrominated BODIPY photosensitizer (compound B15):

[0141] Same as Example 1, except that benzaldehyde is replaced by an equal molar amount of 4-tert-butylbenzaldehyde.

[0142] The structural formula of compound B15 is as follows:

[0143]

[0144] Compound B15 was a reddish brown solid with a yield of 86%; 1 H NMR (600MHz, CDCl3) δ: 7.84 (s, 2H), 7.57 (d, J = 7.7Hz, 2H), 7.49 (d, J = 7.6Hz, 2H), 7.01 (s, 2H), 1.40 (s, 9H). 13 C NMR(101MHz, CDCl3)δ:143.9,132.0,130.7,130.6,130.3,126.0,116.3,115.7,114.3,35.3,31.3.HRMS(ESI)m / z:calcd for C 19 H 17 BBr2F2N2Na[M+Na] + 478.91710, found 478.91705.

[0145] Example 16

[0146] A preparation method of a dibrominated BODIPY photosensitizer (compound B16):

[0147] Same as Example 1, except that benzaldehyde is replaced by an equimolar amount of p-cyanobenzaldehyde.

[0148] The structural formula of compound B16 is as follows:

[0149]

[0150] Compound B16 was a reddish brown solid with a yield of 53%; 1 H NMR (600MHz, CDCl3) δ: 7.93-7.84 (m, 4H), 7.67 (d, J = 7.8Hz, 2H), 6.86 (s, 2H).13 C NMR(101MHz, CDCl3)δ:145.7,143.8,137.1,134.4,132.7,132.7,131.4,130.9,117.7,115.4,108.2.HRMS(APCI)m / z:calcd forC 16 H8BBr2FN3[MF] + 431.91361, found 431.91367.

[0151] Embodiment 17

[0152] A preparation method of a dibrominated BODIPY photosensitizer (compound B17):

[0153] The same as Example 1, except that benzaldehyde is replaced by an equal molar amount of 2,4,6-trimethylbenzaldehyde.

[0154] The structural formula of compound B17 is as follows:

[0155]

[0156] Compound B17 was a reddish brown solid with a yield of 88%; 1 H NMR(600MHz, CDCl3)δ:7.82(s,2H),6.96(s,2H),6.70(s,2H),2.36(s,3H),2.10(s,6H). 13 C NMR(151MHz, CDCl3)δ:144.5,140.7,139.7,136.2,130.3,128.5,115.3,107.4,104.1,21.1,20.0.HRMS(ESI)m / z:calcd forC 18 H 15 BBr2F2N2Na[M+Na] + 490.95349, found 490.95364.

[0157] Embodiment 18

[0158] A preparation method of a dibrominated BODIPY photosensitizer (compound B18):

[0159] Same as Example 1, except that benzaldehyde is replaced by an equimolar amount of pentafluorobenzaldehyde.

[0160] The structural formula of compound B18 is as follows:

[0161]

[0162] Compound B18 was a reddish brown solid with a yield of 52%; 1 H NMR (600MHz, CDCl3) δ: 7.89 (s, 2H), 6.84 (s, 2H). 13 C NMR (101MHz, CDCl3) δ: 147.0, 134.9, 130.6, 130.1, 128.9, 121.8, 119.4, 109.0.

[0163] Embodiment 19

[0164] A preparation method of a dibrominated BODIPY photosensitizer (compound B19):

[0165] The synthetic route of compound B19 is as follows:

[0166]

[0167] (1) Under nitrogen atmosphere, 4-pyridinecarboxaldehyde (3.0 mmol), 2,4-dimethylpyrrole (6.0 mmol, 2 equiv), and 100 μL trifluoroacetic acid were added to 40 mL anhydrous dichloromethane in sequence, and the mixture was stirred at room temperature for 12 h. Then, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (3.0 mmol, 1 equiv) was added for oxidation reaction for 40 min, and triethylamine (TEA) (30.0 mmol, 10 equiv) was added for further reaction for 40 min. BF3·Et2O (30.0 mmol, 10 equiv) was added for coordination reaction for 2 h in an ice bath, and the reaction was stopped. The mixture was separated and purified by silica gel column chromatography using a mixed solution of petroleum ether / ethyl acetate (8:1 = v / v) as the eluent to obtain yellow compound A19.

