WO2021169661A1 - 4-position cation double substituted bodipy compounds, preparation methods therefor, and use thereof - Google Patents

4-position cation double substituted bodipy compounds, preparation methods therefor, and use thereof Download PDF

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WO2021169661A1
WO2021169661A1 PCT/CN2021/072158 CN2021072158W WO2021169661A1 WO 2021169661 A1 WO2021169661 A1 WO 2021169661A1 CN 2021072158 W CN2021072158 W CN 2021072158W WO 2021169661 A1 WO2021169661 A1 WO 2021169661A1
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compound
bodipy
disubstituted
alkyl
following structure
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Chinese (zh)
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赵伟利
李继扬
董肖椿
顾克丹
朱袁兴
林光宇
季鑫
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复旦大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/40—Peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
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    • C07—ORGANIC CHEMISTRY
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    • C07F5/02—Boron compounds
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Definitions

  • the invention belongs to the technical field of photodynamic antibacterial technology, and relates to BODIPY compounds, in particular to 4-position cation double-substituted BODIPY compounds, a preparation method thereof, and use in preparing antibacterial drugs.
  • BODIPY dyes are often used in biological imaging. They have simple synthesis, many modifiable sites, high fluorescence quantum yield, good light stability, insensitive to pH and polarity, relatively small molecular weight, and biological It has good compatibility and other advantages, which is very suitable for biological fluorescence imaging, especially for long-term fluorescence tracking.
  • BODIPY 2,6-position heavy atom is substituted, the probability of inter-system crossing is increased, and the photosensitization efficiency is greatly improved. It can be used as a photosensitizer.
  • gram-negative bacteria are more resistant to photodynamic antibacterial therapy than gram-positive bacteria. Due to the negatively charged components of the bacterial cell wall, cations are introduced into the photosensitizer to enhance the electrostatic interaction between the photosensitizer and the bacteria. At the same time, the oil-water partition coefficient of the photosensitizer is adjusted to make it amphiphilic and can play a spectral antibacterial effect. In addition, due to the structural differences between microbial cells and host cells (such as mammalian cells), the interaction of cationic photosensitizers is significantly different. Therefore, the introduction of cations can increase the selectivity of photosensitizers to pathogenic microorganisms and reduce the damage to the host.
  • the inventor of the present application intends to provide 4-position cation disubstituted BODIPY compounds and their applications, especially the use of the compounds in the preparation of photosensitizers that can be used as fluorescent imaging agents and photodynamic antibacterial agents .
  • the purpose of the present invention is to provide a novel BODIPY compound with good antibacterial effect and fluorescent labeling of microorganisms and a preparation method thereof based on the basis and current situation of the prior art. Specifically, it relates to a 4-position cation double-substituted BODIPY compound and its preparation method and its use in preparing antibacterial drugs, especially its use in preparing photosensitizers that can be used as fluorescent imaging agents and photodynamic antibacterial agents.
  • the present invention provides 4-position substituted BODIPY compounds of general formula (I) or (II):
  • R is independently selected from various types of quaternary ammonium cations, including iodomethane dimethylamino, iodomethane diethylamino, iodomethane pyridine (including adjacent pairs of positions) to obtain quaternary ammonium cations; iodoethane Dimethylamino, iodoethaneated diethylamino, iodoethaneated pyridine (including o-to-pair positions); bromoethaneated dimethylamino, bromoethaneated diethylamino, bromoethaneated pyridine (including o- To each location);
  • n 0 ⁇ 6;
  • X is selected from atoms with heavy atom effects (iodine, bromine, chlorine, sulfur, etc.);
  • R 1 and R 2 are independently selected from the group consisting of C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, amino-substituted C 1-6 alkyl, halogen-substituted C 1-6 alkyl, and aromatic rings connected by a double bond (Benzene ring, naphthalene ring, anthracene ring, carbazole ring);
  • R 3 and R 4 are independently selected from C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, amino substituted C 1-6 alkyl, halogen Substituted C 1-6 alkyl;
  • R 5 is independently selected from C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, amino substituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, phenyl, pyridyl, carboxyl, C 1 -6 ester group, C 1-6 amide.
  • the compound has the structure of the following compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14:
  • Another object of the present invention is to provide a method for preparing the above-mentioned BODIPY compound with the 4-position cation disubstituted.
  • the preparation method of the compound of the present invention is as follows:
  • the present invention provides the use of 4-position cation double-substituted BODIPY compounds in the preparation of antibacterial drugs, especially in the preparation of photosensitizers that can be used as fluorescent imaging agents and photodynamic antibacterial agents.
  • the fluorescent imaging agent and photodynamic antibacterial photosensitizer can be applied to a variety of microorganisms.
  • the compound of the present invention has been tested for antibacterial activity, and the result shows better microbial inhibitory activity.
  • the pharmacodynamic test method used is a method well known to those skilled in the art.
  • the microorganisms used are those that can be obtained commercially by those skilled in the art.
  • the present invention provides a 4-position cation double-substituted BODIPY compound with good antibacterial effect and fluorescent labeling microbial effect.
  • Tests show that the compound can attach to microorganisms through electrostatic action. After photodynamic action occurs, it has good photodynamic antibacterial activity. Play a significant role in inhibiting the growth of microorganisms, and the compounds can be further prepared for new-type antibacterial drugs, especially for preparing photosensitizers as fluorescent imaging agents and photodynamic antibacterial, and further used in clinical, food hygiene, and animal husbandry. microorganism.
  • Figure 1 is the result of the antibacterial dose-dependent experiment of compound 10: Figure 1a is the concentration-dependent curve and light dose-dependent curve of anti-Staphylococcus aureus; Figure 1b is the concentration-dependent curve and light dose-dependent curve of anti-E.coli; Figure 1c is the anti-white The concentration-dependent curve and light dose-dependent curve of Candida; Figure 1d is the concentration-dependent curve and light dose-dependent curve of methicillin-resistant Staphylococcus aureus.
  • Figure 2 shows the antibacterial effect of compound 10 against Staphylococcus aureus.
  • Figure 3 shows the antibacterial effect of compound 10 against Escherichia coli.
  • Figure 4 shows the antibacterial effect of compound 10 against Candida albicans.
  • Figure 5 shows the antibacterial effect of compound 10 against methicillin-resistant Staphylococcus aureus.
  • the synthesized compound was tested for maximum absorption wavelength (abs ⁇ max ), molar extinction coefficient ( ⁇ ), fluorescence emission wavelength (flu ⁇ max ), fluorescence quantum yield ( ⁇ f ), photosensitization efficiency ( 1 O 2) in acetonitrile
  • absorption wavelength ab ⁇ max
  • fluorescence emission wavelength flu ⁇ max
  • fluorescence quantum yield ⁇ f
  • photosensitization efficiency 1 O 2
  • the data corresponding to rate) and the oil-water partition coefficient (logP) are shown in Table 1.
  • the photosensitization efficiency is based on Rose Bengal.
  • Microbial culture Staphylococcus aureus (ATCC25923), E.coli (ATCC25922), Candida albicans (C.albicans, ATCC14053) and methicillin-resistant Staphylococcus aureus (MRSA, ATCC43300), the medium is LB broth medium, which contains tryptone, yeast extract and NaCl, etc., cultured in an incubator containing 5% CO 2 at 37°C.
  • Activity test Incubate bacteria with a CFU concentration of 1 ⁇ 10 5 (Candella albicans with a CFU concentration of 1 ⁇ 10 3 ) and serially diluted compounds for 20 minutes, and then irradiate them with LEDs with a maximum emission wavelength of 520 nm for 30 minutes at a light intensity of 10 mW/ cm 2 , light dose 18J/cm 2 , incubate for 24 hours in a constant temperature box at 37°C, observe that the bacterial solution is clear or turbid, and the minimum concentration of the compound corresponding to the clarification of the bacterial solution is the minimum inhibitory concentration.
  • Table 2 The results are shown in Table 2.
  • Microbial culture Staphylococcus aureus (ATCC25923), E.coli (ATCC25922), Candida albicans (C.albicans, ATCC14053) and methicillin-resistant Staphylococcus aureus (MRSA, ATCC43300), the medium is LB broth medium, which contains tryptone, yeast extract and NaCl, etc., cultured in an incubator containing 5% CO 2 at 37°C.
  • the photosensitizer 10 When the photosensitizer 10 is incubated with the strain without adding light, it has no ability to kill the strain, that is, it does not exhibit dark toxicity.
  • photosensitizer 10 to kill Staphylococcus aureus, Escherichia coli, Candida albicans and methicillin-resistant Staphylococcus aureus after incubation with the strain and light increases with the increase of compound concentration and light dose.

Abstract

The present invention belongs to the field of photodynamic anti-microbial technology, and relates to BODIPY compounds of formula (I) or (II), particularly 4-position cation double-substituted BODIPY compounds, a preparation method therefor, and use thereof in the preparation of anti-microbial medicaments. The compounds of the present invention can attach to microorganisms by means of electrostatic action, and can significantly inhibit the growth of microorganisms after photodynamic action occurs. Test results show that the compounds have good photodynamic anti-microbial activity, and can be further prepared into novel anti-microbial medicaments for clinical use, food hygiene, and animal husbandry.

Description

4位阳离子双取代BODIPY类化合物及其制备方法和用途4-position cation double-substituted BODIPY compound and preparation method and application thereof 技术领域Technical field
本发明属光动力抗菌技术领域，涉及BODIPY化合物，尤其涉及4位阳离子双取代BODIPY化合物及其制备方法和在制备抗菌药物中的用途。The invention belongs to the technical field of photodynamic antibacterial technology, and relates to BODIPY compounds, in particular to 4-position cation double-substituted BODIPY compounds, a preparation method thereof, and use in preparing antibacterial drugs.
背景技术Background technique
据报道,近年来，由于抗生素的滥用导致了“超级细菌”的出现和传播。所谓“超级细菌”是指该些细菌对于目前的抗生素具有多重耐药的特性，这对于临床创伤感染的治疗增添了很大的难度。且耐多重抗生素的超级细菌的爆发性流行尽管只是有潜在的可能，但其可怕之处却引起了世界各国的恐慌。因此发展新的抗感染策略迫在眉睫。研究显示,光动力抗菌治疗方法，就是其中最具前景的新疗法之一，对于细菌、真菌和病毒引起的感染，特别是对于耐药菌感染均显示很好的疗效。光动力灭菌是基于光、光敏剂和氧三种因素协同作用的氧化损伤机制，不会因为单一用药、光敏剂的浓度、曝光时间不足等因素产生耐药问题。According to reports, in recent years, the abuse of antibiotics has led to the emergence and spread of "super bacteria". The so-called "super bacteria" refers to the multi-drug resistance of these bacteria to current antibiotics, which adds great difficulty to the treatment of clinical trauma infections. And although the outbreak of multi-antibiotic-resistant super bacteria is only a potential possibility, its terrible aspects have caused panic in countries around the world. Therefore, the development of new anti-infection strategies is extremely urgent. Studies have shown that photodynamic antibacterial therapy is one of the most promising new therapies. It has shown a good effect on infections caused by bacteria, fungi and viruses, especially for drug-resistant bacteria infections. Photodynamic sterilization is an oxidative damage mechanism based on the synergistic effect of light, photosensitizer and oxygen. It will not cause drug resistance problems due to factors such as single medication, photosensitizer concentration, and insufficient exposure time.
目前，国内外利用不同光敏剂对不同细菌的光动力灭活作用进行了大量的探索，旨在发现理想的光敏药物。业内认为,理想的抗菌光敏剂，应具有高效低毒和好的选择性，对细胞壁的通透性强，高效灭活微生物，而对于正常组织伤害较小。At present, a large number of explorations have been carried out on the photodynamic inactivation of different bacteria by using different photosensitizers at home and abroad, with the aim of discovering ideal photosensitizers. The industry believes that an ideal antibacterial photosensitizer should have high efficiency, low toxicity and good selectivity, strong permeability to cell walls, high efficiency inactivation of microorganisms, and less damage to normal tissues.
氟硼二吡咯甲川类染料(BODIPY)常用于生物成像，具有合成简单、可修饰位点多、荧光量子产率高、光稳定性好、对pH和极性不敏感，分子量相对较小、生物相容性好等优点，非常适用于生物荧光成像，尤其适合长时间荧光追踪。当BODIPY 2，6-位重原子取代后，系间窜越机率提升，光敏化效率大幅提升，可用作光敏剂。BODIPY dyes (BODIPY) are often used in biological imaging. They have simple synthesis, many modifiable sites, high fluorescence quantum yield, good light stability, insensitive to pH and polarity, relatively small molecular weight, and biological It has good compatibility and other advantages, which is very suitable for biological fluorescence imaging, especially for long-term fluorescence tracking. When BODIPY 2,6-position heavy atom is substituted, the probability of inter-system crossing is increased, and the photosensitization efficiency is greatly improved. It can be used as a photosensitizer.
据文献报道，革兰氏阴性菌相较于革兰氏阳性菌对光动力抗菌疗法更加耐受。由于细菌细胞壁带负电荷成分，在光敏剂中引入阳离子，增强其与细菌的静电相互作用，同时调节光敏剂的油水分配系数，使其具有两亲性，可以起到光谱 抗菌的效果。另外，由于微生物细胞和宿主细胞(如哺乳动物细胞)的结构差异，阳离子光敏剂的相互作用显现明显差异，故可用引入阳离子的方式提高光敏剂对病原微生物的选择性，减少对宿主的伤害。According to reports in the literature, gram-negative bacteria are more resistant to photodynamic antibacterial therapy than gram-positive bacteria. Due to the negatively charged components of the bacterial cell wall, cations are introduced into the photosensitizer to enhance the electrostatic interaction between the photosensitizer and the bacteria. At the same time, the oil-water partition coefficient of the photosensitizer is adjusted to make it amphiphilic and can play a spectral antibacterial effect. In addition, due to the structural differences between microbial cells and host cells (such as mammalian cells), the interaction of cationic photosensitizers is significantly different. Therefore, the introduction of cations can increase the selectivity of photosensitizers to pathogenic microorganisms and reduce the damage to the host.
基于现有技术的基础与现状,本申请的发明人拟提供4位阳离子双取代的BODIPY类化合物及其应用,尤其所述化合物在制备可作为荧光显像剂和光动力抗菌的光敏剂中的用途。Based on the basis and current situation of the prior art, the inventor of the present application intends to provide 4-position cation disubstituted BODIPY compounds and their applications, especially the use of the compounds in the preparation of photosensitizers that can be used as fluorescent imaging agents and photodynamic antibacterial agents .
发明内容Summary of the invention
本发明的目的是基于现有技术的基础与现状,提供具有良好抗菌作用和荧光标记微生物作用的的新型BODIPY类化合物及其制备方法。具体涉及4位阳离子双取代的BODIPY类化合物及其制备方法和在制备抗菌药物中的用途，尤其是在制备可作为荧光显像剂和光动力抗菌的光敏剂中的用途。The purpose of the present invention is to provide a novel BODIPY compound with good antibacterial effect and fluorescent labeling of microorganisms and a preparation method thereof based on the basis and current situation of the prior art. Specifically, it relates to a 4-position cation double-substituted BODIPY compound and its preparation method and its use in preparing antibacterial drugs, especially its use in preparing photosensitizers that can be used as fluorescent imaging agents and photodynamic antibacterial agents.
本发明提供了通式(I)或(II)结构的4位取代的BODIPY类化合物：The present invention provides 4-position substituted BODIPY compounds of general formula (I) or (II):
Figure PCTCN2021072158-appb-000001
Figure PCTCN2021072158-appb-000001
其中：in:
R独立地选自各类季铵盐阳离子，包含碘甲烷化二甲氨基、碘甲烷化二乙氨基、碘甲烷化吡啶(包括邻间对各个位置)得到的季铵盐阳离子；碘乙烷化二甲氨基、碘乙烷化二乙氨基、碘乙烷化吡啶(包括邻间对各个位置)；溴乙烷化二甲氨基、溴乙烷化二乙氨基、溴乙烷化吡啶(包括邻间对各个位置)；R is independently selected from various types of quaternary ammonium cations, including iodomethane dimethylamino, iodomethane diethylamino, iodomethane pyridine (including adjacent pairs of positions) to obtain quaternary ammonium cations; iodoethane Dimethylamino, iodoethaneated diethylamino, iodoethaneated pyridine (including o-to-pair positions); bromoethaneated dimethylamino, bromoethaneated diethylamino, bromoethaneated pyridine (including o- To each location);
n＝0～6；n=0～6;
X选自有重原子效应的原子(碘、溴、氯、硫等)；X is selected from atoms with heavy atom effects (iodine, bromine, chlorine, sulfur, etc.);
R 1、R 2独立地选自C 1-6烷基、羟基取代C 1-6烷基、氨基取代C 1-6烷基、卤素取代C 1-6烷基、通过双键连接的芳香环(苯环、萘环、蒽环、咔唑环)；R 3、R 4独立地选自C 1-6烷基、羟基取代C 1-6烷基、氨基取代C 1-6烷基、卤素取代C 1-6烷基； R 1 and R 2 are independently selected from the group consisting of C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, amino-substituted C 1-6 alkyl, halogen-substituted C 1-6 alkyl, and aromatic rings connected by a double bond (Benzene ring, naphthalene ring, anthracene ring, carbazole ring); R 3 and R 4 are independently selected from C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, amino substituted C 1-6 alkyl, halogen Substituted C 1-6 alkyl;
R 5独立地选自C 1-6烷基、羟基取代C 1-6烷基、氨基取代C 1-6烷基、卤素取代C 1-6烷基、苯基、吡啶基、羧基、C 1-6酯基、C 1-6酰胺。 R 5 is independently selected from C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, amino substituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, phenyl, pyridyl, carboxyl, C 1 -6 ester group, C 1-6 amide.
本发明中，所述的化合物具有下述化合物1、2、3、4、5、6、7、8、9、10、11、12、13、14的结构：In the present invention, the compound has the structure of the following compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14:
Figure PCTCN2021072158-appb-000002
Figure PCTCN2021072158-appb-000002
Figure PCTCN2021072158-appb-000003
Figure PCTCN2021072158-appb-000003
Figure PCTCN2021072158-appb-000004
Figure PCTCN2021072158-appb-000004
Figure PCTCN2021072158-appb-000005
Figure PCTCN2021072158-appb-000005
本发明的另一目的是提供上述4位阳离子双取代的BODIPY类化合物的制备方法。Another object of the present invention is to provide a method for preparing the above-mentioned BODIPY compound with the 4-position cation disubstituted.
本发明的化合物的制备方法如下述：The preparation method of the compound of the present invention is as follows:
以化合物4为例，本发明的化合物的制备过程如下：Taking compound 4 as an example, the preparation process of the compound of the present invention is as follows:
Figure PCTCN2021072158-appb-000006
Figure PCTCN2021072158-appb-000006
以化合物10为例，本发明的化合物的制备过程如下：Taking compound 10 as an example, the preparation process of the compound of the present invention is as follows:
Figure PCTCN2021072158-appb-000007
Figure PCTCN2021072158-appb-000007
进一步,本发明提供了4位阳离子双取代BODIPY类化合物在制备抗菌药物中的用途，尤其是在制备可作为荧光显像剂和光动力抗菌的光敏剂中的用途。Further, the present invention provides the use of 4-position cation double-substituted BODIPY compounds in the preparation of antibacterial drugs, especially in the preparation of photosensitizers that can be used as fluorescent imaging agents and photodynamic antibacterial agents.
本发明中,所述的荧光显像剂和光动力抗菌的光敏剂可应用于多种微生物。In the present invention, the fluorescent imaging agent and photodynamic antibacterial photosensitizer can be applied to a variety of microorganisms.
本发明的化合物进行了抗菌活性测试，结果显示出较好的微生物抑制活性。The compound of the present invention has been tested for antibacterial activity, and the result shows better microbial inhibitory activity.
本发明中，所采用的药效学试验方法，是本领域技术人员所熟知的方法。In the present invention, the pharmacodynamic test method used is a method well known to those skilled in the art.
本发明中，所采用的微生物是本领域技术人员可通过市购的途径所获得的。In the present invention, the microorganisms used are those that can be obtained commercially by those skilled in the art.
本发明提供了具有良好抗菌作用和荧光标记微生物作用的4位阳离子双取代的BODIPY类化合物,试验显示所述化合物通过静电作用可附着微生物，发生光动力作用后，具有良好的光动力抗菌活性，起到显著的抑制微生物生长的作用,所述的化合物可进一步制备新型的抗菌药物,尤其制备作为荧光显像剂和光动力 抗菌的光敏剂,进一步用于临床、食品卫生、畜牧业中的多种微生物。The present invention provides a 4-position cation double-substituted BODIPY compound with good antibacterial effect and fluorescent labeling microbial effect. Tests show that the compound can attach to microorganisms through electrostatic action. After photodynamic action occurs, it has good photodynamic antibacterial activity. Play a significant role in inhibiting the growth of microorganisms, and the compounds can be further prepared for new-type antibacterial drugs, especially for preparing photosensitizers as fluorescent imaging agents and photodynamic antibacterial, and further used in clinical, food hygiene, and animal husbandry. microorganism.