[0168] (2) At room temperature, a bromination reagent N-bromosuccinimide (0.4 mmol, 4 equiv) was slowly added to a dichloromethane solution of compound A19 (0.1 mmol) and glacial acetic acid (1.5 mL), and the reaction was stirred for 5 minutes and monitored by TLC. After the reaction was completed, the mixture was washed with an aqueous sodium thiosulfate solution, a saturated sodium bicarbonate solution, and a saturated sodium chloride solution in sequence, and the organic phase was dried over anhydrous sodium sulfate and distilled to dryness under reduced pressure. Finally, the mixture was separated and purified by silica gel column chromatography using a mixed solution of petroleum ether / ethyl acetate (4:1 = v / v) as the eluent to obtain a reddish brown product B19.

[0169] Compound B19 was a reddish brown solid with a yield of 95%; 1 H NMR (600MHz, DMSO-d6) δ: 8.82 (d, J = 4.1Hz, 2H), 7.58 (d, J = 4.1Hz, 2H), 2.53 (s, 6H), 1.37 (s, 6H).13 CNMR(101MHz,DMSO-d6)δ:153.9,150.8,141.6,140.2,139.3,129.0,123.1,111.7,13.6(2),13.6(7).HRMS(ESI)m / z:calcd for C 18 H 16 BBr2F2N3Na[M+Na] + 505.96438, found 505.96484.

[0170] Embodiment 20

[0171] A preparation method of a dibrominated BODIPY photosensitizer (compound B20):

[0172] Same as Example 19, except that 4-pyridinecarboxaldehyde is replaced by an equal molar amount of 2-thiophenecarboxaldehyde.

[0173] The structural formula of compound B20 is as follows:

[0174]

[0175] Compound B20 was a reddish brown solid with a yield of 96%; 1 H NMR (400MHz, CDCl3) δ: 7.57-7.52 (m, 1H), 7.16 (d, J = 3.2Hz, 1H), 6.99 (d, J = 3.5Hz, 1H), 2.60 (s, 6H), 1.56 (s, 6H). 13 C NMR (101MHz, CDCl3) δ: 154.7, 141.1, 134.6, 134.1, 131.5, 128.4, 128.3, 128.1, 112.3, 13.9, 13.1.

[0176] Embodiment 21

[0177] Same as Example 19, except that 4-pyridinecarboxaldehyde is replaced by an equal molar amount of 2,4,6-trimethylbenzaldehyde.

[0178] The structural formula of compound B21 is as follows:

[0179]

[0180] Compound B21 was a reddish brown solid with a yield of 93%; 1 H NMR (400MHz, CDCl3) δ: 6.98 (s, 2H), 2.61 (s, 6H), 2.35 (s, 3H), 2.07 (s, 6H), 1.38 (s, 6H).13 C NMR (101MHz, CDCl3) δ: 153.7, 142.5, 140.0, 139.4, 134.9, 130.6, 129.7, 129.4, 111.5, 21.4, 19.6, 13.8, 12.7.

[0181] Embodiment 22

[0182] Same as Example 19, except that 4-pyridinecarboxaldehyde is replaced by an equal molar amount of 2,4,6-trimethylbenzaldehyde, and N-bromosuccinimide (NBS) is replaced by N-chlorosuccinimide (NCS).

[0183] The structural formula of compound B22 is as follows:

[0184]

[0185] Compound B22 was an orange-red solid with a yield of 76%; 1 H NMR (400MHz, CDCl3) δ: 6.98 (s, 2H), 2.58 (s, 6H), 2.35 (s, 3H), 2.07 (s, 6H), 1.37 (s, 6H). 13 C NMR (101MHz, CDCl3) δ: 152.3, 142.8, 139.4, 137.4, 134.9, 130.5, 129.4, 129.0, 122.4, 21.4, 19.6, 12.6, 11.0.

[0186] Embodiment 23

[0187] Same as Example 19, except that 4-pyridinecarboxaldehyde is replaced by an equal molar amount of 2,4,6-trimethylbenzaldehyde, and N-bromosuccinimide (NBS) is replaced by N-iodosuccinimide (NIS).