附图说明Description of the drawings
图1是化合物10的抗菌剂量依赖实验结果图：图1a是抗金黄色葡萄球菌的浓度依赖曲线和光剂量依赖曲线；图1b是抗大肠杆菌的浓度依赖曲线和光剂量依赖曲线；图1c是抗白色念珠菌的浓度依赖曲线和光剂量依赖曲线；图1d是抗耐甲氧西林的金黄色葡萄球菌的浓度依赖曲线和光剂量依赖曲线。Figure 1 is the result of the antibacterial dose-dependent experiment of compound 10: Figure 1a is the concentration-dependent curve and light dose-dependent curve of anti-Staphylococcus aureus; Figure 1b is the concentration-dependent curve and light dose-dependent curve of anti-E.coli; Figure 1c is the anti-white The concentration-dependent curve and light dose-dependent curve of Candida; Figure 1d is the concentration-dependent curve and light dose-dependent curve of methicillin-resistant Staphylococcus aureus.
图2是化合物10针对金黄色葡萄球菌的抗菌效果。Figure 2 shows the antibacterial effect of compound 10 against Staphylococcus aureus.
图3是化合物10针对大肠杆菌的抗菌效果。Figure 3 shows the antibacterial effect of compound 10 against Escherichia coli.
图4是化合物10针对白色念珠菌的抗菌效果。Figure 4 shows the antibacterial effect of compound 10 against Candida albicans.
图5是化合物10针对耐甲氧西林的金黄色葡萄球菌的抗菌效果。Figure 5 shows the antibacterial effect of compound 10 against methicillin-resistant Staphylococcus aureus.
具体实施方式Detailed ways
通过下面的实施例可以对本发明进行详细的描述，但并不意味着对本发明任何不利限制。所描述的实施例是本发明的一部分实施例，而不是全部实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前题下所获得的所有实施例，都属于本发明保护范围。The present invention can be described in detail through the following embodiments, but it is not meant to impose any disadvantageous restriction on the present invention. The described embodiments are a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all the embodiments obtained by those of ordinary skill in the art without creative work shall fall within the protection scope of the present invention.
对于以下全部实施例，可使用本领域技术人员已知的标准操作和纯化方法。除非另有说明，所有温度以℃(摄氏度)表示。终产物的结构式通过 1H NMR、 13C NMR和质谱进行确定。 For all the following examples, standard operations and purification methods known to those skilled in the art can be used. Unless otherwise stated, all temperatures are expressed in °C (Celsius). The structural formula of the final product was confirmed by 1 H NMR, 13 C NMR and mass spectrometry.
实施例1：合成化合物1Example 1: Synthesis of compound 1
Figure PCTCN2021072158-appb-000008
Figure PCTCN2021072158-appb-000008
氮气保护条件下，将2I-BDP(100mg,0.2mmol)溶于干燥的DCM(20ml)中，然后加入三氯化硼(0.5ml,0.5mmol)，室温搅拌1.5小时，然后加入二乙氨基乙醇(234mg,2mmol)，室温搅拌过夜。反应结束后，反应液分别用DCM和水溶液萃取，DCM和饱和氯化钠水溶液萃取，分离有机相，无水硫酸钠干燥，减压旋蒸浓缩，通过氧化铝层析(DCM/MeOH＝100/1,v/v)纯化后得到红色固体 粉末69.4mg，产率50％。 1H NMR(400MHz,CDCl 3)δ7.05(s,1H),2.96(t,J＝7.1Hz,4H),2.60(s,6H),2.51–2.36(overlap,12H),2.22(s,6H),0.90(t,J＝6.5Hz,12H).MS(ESI)m/z:[M+2H] 2+found 348.1；calcd.694.1. Under nitrogen protection, dissolve 2I-BDP (100mg, 0.2mmol) in dry DCM (20ml), then add boron trichloride (0.5ml, 0.5mmol), stir at room temperature for 1.5 hours, then add diethylaminoethanol (234mg, 2mmol), stirred at room temperature overnight. After the reaction, the reaction solution was extracted with DCM and aqueous solution respectively, DCM and saturated aqueous sodium chloride solution were extracted, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and passed through alumina chromatography (DCM/MeOH=100/ 1, v/v) After purification, 69.4 mg of red solid powder was obtained, with a yield of 50%. 1 H NMR (400MHz, CDCl 3 ) δ7.05 (s, 1H), 2.96 (t, J = 7.1Hz, 4H), 2.60 (s, 6H), 2.51-2.36 (overlap, 12H), 2.22 (s, 6H),0.90(t,J=6.5Hz,12H).MS(ESI)m/z:[M+2H] 2+ found 348.1; calcd.694.1.
氮气保护条件下，将此红色固体粉末(69.4mg,0.1mmol)溶于乙腈(15ml)，加入过量的碘甲烷，室温搅拌过夜，待反应结束后，减压旋干溶剂，将残余物溶于适量甲醇，以乙醚为不良溶剂，重结晶得到化合物1 90.0mg，产率92％。 1H NMR(400MHz,CD 3OD)δ7.72(s,1H),3.40(q,J＝7.1Hz,8H),3.01(s,6H),2.68(s,6H),2.30(s,6H),1.29(t,J＝7.0Hz,12H). 13C NMR(151MHz,CD 3OD)δ158.29,146.54,135.70,123.75,83.46,62.43,58.55,56.81,16.73,13.91,8.25.HRMS(ESI)m/z:[M-2I] 2+found 362.0939；calcd.362.0935.。 Under nitrogen protection, dissolve this red solid powder (69.4mg, 0.1mmol) in acetonitrile (15ml), add excess methyl iodide, and stir overnight at room temperature. After the reaction is over, the solvent is spin-dried under reduced pressure, and the residue is dissolved in An appropriate amount of methanol was used as a poor solvent to recrystallize to obtain compound 1 90.0 mg, with a yield of 92%. 1 H NMR (400MHz, CD 3 OD) δ7.72 (s, 1H), 3.40 (q, J = 7.1Hz, 8H), 3.01 (s, 6H), 2.68 (s, 6H), 2.30 (s, 6H) ), 1.29 (t, J = 7.0 Hz, 12H). 13 C NMR (151MHz, CD 3 OD) δ158.29,146.54,135.70,123.75,83.46,62.43,58.55,56.81,16.73,13.91,8.25.HRMS (ESI) m/z: [M-2I] 2+ found 362.0939; calcd. 362.0935.
实施例2：合成化合物2Example 2: Synthesis of compound 2
Figure PCTCN2021072158-appb-000009
Figure PCTCN2021072158-appb-000009
氮气保护条件下，将2I-BDP(100mg,0.2mmol)溶于干燥的DCM(20ml)中，然后加入三氯化硼(0.5ml,0.5mmol)，室温搅拌1.5小时，然后加入二乙氨基丙醇(262mg,2mmol)，室温搅拌过夜。反应结束后，反应液分别用DCM和水溶液萃取，DCM和饱和氯化钠水溶液萃取，分离有机相，无水硫酸钠干燥，减压旋蒸浓缩，通过氧化铝层析(DCM/MeOH＝100/1,v/v)纯化后得到红色固体粉末79.5mg，产率55％。 1H NMR(400MHz,CDCl 3)δ7.07(s,1H),2.88(t,J＝6.5Hz,4H),2.60(s,6H),2.46(dd,J＝13.9,6.9Hz,8H),2.40–2.34(m,4H),2.24(s,6H),1.61–1.52(m,4H),0.96(t,J＝7.0Hz,12H).M2S(ESI)m/z:[M+2H] 2+found 362.1；calcd.722.2. Under nitrogen protection, dissolve 2I-BDP (100mg, 0.2mmol) in dry DCM (20ml), then add boron trichloride (0.5ml, 0.5mmol), stir at room temperature for 1.5 hours, then add diethylaminopropyl Alcohol (262mg, 2mmol), stirred at room temperature overnight. After the reaction, the reaction solution was extracted with DCM and aqueous solution respectively, DCM and saturated aqueous sodium chloride solution were extracted, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and passed through alumina chromatography (DCM/MeOH=100/ 1, v/v) After purification, 79.5 mg of red solid powder was obtained, with a yield of 55%. 1 H NMR(400MHz, CDCl 3 )δ7.07(s,1H), 2.88(t,J=6.5Hz,4H), 2.60(s,6H), 2.46(dd,J=13.9,6.9Hz,8H) ,2.40–2.34(m,4H),2.24(s,6H),1.61–1.52(m,4H),0.96(t,J=7.0Hz,12H).M2S(ESI)m/z:[M+2H ] 2+ found 362.1; calcd.722.2.
氮气保护条件下，将此红色固体粉末(72mg,0.1mmol)溶于乙腈(15ml)，加入过量的碘甲烷，室温搅拌过夜，待反应结束后，减压旋干溶剂，将残余物溶于适量甲醇，以乙醚为不良溶剂，重结晶得到化合物2 90.6mg，产率90％。 1H NMR(400MHz,CD 3OD)δ7.67(s,1H),3.37–3.32(m,8H),3.28–3.23(m,4H),3.01(t,J＝5.7Hz,4H),2.96(s,6H),2.62(s,6H),2.29(s,6H),1.79(tt,J＝12.3,6.1Hz,4H),1.31(t,J＝7.0Hz,12H). 13C NMR(151MHz,CD 3OD)δ158.21,146.03, 135.73,123.55,83.02,59.96,59.68,57.78,47.83,25.56,16.41,13.88,8.16.HRMS(ESI)m/z:[M-2I] 2+found 376.1089；calcd.376.1092.。 Under nitrogen protection, dissolve this red solid powder (72mg, 0.1mmol) in acetonitrile (15ml), add excess methyl iodide, and stir overnight at room temperature. After the reaction is over, the solvent is spin-dried under reduced pressure and the residue is dissolved in an appropriate amount Methanol and ether were used as poor solvents to recrystallize to obtain 90.6 mg of compound 2 with a yield of 90%. 1 H NMR(400MHz,CD 3 OD)δ7.67(s,1H), 3.37–3.32(m,8H), 3.28–3.23(m,4H), 3.01(t,J=5.7Hz,4H), 2.96 (s, 6H), 2.62 (s, 6H), 2.29 (s, 6H), 1.79 (tt, J = 12.3, 6.1 Hz, 4H), 1.31 (t, J = 7.0 Hz, 12H). 13 C NMR( 151MHz, CD 3 OD)δ158.21,146.03, 135.73,123.55,83.02,59.96,59.68,57.78,47.83,25.56,16.41,13.88,8.16.HRMS(ESI)m/z:[M-2I] 2+ found 376.1089; calcd.376.1092..