[0188] The structural formula of compound B23 is as follows:

[0189]

[0190] Compound B23 was a reddish brown solid with a yield of 97%; 1 H NMR (400MHz, CDCl3) δ: 1H NMR (400MHz, Chloroform-d) δ6.97 (s, 2H), 2.64 (s, 6H), 2.35 (s, 3H), 2.06 (s, 6H), 1.40 (s, 6H). 13C NMR (101MHz, CDCl3) δ: 156.54, 144.71, 141.85, 139.40, 134.92, 130.96, 130.65, 129.44, 85.43, 21.38, 19.66, 16.16, 15.92.

[0191] Effect Example 1

[0192] The spectral properties of the dibromo-BODIPY photosensitizer prepared in the example were studied:

[0193] The UV absorption of the target compounds was determined using a UV-visible spectrophotometer (UV-2450, Shimadzu). Some of the test results are shown in Figure 1 .

[0194] from Figure 1 It can be seen that the target compound has strong absorption in the wavelength range of 300-600nm ( Figure 1 The remaining compounds prepared by the present invention which are not shown in the figure also have strong absorption in the wavelength range of 300 to 600 nm), which means that such compounds can be well excited by natural light sources or artificial light sources.

[0195] Effect Example 2

[0196] The antifungal activity of the dibrominated BODIPY photosensitizer prepared in the examples of the present invention was studied:

[0197] Experimental subjects: Compounds B1-B23, with commercial fungicide Thifluzamide and commercial photosensitizer Rose Bengal RB as positive controls.

[0198] Experimental methods:

[0199] The mycelium growth rate inhibition method was used to determine the in vitro inhibitory activity of compounds B1-B23 against eight plant pathogenic fungi, including Valsa mali, Physalospora piricola, Sclerotinia scleotiorum, Botrytis cinerea, Rhizoctonia solani, Fusarium graminicola, Trichoderma viride and Curvularia lunata. The selected fungi were provided by the Plant Disease Control Laboratory of Anhui Agricultural University.

[0200] The accurately weighed test compound (prepared in the example) was dissolved in DMSO and added to a potato dextrose agar (PDA) medium at about 50°C to make the concentration of the compound in the medium reach 20 mg / L. After the medium solidified, the above-mentioned test plant pathogenic fungi (the diameter of the fungus cake was 5 mm) were inoculated, and 20 mg / L thiothiocarb and Bengal rose red were used as positive controls, and 1% DMSO aqueous solution was used as blank control. Each test group was set up with 3 parallels; after the inoculation, the mixture was placed in a constant temperature incubator at 25°C for 2 to 5 days (the colony diameter was measured when the colony of the blank control group grew to more than 7 cm) (the culture conditions were dark or 3.4 W white light irradiation (distance 21 cm)), and the colony diameter (mm) was measured by the cross method, and the mycelium growth inhibition rate (IR) was calculated according to formula (1):

[0201] IR(%)=(d c -d s ) / (d c -d o )×100% Formula (1)

[0202] Among them, d c Indicates the colony diameter of blank culture medium, d s Indicates the colony diameter of the treatment group, d o Indicates the diameter of the mushroom cake (5mm).

[0203] The measurement results are shown in Table 1.

[0204] Table 1 In vitro antifungal activity of compounds B1-B23 under light and dark conditions a

[0205]

[0206]

[0207] Note: a Values ​​are mean standard deviation (SD) of three replicates. L: light, D: dark.

[0208] Vm b :Valsa mal, Pp c :Physalospora piricola, Ss d :Sclerotinia scleotiorum, Bc e :Botrytis cinerea, Rs f :Rhizoctonia solani, Fg g:Fusarium graminicola, Tv h :Trichoderma viride and Cl i :Curvularia lunata.

[0209] The present invention preliminarily screened 23 dihalogenated BODIPY photosensitizers for in vitro antifungal activity against eight plant pathogenic fungi at a concentration of 20 mg / L. The preliminary screening results shown in Table 1 show that under light, these target compounds have effective inhibitory activity against a variety of tested fungi, such as more than three-quarters of the target compounds have significant antifungal activity against apple rot pathogens and Rhizoctonia solani (inhibition rate ≥ 70%), and about one-third of the compounds have an inhibition rate of more than 90% against Rhizoctonia solani. Some compounds are relatively broad-spectrum, such as compound B19, which has a broad-spectrum activity ranging from 70.9% to 93.3% against apple rot pathogens, rapeseed sclerotinia, Rhizoctonia solani and green Trichoderma. On the contrary, the antifungal activity of the target compound decreased significantly in the dark, indicating that the antifungal activity of this type of photosensitizer is highly correlated with light exposure.