实施例3：合成化合物3Example 3: Synthesis of compound 3
Figure PCTCN2021072158-appb-000010
Figure PCTCN2021072158-appb-000010
氮气保护条件下，将2I-BDP(100mg,0.2mmol)溶于干燥的DCM(20ml)中，然后加入三氯化硼(0.5ml,0.5mmol)，室温搅拌1.5小时，然后加入二甲氨基乙醇(178mg,2mmol)，室温搅拌过夜。反应结束后，反应液分别用DCM和水溶液萃取，DCM和饱和氯化钠水溶液萃取，分离有机相，无水硫酸钠干燥，减压旋蒸浓缩，通过氧化铝层析(DCM/MeOH＝100/1,v/v)纯化后得到红色固体粉末70.2mg，产率55％。 1H NMR(400MHz,CDCl 3)δ7.04(s,1H),3.03–2.92(m,4H),2.60(s,6H),2.41–2.30(m,4H),2.22(s,6H),2.10(s,12H).MS(ESI)m/z:[M+2H] 2+found 320.1；calcd.638.1. Under nitrogen protection, dissolve 2I-BDP (100mg, 0.2mmol) in dry DCM (20ml), then add boron trichloride (0.5ml, 0.5mmol), stir at room temperature for 1.5 hours, then add dimethylaminoethanol (178mg, 2mmol), stirred at room temperature overnight. After the reaction, the reaction solution was extracted with DCM and aqueous solution respectively, DCM and saturated aqueous sodium chloride solution were extracted, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and passed through alumina chromatography (DCM/MeOH=100/ 1. v/v) After purification, 70.2 mg of red solid powder was obtained, with a yield of 55%. 1 H NMR(400MHz, CDCl 3 )δ7.04(s,1H), 3.03-2.92(m,4H), 2.60(s,6H), 2.41--2.30(m,4H), 2.22(s,6H), 2.10(s,12H).MS(ESI)m/z:[M+2H] 2+ found 320.1; calcd.638.1.
氮气保护条件下，将此红色固体粉末(64mg,0.1mmol)溶于乙腈(15ml)，加入过量的碘甲烷，室温搅拌过夜，待反应结束后，减压旋干溶剂，将残余物溶于适量甲醇，以乙醚为不良溶剂，重结晶得到化合物3 82.1mg，产率89％。 1H NMR(400MHz,CD 3OD)δ8.72(d,J＝6.2Hz,1H),7.86(d,J＝6.1Hz,1H),7.63(s,1H),4.33(s,2H),3.00(t,J＝6.0Hz,1H),2.96–2.85(m,1H),2.61(s,2H),2.29(s,2H),1.91–1.67(m,1H). 13C NMR(151MHz,CD 3OD)δ158.35,146.49,135.70,123.58,83.36,68.25,57.40,54.73,16.63,13.84.HRMS(ESI)m/z:[M-2I] 2+found 334.0626；calcd.334.0622.。 Under nitrogen protection, dissolve this red solid powder (64mg, 0.1mmol) in acetonitrile (15ml), add excess methyl iodide, and stir overnight at room temperature. After the reaction is over, the solvent is spin-dried under reduced pressure, and the residue is dissolved in an appropriate amount Methanol and ether were used as poor solvents to recrystallize to obtain 82.1 mg of compound 3, with a yield of 89%. 1 H NMR (400MHz, CD 3 OD) δ8.72 (d, J = 6.2Hz, 1H), 7.86 (d, J = 6.1Hz, 1H), 7.63 (s, 1H), 4.33 (s, 2H), 3.00(t,J=6.0Hz,1H), 2.96–2.85(m,1H), 2.61(s,2H), 2.29(s,2H), 1.91–1.67(m,1H). 13 C NMR(151MHz, CD 3 OD)δ158.35,146.49,135.70,123.58,83.36,68.25,57.40,54.73,16.63,13.84.HRMS(ESI)m/z: [M-2I] 2+ found 334.0626; calcd.334.0622.
实施例4：合成化合物4Example 4: Synthesis of compound 4
Figure PCTCN2021072158-appb-000011
Figure PCTCN2021072158-appb-000011
氮气保护条件下，将2I-BDP(100mg,0.2mmol)溶于干燥的DCM(20ml) 中，然后加入三氯化硼(0.5ml,0.5mmol)，室温搅拌1.5小时，然后加入二甲氨基丙醇(206mg,2mmol)，室温搅拌过夜。反应结束后，反应液分别用DCM和水溶液萃取，DCM和饱和氯化钠水溶液萃取，分离有机相，无水硫酸钠干燥，减压旋蒸浓缩，通过氧化铝层析(DCM/MeOH＝100/1,v/v)纯化后得到红色固体粉末80.0mg，产率60％。 1H NMR(400MHz,CDCl 3)δ7.06(s,1H),2.89(t,J＝6.5Hz,4H),2.60(s,6H),2.25–2.18(m,10H),2.13(s,12H),1.57(dt,J＝13.6,6.7Hz,4H).MS(ESI)m/z:[M+2H] 2+found 334.1；calcd.666.1. Under nitrogen protection, dissolve 2I-BDP (100mg, 0.2mmol) in dry DCM (20ml), then add boron trichloride (0.5ml, 0.5mmol), stir at room temperature for 1.5 hours, then add dimethylaminopropyl Alcohol (206mg, 2mmol), stirred at room temperature overnight. After the reaction, the reaction solution was extracted with DCM and aqueous solution respectively, DCM and saturated aqueous sodium chloride solution were extracted, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and passed through alumina chromatography (DCM/MeOH=100/ 1, v/v) After purification, 80.0 mg of red solid powder was obtained, with a yield of 60%. 1 H NMR (400MHz, CDCl 3 ) δ7.06 (s, 1H), 2.89 (t, J = 6.5Hz, 4H), 2.60 (s, 6H), 2.25-2.18 (m, 10H), 2.13 (s, 12H), 1.57(dt,J=13.6,6.7Hz,4H).MS(ESI)m/z:[M+2H] 2+ found 334.1; calcd.666.1.
氮气保护条件下，将此红色固体粉末(67mg,0.1mmol)溶于乙腈(15ml)，加入过量的碘甲烷，室温搅拌过夜，待反应结束后，减压旋干溶剂，将残余物溶于适量甲醇，以乙醚为不良溶剂，重结晶得到化合物4 72.2mg，产率76％。 1H NMR(400MHz,CD 3OD)δ7.66(s,1H),3.42–3.32(m,4H),3.11(s,18H),3.00(t,J＝5.9Hz,4H),2.61(s,6H),2.29(s,6H),1.86(td,J＝12.0,5.9Hz,4H). 13C NMR(151MHz,CD 3OD)δ156.17,143.92,133.64,121.43,80.92,64.08,57.49,51.69,24.34,14.33,11.82.HRMS(ESI)m/z:[M-2I] 2+found 348.0782；calcd.348.0779.。 Under nitrogen protection, dissolve this red solid powder (67mg, 0.1mmol) in acetonitrile (15ml), add excess methyl iodide, and stir overnight at room temperature. After the reaction is over, the solvent is spin-dried under reduced pressure, and the residue is dissolved in an appropriate amount Methanol and ether were used as poor solvents to recrystallize to obtain 72.2 mg of compound 4, with a yield of 76%. 1 H NMR(400MHz,CD 3 OD)δ7.66(s,1H),3.42–3.32(m,4H),3.11(s,18H), 3.00(t,J=5.9Hz,4H), 2.61(s , 6H), 2.29 (s, 6H), 1.86 (td, J = 12.0, 5.9 Hz, 4H). 13 C NMR (151MHz, CD 3 OD) δ156.17,143.92,133.64,121.43,80.92,64.08,57.49,51.69 ,24.34,14.33,11.82.HRMS(ESI)m/z: [M-2I] 2+ found 348.0782; calcd.348.0779..
实施例5：合成化合物5Example 5: Synthesis of compound 5
Figure PCTCN2021072158-appb-000012
Figure PCTCN2021072158-appb-000012
氮气保护条件下，将2I-BDP(100mg,0.2mmol)溶于干燥的DCM(20ml)中，然后加入三氯化硼(0.5ml,0.5mmol)，室温搅拌1.5小时，然后加入4-羟基吡啶(190mg,2mmol)，室温搅拌过夜。反应结束后，反应液分别用DCM和水溶液萃取，DCM和饱和氯化钠水溶液萃取，分离有机相，无水硫酸钠干燥，减压旋蒸浓缩，通过氧化铝层析(DCM/MeOH＝100/1,v/v)纯化后得到红色固体粉末65.0mg，产率50％。 1H NMR(400MHz,cdcl 3)δ8.21(d,J＝4.0Hz,4H),7.40(s,1H),6.39(d,J＝4.2Hz,4H),2.49(s,6H),2.33(s,6H).MS(ESI)m/z:[M+2H] 2+found 325.6；calcd.650.0. Under nitrogen protection, dissolve 2I-BDP (100mg, 0.2mmol) in dry DCM (20ml), then add boron trichloride (0.5ml, 0.5mmol), stir at room temperature for 1.5 hours, then add 4-hydroxypyridine (190mg, 2mmol), stirred at room temperature overnight. After the reaction, the reaction solution was extracted with DCM and aqueous solution respectively, DCM and saturated aqueous sodium chloride solution were extracted, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and passed through alumina chromatography (DCM/MeOH=100/ 1. v/v) After purification, 65.0 mg of red solid powder was obtained, and the yield was 50%. 1 H NMR (400MHz, cdcl 3 ) δ 8.21 (d, J = 4.0 Hz, 4H), 7.40 (s, 1H), 6.39 (d, J = 4.2 Hz, 4H), 2.49 (s, 6H), 2.33 (s,6H).MS(ESI)m/z:[M+2H] 2+ found 325.6; calcd.650.0.
氮气保护条件下，将此红色固体粉末(65mg,0.1mmol)溶于乙腈(15ml)，加入过量的碘甲烷，室温搅拌过夜，待反应结束后，减压旋干溶剂，将残余物溶于适量甲醇，以乙醚为不良溶剂，重结晶得到化合物5 74.7mg，产率80％。 1H  NMR(600MHz,CD 3OD)δ8.45(d,J＝7.3Hz,4H),8.27(s,1H),6.97(d,J＝7.4Hz,4H),4.10(s,6H),2.47(s,6H),2.45(s,6H). 13C NMR(151MHz,CD 3OD)δ169.17,159.88,150.34,148.48,134.71,125.47,117.44,85.34,47.02,16.43,14.83.HRMS(ESI)m/z:[M-2I] 2+found 340.0156；calcd.340.0153.。 Under nitrogen protection, dissolve this red solid powder (65mg, 0.1mmol) in acetonitrile (15ml), add excess methyl iodide, and stir overnight at room temperature. After the reaction is over, the solvent is spin-dried under reduced pressure, and the residue is dissolved in an appropriate amount Methanol and ether were used as poor solvent to recrystallize to obtain compound 5, 74.7 mg, with a yield of 80%. 1 H NMR(600MHz,CD 3 OD)δ8.45(d,J=7.3Hz,4H), 8.27(s,1H), 6.97(d,J=7.4Hz,4H), 4.10(s,6H), 2.47 (s, 6H), 2.45 (s, 6H). 13 C NMR (151MHz, CD 3 OD) δ169.17,159.88,150.34,148.48,134.71,125.47,117.44,85.34,47.02,16.43,14.83.HRMS (ESI) m/z: [M-2I] 2+ found 340.0156; calcd.340.0153.
实施例6：合成化合物6Example 6: Synthesis of compound 6
Figure PCTCN2021072158-appb-000013
Figure PCTCN2021072158-appb-000013
氮气保护条件下，将2I-BDP(100mg,0.2mmol)溶于干燥的DCM(20ml)中，然后加入三氯化硼(0.5ml,0.5mmol)，室温搅拌1.5小时，然后加入4-吡啶甲醇(218mg,2mmol)，室温搅拌过夜。反应结束后，反应液分别用DCM和水溶液萃取，DCM和饱和氯化钠水溶液萃取，分离有机相，无水硫酸钠干燥，减压旋蒸浓缩，通过氧化铝层析(DCM/MeOH＝100/1,v/v)纯化后得到红色固体粉末91.0mg，产率67％。 1H NMR(400MHz,cdcl 3)δ8.45(d,J＝4.5Hz,4H),7.14(d,J＝4.9Hz,4H),4.06(s,4H),2.51(s,6H),2.27(s,6H).MS(ESI)m/z:[M+2H] 2+found 339.6；calcd.678.0. Under nitrogen protection, dissolve 2I-BDP (100mg, 0.2mmol) in dry DCM (20ml), then add boron trichloride (0.5ml, 0.5mmol), stir at room temperature for 1.5 hours, then add 4-pyridine methanol (218mg, 2mmol), stirred overnight at room temperature. After the reaction, the reaction solution was extracted with DCM and aqueous solution respectively, DCM and saturated aqueous sodium chloride solution were extracted, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and passed through alumina chromatography (DCM/MeOH=100/ 1, v/v) After purification, 91.0 mg of red solid powder was obtained, with a yield of 67%. 1 H NMR (400MHz, cdcl 3 ) δ8.45 (d, J = 4.5 Hz, 4H), 7.14 (d, J = 4.9 Hz, 4H), 4.06 (s, 4H), 2.51 (s, 6H), 2.27 (s,6H).MS(ESI)m/z:[M+2H] 2+ found 339.6; calcd.678.0.
氮气保护条件下，将此红色固体粉末(68mg,0.1mmol)溶于乙腈(15ml)，加入过量的碘甲烷，室温搅拌过夜，待反应结束后，减压旋干溶剂，将残余物溶于适量甲醇，以乙醚为不良溶剂，重结晶得到化合物6 83.6mg，产率87％。 1H NMR(600MHz,CD 3OD)δ8.76(d,J＝6.6Hz,4H),8.00(d,J＝6.6Hz,4H),7.78(s,1H),4.38(s,4H),4.35(s,6H),2.54(s,6H),2.32(s,6H). 13CNMR(151MHz,CD 3OD)δ162.97,158.63,146.72,146.02,135.74,126.03,123.91,83.43,63.50,48.30,16.31,13.94.HRMS(ESI)m/z:[M-2I] 2+found 354.0313；calcd.354.0309.。 Under nitrogen protection, dissolve this red solid powder (68mg, 0.1mmol) in acetonitrile (15ml), add excess methyl iodide, and stir overnight at room temperature. After the reaction is over, the solvent is spin-dried under reduced pressure, and the residue is dissolved in an appropriate amount Methanol and ether were used as poor solvents to recrystallize to obtain Compound 6 83.6 mg, with a yield of 87%. 1 H NMR (600MHz, CD 3 OD) δ8.76 (d, J = 6.6Hz, 4H), 8.00 (d, J = 6.6Hz, 4H), 7.78 (s, 1H), 4.38 (s, 4H), 4.35 (s, 6H), 2.54 (s, 6H), 2.32 (s, 6H). 13 CNMR (151MHz, CD 3 OD) δ162.97,158.63,146.72,146.02,135.74,126.03,123.91,83.43,63.50,48.30, 16.31, 13.94. HRMS(ESI) m/z: [M-2I] 2+ found 354.0313; calcd. 354.0309.
实施例7：合成化合物7Example 7: Synthesis of compound 7
Figure PCTCN2021072158-appb-000014
Figure PCTCN2021072158-appb-000014
氮气保护条件下，将2I-BDP(100mg,0.2mmol)溶于干燥的DCM(20ml) 中，然后加入三氯化硼(0.5ml,0.5mmol)，室温搅拌1.5小时，然后加入4-吡啶乙醇(246mg,2mmol)，室温搅拌过夜。反应结束后，反应液分别用DCM和水溶液萃取，DCM和饱和氯化钠水溶液萃取，分离有机相，无水硫酸钠干燥，减压旋蒸浓缩，通过氧化铝层析(DCM/MeOH＝100/1,v/v)纯化后得到红色固体粉末98.8mg，产率70％。 1H NMR(400MHz,CDCl 3)δ8.40(d,J＝4.0Hz,4H),7.07(s,1H),6.95(d,J＝4.2Hz,4H),3.12(s,4H),2.68(s,4H),2.23-2.21(overlap,12H).MS(ESI)m/z:[M+2H] 2+found 354.0；calcd.706.0. Under nitrogen protection, dissolve 2I-BDP (100mg, 0.2mmol) in dry DCM (20ml), then add boron trichloride (0.5ml, 0.5mmol), stir at room temperature for 1.5 hours, then add 4-pyridineethanol (246mg, 2mmol), stirred at room temperature overnight. After the reaction, the reaction solution was extracted with DCM and aqueous solution respectively, DCM and saturated aqueous sodium chloride solution were extracted, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and passed through alumina chromatography (DCM/MeOH=100/ 1, v/v) After purification, 98.8 mg of red solid powder was obtained, and the yield was 70%. 1 H NMR(400MHz,CDCl 3 )δ8.40(d,J=4.0Hz,4H), 7.07(s,1H), 6.95(d,J=4.2Hz,4H), 3.12(s,4H), 2.68 (s,4H),2.23-2.21(overlap,12H).MS(ESI)m/z:[M+2H] 2+ found 354.0;calcd.706.0.
氮气保护条件下，将此红色固体粉末(71mg,0.1mmol)溶于乙腈(15ml)，加入过量的碘甲烷，室温搅拌过夜，待反应结束后，减压旋干溶剂，将残余物溶于适量甲醇，以乙醚为不良溶剂，重结晶得到化合物7 76.2mg，产率77％。 1H NMR(400MHz,CD 3OD)δ8.73(d,J＝6.2Hz,4H),7.83(d,J＝5.8Hz,4H),7.67(s,1H),4.38(s,6H),3.27(d,J＝5.9Hz,4H),2.95(t,J＝5.9Hz,4H),2.30(s,6H),2.22(s,6H). 13C NMR(151MHz,CD 3OD)δ160.64,156.04,144.03,143.66,133.47,127.42,121.56,80.87,60.05,46.35,36.74,14.10,11.83.HRMS(ESI)m/z:[M-2I] 2+found 368.0478；calcd.368.0466.。 Under nitrogen protection, dissolve this red solid powder (71mg, 0.1mmol) in acetonitrile (15ml), add excess methyl iodide, and stir overnight at room temperature. After the reaction is over, the solvent is spin-dried under reduced pressure, and the residue is dissolved in an appropriate amount Methanol and ether were used as poor solvents to recrystallize to obtain 76.2 mg of compound 7 with a yield of 77%. 1 H NMR(400MHz,CD 3 OD)δ8.73(d,J=6.2Hz,4H), 7.83(d,J=5.8Hz,4H), 7.67(s,1H), 4.38(s,6H), 3.27 (d, J = 5.9 Hz, 4H), 2.95 (t, J = 5.9 Hz, 4H), 2.30 (s, 6H), 2.22 (s, 6H). 13 C NMR (151MHz, CD 3 OD) δ160. 64,156.04,144.03,143.66,133.47,127.42,121.56,80.87,60.05,46.35,36.74,14.10,11.83.HRMS(ESI)m/z: [M-2I] 2+ found 368.0478; calcd.368.0466..
实施例8：合成化合物8Example 8: Synthesis of compound 8
Figure PCTCN2021072158-appb-000015
Figure PCTCN2021072158-appb-000015
氮气保护条件下，将2I-BDP(100mg,0.2mmol)溶于干燥的DCM(20ml)中，然后加入三氯化硼(0.5ml,0.5mmol)，室温搅拌1.5小时，然后加入4-吡啶丙醇(274mg,2mmol)，室温搅拌过夜。反应结束后，反应液分别用DCM和水溶液萃取，DCM和饱和氯化钠水溶液萃取，分离有机相，无水硫酸钠干燥，减压旋蒸浓缩，通过氧化铝层析(DCM/MeOH＝100/1,v/v)纯化后得到红色固体粉末86.6mg，产率59％。 1H NMR(400MHz,CDCl 3)δ8.42(dd,J＝5.3Hz,4H),7.05(s,1H),6.99(dd,J＝5.0Hz,4H),2.89(d,J＝4.0Hz,4H),2.64(s,6H),2.59(d,J＝6.0Hz,4H),2.24(s,6H),1.76–1.67(m,4H).MS(ESI)m/z:[M+2H] 2+found 368.0；calcd.734.1. Under nitrogen protection, dissolve 2I-BDP (100mg, 0.2mmol) in dry DCM (20ml), then add boron trichloride (0.5ml, 0.5mmol), stir at room temperature for 1.5 hours, and then add 4-pyridinepropionate Alcohol (274mg, 2mmol), stirred at room temperature overnight. After the reaction, the reaction solution was extracted with DCM and aqueous solution respectively, DCM and saturated aqueous sodium chloride solution were extracted, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and passed through alumina chromatography (DCM/MeOH=100/ 1. v/v) After purification, 86.6 mg of red solid powder was obtained, with a yield of 59%. 1 H NMR(400MHz,CDCl 3 )δ8.42(dd,J=5.3Hz,4H), 7.05(s,1H), 6.99(dd,J=5.0Hz,4H), 2.89(d,J=4.0Hz ,4H),2.64(s,6H),2.59(d,J=6.0Hz,4H),2.24(s,6H),1.76-1.67(m,4H).MS(ESI)m/z:[M+ 2H] 2+ found 368.0; calcd.734.1.