[0210] Effect Example 3

[0211] Plant (wheat seedling) safety study was conducted on compound B19 prepared in Example 19 of the present invention:

[0212] Experimental object: Compound B19, monocotyledonous wheat was used as the test plant (variety: Guoshen Jimai 22).

[0213] Experimental methods:

[0214] (1) Wheat seeds were germinated and grown at 25°C with a 14-h light-dark cycle (18 W white light, lamp distance 20 cm).

[0215] (2) Compound B19, which had been accurately weighed, was dissolved in DMSO and added to an aqueous solution containing 1% Tween 80 to make the concentration of the compound reach 100 mg / L; an aqueous solution containing 1% DMSO and 1% Tween 80 was used as a blank control.

[0216] (3) When wheat seedlings were at the 1-2 leaf stage (about 80 plants per pot), 20 mL of 100 mg / L B19 was sprayed daily for 3 consecutive days. The treatment group and the control group were monitored and recorded for 7 days. The experimental results are shown in Figure 2 . Figure 2 In the figure, A is the blank control group, and B is the compound B19-treated group.

[0217] from Figure 2It can be seen that compared with the control group, the growth of wheat seedlings in the compound B19 treatment group was not inhibited, and no obvious leaf deformation or yellowing was observed. This shows that dibrominated BODIPY photosensitizers will not have a negative impact on plant growth while killing fungi.

[0218] The above results demonstrate the rationality of using dibrominated BODIPY-based photosensitizers as agricultural aPDT photosensitizers.

[0219] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A dihalogenated BODIPY photosensitizer, characterized in that: The structural formula is shown in formula (1): Among them, R 1 is phenyl, substituted phenyl or heterocyclic aromatic group; R 2 is hydrogen or methyl; X is Cl, Br or I.

2. The dihalogenated BODIPY photosensitizer according to claim 1, characterized in that: The substituted phenyl group is selected from one of o-fluorophenyl, p-fluorophenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, m-methoxyphenyl, p-methoxyphenyl, 4-tert-butylphenyl, p-cyanophenyl, 2,4,6-trimethylphenyl and pentafluorophenyl; The heterocyclic aromatic group is 4-pyridyl or 2-thienyl; The halogen atom is chlorine, bromine or iodine.

3. A method for preparing the dihalogenated BODIPY photosensitizer according to any one of claims 1 to 2, characterized in that: The following steps are involved: When R 2 When it is hydrogen, the preparation method comprises: mixing compound 1, pyrrole and hydrochloric acid for condensation reaction, then dissolving the obtained product in an organic solvent, and then sequentially adding an oxidant, a base and a ligand for reaction to obtain compound 2; mixing compound 2 with a halogenating agent for reaction to obtain the dihalogenated BODIPY photosensitizer; The structural formula of the compound 1 is as follows: The structural formula of the compound 2 is as follows: When R 2 When it is methyl, the preparation method comprises: mixing compound 1, 2,4-dimethylpyrrole, an organic solvent and trifluoroacetic acid, performing a condensation reaction, and then sequentially adding an oxidant, a base and a ligand to react to obtain compound 3; mixing compound 3, glacial acetic acid and a halogenating agent to react to obtain the dihalogenated BODIPY photosensitizer; The structural formula of the compound 3 is as follows: R in the compound 1, compound 2 and compound 3 1 All are phenyl, substituted phenyl or heterocyclic aryl.

4. The preparation method according to claim 3, characterized in that: The oxidant includes 2,3-dichloro-5,6-dicyanobenzoquinone; The base includes triethylamine; The complexing agent includes boron trifluoride etherate.

5. Use of the dihalogenated BODIPY photosensitizer according to any one of claims 1 to 2 as an anti-plant pathogenic fungus drug.

6. The use according to claim 5, characterized in that: The plant pathogenic fungi include apple rot fungus, apple ring rot fungus, sclerotinia, gray mold fungus, Rhizoctonia solani, Fusarium graminearum, Trichoderma viride or Curvularia lunulata.

7. A drug for resisting plant pathogenic fungi, characterized in that: The dihalogenated BODIPY photosensitizer according to any one of claims 1 to 2 is used as an active ingredient.

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