氮气保护条件下，将此红色固体粉末(73.4mg,0.1mmol)溶于乙腈(15ml)， 加入过量的碘甲烷，室温搅拌过夜，待反应结束后，减压旋干溶剂，将残余物溶于适量甲醇，以乙醚为不良溶剂，重结晶得到化合物8 92.6mg，产率91％。 1H NMR(400MHz,CD 3OD)δ8.72(d,J＝6.2Hz,4H),7.86(d,J＝6.1Hz,4H),7.63(s,1H),4.33(s,6H),3.00(t,J＝6.0Hz,4H),2.94–2.87(m,4H),2.61(s,6H),2.29(s,6H),1.84–1.73(m,4H). 13C NMR(151MHz,CD 3OD)δ156.17,143.92,133.64,121.43,80.92,64.08,57.49,51.69,24.34,14.33,11.82.HRMS(ESI)m/z:[M-2I] 2+found 382.0626；calcd.382.0622.。 Under nitrogen protection, dissolve the red solid powder (73.4mg, 0.1mmol) in acetonitrile (15ml), add excess methyl iodide, and stir overnight at room temperature. After the reaction is over, the solvent is spin-dried under reduced pressure, and the residue is dissolved in Appropriate amount of methanol and ether as a poor solvent were recrystallized to obtain 92.6 mg of compound 8 with a yield of 91%. 1 H NMR (400MHz, CD 3 OD) δ8.72 (d, J = 6.2Hz, 4H), 7.86 (d, J = 6.1Hz, 4H), 7.63 (s, 1H), 4.33 (s, 6H), 3.00(t,J=6.0Hz,4H), 2.94–2.87(m,4H), 2.61(s,6H), 2.29(s,6H), 1.84–1.73(m,4H). 13 C NMR(151MHz, CD 3 OD)δ156.17,143.92,133.64,121.43,80.92,64.08,57.49,51.69,24.34,14.33,11.82.HRMS(ESI)m/z: [M-2I] 2+ found 382.0626; calcd.382.0622.
实施例9：合成化合物9Example 9: Synthesis of compound 9
Figure PCTCN2021072158-appb-000016
Figure PCTCN2021072158-appb-000016
氮气保护条件下，将2I-BDP(100mg,0.2mmol)溶于干燥的DCM(20ml)中，然后加入三氯化硼(0.5ml,0.5mmol)，室温搅拌1.5小时，然后加入4-吡啶丁醇(302mg,2mmol)，室温搅拌过夜。反应结束后，反应液分别用DCM和水溶液萃取，DCM和饱和氯化钠水溶液萃取，分离有机相，无水硫酸钠干燥，减压旋蒸浓缩，通过氧化铝层析(DCM/MeOH＝100/1,v/v)纯化后得到红色固体粉末97.5mg，产率64％。 1H NMR(400MHz,CDCl 3)δ8.44(d,J＝4.6Hz,4H),7.07(s,1H),7.03(d,J＝5.0Hz,4H),2.84(t,J＝6.1Hz,4H),2.55(s,6H),2.48(t,J＝7.7Hz,4H),2.24(s,6H),1.57(dd,J＝15.3,7.9Hz,4H),1.48–1.39(m,4H).MS(ESI)m/z:[M+2H] 2+found 381.8；calcd.762.1. Under nitrogen protection, dissolve 2I-BDP (100mg, 0.2mmol) in dry DCM (20ml), then add boron trichloride (0.5ml, 0.5mmol), stir at room temperature for 1.5 hours, and then add 4-pyridin Alcohol (302mg, 2mmol), stirred at room temperature overnight. After the reaction, the reaction solution was extracted with DCM and aqueous solution respectively, DCM and saturated aqueous sodium chloride solution were extracted, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and passed through alumina chromatography (DCM/MeOH=100/ 1. v/v) After purification, 97.5 mg of red solid powder was obtained, with a yield of 64%. 1 H NMR(400MHz,CDCl 3 )δ8.44(d,J=4.6Hz,4H), 7.07(s,1H), 7.03(d,J=5.0Hz,4H), 2.84(t,J=6.1Hz ,4H),2.55(s,6H),2.48(t,J=7.7Hz,4H),2.24(s,6H),1.57(dd,J=15.3,7.9Hz,4H),1.48–1.39(m, 4H).MS(ESI)m/z:[M+2H] 2+ found 381.8; calcd.762.1.
氮气保护条件下，将此红色固体粉末(76mg,0.1mmol)溶于乙腈(15ml)，加入过量的碘甲烷，室温搅拌过夜，待反应结束后，减压旋干溶剂，将残余物溶于适量甲醇，以乙醚为不良溶剂，重结晶得到化合物9 91.0mg，产率87％。 1H NMR(400MHz,CD 3OD)δ8.74(d,J＝5.3Hz,4H),7.87(d,J＝5.7Hz,4H),7.61(s,1H),4.31(s,6H),2.92(t,J＝6.0Hz,4H),2.83(t,J＝7.2Hz,4H),2.53(s,6H),2.28(s,6H),1.71–1.60(m,4H),1.50–1.37(m,3H). 13CNMR(151MHz,CD 3OD)δ164.65,158.13,146.01,145.52,135.73,128.89,123.31,82.64,62.28,48.21,36.26,32.20,27.66,16.23,13.86.HRMS(ESI)m/z:[M-2I] 2+found 396.0778；calcd.396.0779.。 Under nitrogen protection, dissolve this red solid powder (76mg, 0.1mmol) in acetonitrile (15ml), add excess methyl iodide, and stir overnight at room temperature. After the reaction is over, the solvent is spin-dried under reduced pressure, and the residue is dissolved in an appropriate amount Methanol and ether were used as poor solvents to recrystallize to obtain 91.0 mg of compound 9 with a yield of 87%. 1 H NMR(400MHz,CD 3 OD)δ8.74(d,J=5.3Hz,4H), 7.87(d,J=5.7Hz,4H), 7.61(s,1H), 4.31(s,6H), 2.92(t,J=6.0Hz,4H),2.83(t,J=7.2Hz,4H),2.53(s,6H),2.28(s,6H),1.71-1.60(m,4H),1.50-1.37 (m,3H). 13 CNMR (151MHz, CD 3 OD) δ164.65,158.13,146.01,145.52,135.73,128.89,123.31,82.64,62.28,48.21,36.26,32.20,27.66,16.23,13.86.HRMS(ESI)m /z:[M-2I] 2+ found 396.0778; calcd.396.0779.
实施例10：合成化合物10Example 10: Synthesis of compound 10
Figure PCTCN2021072158-appb-000017
Figure PCTCN2021072158-appb-000017
氮气保护条件下，将炔丙胺(166mg,2mmol)，乙基溴化镁(2ml,2mmol)溶于干燥的THF(20ml)，60℃反应2小时，将2I-BDP(100mg,0.2mmol)加入此反应液中，搅拌过夜。反应结束后，反应液旋干后用DCM和饱和氯化钠水溶液萃取，分离有机相，无水硫酸钠干燥，减压旋蒸浓缩，通过氧化铝层析(DCM/MeOH＝200/1,v/v)纯化后得到红色固体粉末87.6mg，产率70％。 1H NMR(400MHz,CDCl 3)δ6.86(s,1H),2.92(s,4H),2.53(d,J＝12.7Hz,6H),2.01(s,12H),1.98(s,6H).MS(ESI)m/z:[M+2H] 2+found 314.1；calcd.626.1. Under nitrogen protection, dissolve propargylamine (166mg, 2mmol) and ethyl magnesium bromide (2ml, 2mmol) in dry THF (20ml), react at 60°C for 2 hours, add 2I-BDP (100mg, 0.2mmol) In this reaction solution, stir overnight. After the reaction, the reaction solution was spin-dried and then extracted with DCM and saturated aqueous sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and passed through alumina chromatography (DCM/MeOH=200/1, v /v) After purification, 87.6 mg of red solid powder was obtained, with a yield of 70%. 1 H NMR (400MHz, CDCl 3 ) δ 6.86 (s, 1H), 2.92 (s, 4H), 2.53 (d, J = 12.7 Hz, 6H), 2.01 (s, 12H), 1.98 (s, 6H) .MS(ESI)m/z:[M+2H] 2+ found 314.1; calcd.626.1.
氮气保护条件下，将此红色固体粉末(63mg,0.1mmol)溶于乙腈(15ml)，加入过量的碘甲烷，室温搅拌过夜，待反应结束后，减压旋干溶剂，将残余物溶于适量甲醇，以乙醚为不良溶剂，重结晶得到化合物10 81.9mg，产率90％。 1H NMR(400MHz,CD 3OD)δ7.73(s,1H),4.32(s,4H),3.15(s,18H),2.79(s,6H),2.31(s,6H). 13CNMR(151MHz,CD 3OD)δ157.86,145.90,132.52,123.64,84.86,83.06,58.33,53.36,49.61,17.81,13.85.HRMS(ESI)m/z:[M-2I] 2+found 328.0522；calcd.328.0517.。 Under nitrogen protection, dissolve this red solid powder (63mg, 0.1mmol) in acetonitrile (15ml), add excess methyl iodide, and stir overnight at room temperature. After the reaction is over, the solvent is spin-dried under reduced pressure and the residue is dissolved in an appropriate amount Methanol and ether were used as a poor solvent to recrystallize to obtain 81.9 mg of compound 10, with a yield of 90%. 1 H NMR (400MHz, CD 3 OD) δ 7.73 (s, 1H), 4.32 (s, 4H), 3.15 (s, 18H), 2.79 (s, 6H), 2.31 (s, 6H). 13 CNMR ( 151MHz, CD 3 OD) δ157.86,145.90,132.52,123.64,84.86,83.06,58.33,53.36,49.61,17.81,13.85.HRMS(ESI)m/z: [M-2I] 2+ found 328.0522; calcd.328.0517. .
实施例11：合成化合物11Example 11: Synthesis of compound 11
Figure PCTCN2021072158-appb-000018
Figure PCTCN2021072158-appb-000018
氮气保护条件下，将4-炔基吡啶(154mg,1.5mmol)，乙基溴化镁(1.5ml,1.5mmol)溶于干燥的THF(20ml)，60℃反应2小时，将2I-BDP(75mg,0.15mmol)加入此反应液中，搅拌过夜。反应结束后，反应液旋干后用DCM和饱和氯化钠水溶液萃取，分离有机相，无水硫酸钠干燥，减压旋蒸浓缩，通过氧化铝层析(DCM/MeOH＝200/1,v/v)纯化后得到红色固体粉末45.6mg，产率45％。 1H NMR(400MHz,CDCl 3)δ8.50(d,J＝2.2Hz,4H),7.23(d,J＝0.6Hz,5H),2.86(s,6H),2.29(s,6H).MS(ESI)m/z:[M+2H] 2+found 338.0；calcd.666.0 Under nitrogen protection, dissolve 4-alkynylpyridine (154mg, 1.5mmol) and ethylmagnesium bromide (1.5ml, 1.5mmol) in dry THF (20ml) and react at 60°C for 2 hours. The 2I-BDP( 75mg, 0.15mmol) was added to the reaction solution and stirred overnight. After the reaction, the reaction solution was spin-dried and then extracted with DCM and saturated aqueous sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and passed through alumina chromatography (DCM/MeOH=200/1, v /v) After purification, 45.6 mg of red solid powder was obtained, with a yield of 45%. 1 H NMR(400MHz, CDCl 3 )δ8.50(d,J=2.2Hz,4H), 7.23(d,J=0.6Hz,5H), 2.86(s,6H), 2.29(s,6H).MS (ESI)m/z:[M+2H] 2+ found 338.0; calcd.666.0
氮气保护条件下，将此红色固体粉末(40mg,0.06mmol)溶于乙腈(15ml)，加入过量的碘甲烷，室温搅拌过夜，待反应结束后，减压旋干溶剂，将残余物溶于适量甲醇，以乙醚为不良溶剂，重结晶得到化合物11 29mg，产率51％。 1H NMR(600MHz,CD 3OD)δ8.80(d,J＝6.7Hz,4H),8.00(d,J＝6.8Hz,4H),7.82(s,1H),4.36(s,6H),2.87(s,6H),2.37(s,6H). 13C NMR(151MHz,CD 3OD)δ156.22,144.46,144.32,140.18,130.56,128.81,128.68,121.70,81.24,47.53,15.57,11.83.HRMS(ESI)m/z:[M-2I] 2+found 348.0213；calcd.348.0204.。 Under nitrogen protection, dissolve this red solid powder (40mg, 0.06mmol) in acetonitrile (15ml), add excess methyl iodide, and stir overnight at room temperature. After the reaction is over, the solvent is spin-dried under reduced pressure and the residue is dissolved in an appropriate amount Methanol and ether were used as poor solvent to recrystallize to obtain 29 mg of compound 11, with a yield of 51%. 1 H NMR (600MHz, CD 3 OD) δ 8.80 (d, J = 6.7 Hz, 4H), 8.00 (d, J = 6.8 Hz, 4H), 7.82 (s, 1H), 4.36 (s, 6H), 2.87(s,6H), 2.37(s,6H). 13 C NMR(151MHz, CD 3 OD) δ156.22,144.46,144.32,140.18,130.56,128.81,128.68,121.70,81.24,47.53,15.57,11.83.HRMS( ESI) m/z: [M-2I] 2+ found 348.0213; calcd. 348.0204.
实施例12：合成化合物12Example 12: Synthesis of compound 12
Figure PCTCN2021072158-appb-000019
Figure PCTCN2021072158-appb-000019
氮气保护条件下，将3-炔基吡啶(154mg,1.5mmol)，乙基溴化镁(1.5ml,1.5mmol)溶于干燥的THF(20ml)，60℃反应2小时，将2I-BDP(75mg,0.15mmol)加入此反应液中，搅拌过夜。反应结束后，反应液旋干后用DCM和饱和氯化钠水溶液萃取，分离有机相，无水硫酸钠干燥，减压旋蒸浓缩，通过氧化铝层析(DCM/MeOH＝200/1,v/v)纯化后得到红色固体粉末66mg，产率66％。 1H NMR(400MHz,CDCl 3)δ8.61(s,2H),8.45(d,J＝3.8Hz,2H),7.67(d,J＝7.0Hz,2H),7.22(s,1H),7.19(dd,J＝6.9,4.7Hz,2H),2.89(s,6H),2.29(s,6H).MS(ESI)m/z:[M+2H] 2+found 338.0；calcd.666.0 Under nitrogen protection, dissolve 3-alkynylpyridine (154mg, 1.5mmol) and ethylmagnesium bromide (1.5ml, 1.5mmol) in dry THF (20ml) and react at 60°C for 2 hours. The 2I-BDP( 75mg, 0.15mmol) was added to the reaction solution and stirred overnight. After the reaction, the reaction solution was spin-dried and then extracted with DCM and saturated aqueous sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and passed through alumina chromatography (DCM/MeOH=200/1, v /v) After purification, 66 mg of red solid powder was obtained, with a yield of 66%. 1 H NMR(400MHz,CDCl 3 )δ8.61(s,2H), 8.45(d,J=3.8Hz,2H), 7.67(d,J=7.0Hz,2H), 7.22(s,1H), 7.19 (dd,J=6.9,4.7Hz,2H),2.89(s,6H),2.29(s,6H).MS(ESI)m/z:[M+2H] 2+ found 338.0; calcd.666.0
氮气保护条件下，将此红色固体粉末(40mg,0.06mmol)溶于乙腈(15ml)，加入过量的碘甲烷，室温搅拌过夜，待反应结束后，减压旋干溶剂，将残余物溶于适量甲醇，以乙醚为不良溶剂，重结晶得到化合物12 38mg，产率67％。 1H NMR(400MHz,D6-DMSO)δ9.13(s,2H),8.88(s,2H),8.56(d,J＝7.1Hz,2H),8.04(s,3H),4.26(s,6H),2.83(s,6H),2.30(s,6H). 13C NMR(151MHz,D6-DMSO)δ156.58,151.68,147.25,142.33,137.82,130.47,122.18,120.99,119.99,92.06,81.87,65.24,16.45,13.22.HRMS(ESI)m/z:[M-2I] 2+found 348.0211；calcd.348.0204.。 Under nitrogen protection, dissolve this red solid powder (40mg, 0.06mmol) in acetonitrile (15ml), add excess methyl iodide, and stir overnight at room temperature. After the reaction is over, the solvent is spin-dried under reduced pressure and the residue is dissolved in an appropriate amount Methanol and ether were used as poor solvent to recrystallize to obtain 38 mg of compound 12 with a yield of 67%. 1 H NMR(400MHz,D6-DMSO)δ9.13(s,2H),8.88(s,2H), 8.56(d,J=7.1Hz,2H), 8.04(s,3H), 4.26(s,6H) ), 2.83 (s, 6H), 2.30 (s, 6H). 13 C NMR (151MHz, D6-DMSO) δ156.58,151.68,147.25,142.33,137.82,130.47,122.18,120.99,119.99,92.06,81.87,65.24, 16.45, 13.22. HRMS(ESI) m/z: [M-2I] 2+ found 348.0211; calcd. 348.0204.
实施例13：化合物光学参数的测试Example 13: Test of optical parameters of compounds
将所合成的化合物测试了在乙腈中的最大吸收波长(absλ max)、摩尔消光系数(ε)、荧光发射波长(fluλ max)、荧光量子产率(Φ f)，光敏化效率( 1O 2rate)和油水分配系数(logP)对应的数据如表1所示，光敏化效率以Rose Bengal为参照。结果显示,BODIPY4位引入双阳离子基团使其具有两亲性，不同取代基对染料的光谱性质影响并不显著；碘原子的引入使分子光谱红移，摩尔消光系数变化不大，荧光量子产率降低，光敏化效率显著提升，化合物1-12均具有较强的光敏化效率，显示为优良的光敏剂。 The synthesized compound was tested for maximum absorption wavelength (absλ max ), molar extinction coefficient (ε), fluorescence emission wavelength (fluλ max ), fluorescence quantum yield (Φ f ), photosensitization efficiency ( 1 O 2) in acetonitrile The data corresponding to rate) and the oil-water partition coefficient (logP) are shown in Table 1. The photosensitization efficiency is based on Rose Bengal. The results show that the introduction of a double cationic group at the 4 position of BODIPY makes it amphiphilic, and the different substituents have no significant effect on the spectral properties of the dye; the introduction of iodine atoms makes the molecular spectrum red shift, the molar extinction coefficient changes little, and the fluorescence quantum yields The photosensitization efficiency is reduced, and the photosensitization efficiency is significantly improved. Compounds 1-12 all have strong photosensitization efficiency and are shown to be excellent photosensitizers.
表1 BODIPY染料的性质Table 1 Properties of BODIPY dyes
Figure PCTCN2021072158-appb-000020
Figure PCTCN2021072158-appb-000020
实施例14：抗菌活性测试Example 14: Antibacterial activity test
微生物培养：实验选用金黄色葡萄球菌(S.aureus，ATCC25923)，大肠杆菌(E.coli,ATCC25922)，白色念珠菌(C.albicans，ATCC14053)以及耐甲氧西林的金黄色葡萄球菌(MRSA,ATCC43300),培养基为LB肉汤培养基，培养基内含胰蛋白胨、酵母提取物和NaCl等，在37℃含有5％CO 2培养箱中培养。 Microbial culture: Staphylococcus aureus (ATCC25923), E.coli (ATCC25922), Candida albicans (C.albicans, ATCC14053) and methicillin-resistant Staphylococcus aureus (MRSA, ATCC43300), the medium is LB broth medium, which contains tryptone, yeast extract and NaCl, etc., cultured in an incubator containing 5% CO 2 at 37°C.
活性测试：将CFU浓度为1×10 5的细菌(CFU浓度为1×10 3的白念菌)与 系列稀释的化合物孵育20min，而后用最大发射波长520nm的LED等照射30min,光强10mW/cm 2,光剂量18J/cm 2，至37℃恒温箱培养24小时，观察菌溶液澄清或是浑浊，以菌溶液澄清所对应的化合物最小浓度为最小抑菌浓度。结果如表2所示。 Activity test: Incubate bacteria with a CFU concentration of 1×10 5 (Candella albicans with a CFU concentration of 1×10 3 ) and serially diluted compounds for 20 minutes, and then irradiate them with LEDs with a maximum emission wavelength of 520 nm for 30 minutes at a light intensity of 10 mW/ cm 2 , light dose 18J/cm 2 , incubate for 24 hours in a constant temperature box at 37°C, observe that the bacterial solution is clear or turbid, and the minimum concentration of the compound corresponding to the clarification of the bacterial solution is the minimum inhibitory concentration. The results are shown in Table 2.
表2光敏剂的MICTable 2 MIC of photosensitizer
Figure PCTCN2021072158-appb-000021
Figure PCTCN2021072158-appb-000021
实施例15：剂量依赖测试Example 15: Dose dependent test
微生物培养：实验选用金黄色葡萄球菌(S.aureus，ATCC25923)，大肠杆菌(E.coli,ATCC25922)，白色念珠菌(C.albicans，ATCC14053)以及耐甲氧西林的金黄色葡萄球菌(MRSA,ATCC43300),培养基为LB肉汤培养基，培养基内含胰蛋白胨、酵母提取物和NaCl等，在37℃含有5％CO 2培养箱中培养。 Microbial culture: Staphylococcus aureus (ATCC25923), E.coli (ATCC25922), Candida albicans (C.albicans, ATCC14053) and methicillin-resistant Staphylococcus aureus (MRSA, ATCC43300), the medium is LB broth medium, which contains tryptone, yeast extract and NaCl, etc., cultured in an incubator containing 5% CO 2 at 37°C.
浓度依赖测试：将CFU浓度为OD 600nm＝1.0的微生物与系列稀释的化合物10孵育10min，而后用最大发射波长520nm的LED等照射10min,光强10mW/cm 2,光剂量6J/cm 2(对白念菌9J/cm 2),对照组无光照，而后采用平板计 数法测量抑菌曲线，结果如图1与图2-5所示。 Concentration-dependent test: Incubate microorganisms with a CFU concentration of OD 600nm = 1.0 with serially diluted compound 10 for 10 minutes, and then irradiate them with LEDs with a maximum emission wavelength of 520 nm for 10 minutes, with a light intensity of 10 mW/cm 2 , and a light dose of 6 J/cm 2 (on white Candida 9J/cm 2 ), the control group has no light, and then the antibacterial curve is measured by the plate counting method. The results are shown in Figure 1 and Figure 2-5.
光剂量依赖测试：将CFU浓度为OD 600nm＝1.0的微生物与一定浓度的化合物10孵育10min，而后用最大发射波长520nm的LED等照射0～15min,光强10mW/cm 2,光剂量0～9J/cm 2，对照组不加化合物10，而后采用平板计数法测量抑菌曲线，结果如图1与图2-5所示。 Light dose dependent test: Incubate microorganisms with a CFU concentration of OD 600nm = 1.0 with a certain concentration of compound 10 for 10 minutes, and then irradiate them with LEDs with a maximum emission wavelength of 520 nm for 0-15 minutes, light intensity 10mW/cm 2 , and light dose 0-9J /cm 2 , compound 10 was not added to the control group, and then the antibacterial curve was measured by the plate counting method. The results are shown in Figure 1 and Figure 2-5.
光敏剂10与菌株孵育后不加光照时，对菌株无杀灭能力，即没有表现出暗毒性。When the photosensitizer 10 is incubated with the strain without adding light, it has no ability to kill the strain, that is, it does not exhibit dark toxicity.
光敏剂10与菌株孵育加光照后对金黄色葡萄球菌、大肠杆菌、白色念珠菌以及耐甲氧西林的金黄色葡萄球菌的杀灭能力随化合物浓度和光剂量的增加而增加。The ability of photosensitizer 10 to kill Staphylococcus aureus, Escherichia coli, Candida albicans and methicillin-resistant Staphylococcus aureus after incubation with the strain and light increases with the increase of compound concentration and light dose.

Claims (20)

  1. 式(Ⅰ)或(Ⅱ)结构的4位阳离子双取代BODIPY化合物，The 4-position cation disubstituted BODIPY compound of formula (Ⅰ) or (Ⅱ) structure,
    Figure PCTCN2021072158-appb-100001
    Figure PCTCN2021072158-appb-100001
    其中：in:
    R独立地选自各类季铵盐阳离子，包含碘甲烷化二甲氨基、碘甲烷化二乙氨基、碘甲烷化吡啶(包括邻间对各个位置)得到的季铵盐阳离子；碘乙烷化二甲氨基、碘乙烷化二乙氨基、碘乙烷化吡啶(包括邻间对各个位置)；溴乙烷化二甲氨基、溴乙烷化二乙氨基、溴乙烷化吡啶(包括邻间对各个位置)；n＝0～6；R is independently selected from various types of quaternary ammonium cations, including methyl iodide, dimethylamino iodide, diethylamino iodide, and pyridine iodide (including adjacent pairs); Dimethylamino, iodoethaneated diethylamino, iodoethaneated pyridine (including o-to-pair positions); bromoethaneated dimethylamino, bromoethaneated diethylamino, bromoethaneated pyridine (including o- To each position); n=0～6;
    X选自有重原子效应的原子：碘、溴、氯、硫；X is selected from atoms with heavy atom effect: iodine, bromine, chlorine, sulfur;
    R 1、R 2独立地选自C 1-6烷基、羟基取代C 1-6烷基、氨基取代C 1-6烷基、卤素取代C 1-6烷基、通过双键连接的芳香环：苯环、萘环、蒽环、咔唑环； R 1 and R 2 are independently selected from the group consisting of C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, amino-substituted C 1-6 alkyl, halogen-substituted C 1-6 alkyl, and aromatic rings connected by a double bond ：Benzene ring, naphthalene ring, anthracene ring, carbazole ring;
    R 3、R 4独立地选自C 1-6烷基、羟基取代C 1-6烷基、氨基取代C 1-6烷基、卤素取代C 1-6烷基； R 3 and R 4 are independently selected from C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, amino substituted C 1-6 alkyl, halogen substituted C 1-6 alkyl;
    R 5独立地选自C 1-6烷基、羟基取代C 1-6烷基、氨基取代C 1-6烷基、卤素取代C 1-6烷基、苯基、吡啶基、羧基、C 1-6酯基、C 1-6酰胺。 R 5 is independently selected from C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, amino substituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, phenyl, pyridyl, carboxyl, C 1 -6 ester group, C 1-6 amide.
  2. 根据权利要求1所述的4位阳离子双取代BODIPY化合物，其特征在于，其中R独立地选自碘甲烷化二甲氨基、碘甲烷化二乙氨基、碘甲烷化吡啶(包括间位、对位)得到的季铵盐阳离子；通式I的n＝1～4，通式II的n＝1；X优选为碘原子；R 1-R 4为甲基。 The 4-position cation disubstituted BODIPY compound according to claim 1, wherein R is independently selected from the group consisting of iodomethane dimethylamino, iodomethane diethylamino, iodomethane pyridine (including meta and para ) The obtained quaternary ammonium salt cation; n=1 to 4 in general formula I, n=1 in general formula II; X is preferably an iodine atom; R 1 -R 4 are methyl groups.
  3. 根据权利要求1或2所述的4位阳离子双取代BODIPY化合物，其特征在于，所述的化合物为下述结构的化合物1，The 4-position cation disubstituted BODIPY compound according to claim 1 or 2, wherein the compound is compound 1 of the following structure,
    Figure PCTCN2021072158-appb-100002
    Figure PCTCN2021072158-appb-100002
  4. 根据权利要求1或2所述的4位阳离子双取代BODIPY化合物，其特征在于，所述的化合物为下述结构的化合物2，The 4-position cation disubstituted BODIPY compound according to claim 1 or 2, wherein the compound is compound 2 of the following structure,
    Figure PCTCN2021072158-appb-100003
    Figure PCTCN2021072158-appb-100003
  5. 根据权利要求1或2所述的4位阳离子双取代BODIPY化合物，其特征在于，所述的化合物为下述结构的化合物3，The 4-position cation disubstituted BODIPY compound according to claim 1 or 2, wherein the compound is compound 3 of the following structure,
    Figure PCTCN2021072158-appb-100004
    Figure PCTCN2021072158-appb-100004
  6. 根据权利要求1或2所述的4位阳离子双取代BODIPY化合物，其特征在于，所述的化合物为下述结构的化合物4，The 4-position cation disubstituted BODIPY compound according to claim 1 or 2, wherein the compound is compound 4 of the following structure,
    Figure PCTCN2021072158-appb-100005
    Figure PCTCN2021072158-appb-100005
    Figure PCTCN2021072158-appb-100006
    Figure PCTCN2021072158-appb-100006
  7. 根据权利要求1或2所述的4位阳离子双取代BODIPY化合物，其特征在于，所述的化合物为下述结构的化合物5，The 4-position cation disubstituted BODIPY compound according to claim 1 or 2, wherein the compound is compound 5 of the following structure,
    Figure PCTCN2021072158-appb-100007
    Figure PCTCN2021072158-appb-100007
  8. 根据权利要求1或2所述的4位阳离子双取代BODIPY化合物，其特征在于，所述的化合物为下述结构的化合物6，The 4-position cation disubstituted BODIPY compound according to claim 1 or 2, wherein the compound is compound 6 of the following structure,
    Figure PCTCN2021072158-appb-100008
    Figure PCTCN2021072158-appb-100008
  9. 根据权利要求1或2所述的4位阳离子双取代BODIPY化合物，其特征在于，所述的化合物为下述结构的化合物7，The 4-position cation disubstituted BODIPY compound according to claim 1 or 2, wherein the compound is compound 7 of the following structure,
    Figure PCTCN2021072158-appb-100009
    Figure PCTCN2021072158-appb-100009
  10. 根据权利要求1或2所述的4位阳离子双取代BODIPY化合物，其特征在于，所述的化合物为下述结构的化合物8，The 4-position cation disubstituted BODIPY compound according to claim 1 or 2, wherein the compound is compound 8 of the following structure,
    Figure PCTCN2021072158-appb-100010
    Figure PCTCN2021072158-appb-100010
  11. 根据权利要求1或2所述的4位阳离子双取代BODIPY化合物，其特征在于，所述的化合物为下述结构的化合物9，The 4-position cation disubstituted BODIPY compound according to claim 1 or 2, wherein the compound is compound 9 of the following structure,
    Figure PCTCN2021072158-appb-100011
    Figure PCTCN2021072158-appb-100011
  12. 根据权利要求1或2所述的4位阳离子双取代BODIPY化合物，其特征在于，所述的化合物为下述结构的化合物10，The 4-position cation disubstituted BODIPY compound according to claim 1 or 2, wherein the compound is compound 10 of the following structure,
    Figure PCTCN2021072158-appb-100012
    Figure PCTCN2021072158-appb-100012
  13. 根据权利要求1或2所述的4位阳离子双取代BODIPY化合物，其特征在于，所述的化合物为下述结构的化合物11，The 4-position cation disubstituted BODIPY compound according to claim 1 or 2, wherein the compound is compound 11 of the following structure,
    Figure PCTCN2021072158-appb-100013
    Figure PCTCN2021072158-appb-100013
  14. 根据权利要求1或2所述的4位阳离子双取代BODIPY化合物，其特征在于，所述的化合物为下述结构的化合物12，The 4-position cation disubstituted BODIPY compound according to claim 1 or 2, wherein the compound is compound 12 of the following structure,
    Figure PCTCN2021072158-appb-100014
    Figure PCTCN2021072158-appb-100014
  15. 根据权利要求1或2所述的4位阳离子双取代BODIPY化合物，其特征在于，所述的化合物为下述结构的化合物13，The 4-position cation disubstituted BODIPY compound according to claim 1 or 2, wherein the compound is compound 13 of the following structure,
    Figure PCTCN2021072158-appb-100015
    Figure PCTCN2021072158-appb-100015
  16. 根据权利要求1或2所述的4位阳离子双取代BODIPY化合物，其特征在于，所述的化合物为下述结构的化合物14，The 4-position cation disubstituted BODIPY compound according to claim 1 or 2, wherein the compound is compound 14 of the following structure,
    Figure PCTCN2021072158-appb-100016
    Figure PCTCN2021072158-appb-100016
  17. 权利要求1-16所述的4位阳离子双取代BODIPY化合物在制备光动力抗菌药物中的用途。Use of the 4-position cation double-substituted BODIPY compound described in claims 1-16 in the preparation of photodynamic antibacterial drugs.
  18. 按权利要求17所述的用途，其特征在于，所述的抗菌药物为可作为荧光显像剂和光动力抗菌的光敏剂。The use according to claim 17, wherein the antibacterial drug is a photosensitizer that can be used as a fluorescent imaging agent and photodynamic antibacterial.
  19. 按权利要求17所述的用途，其特征在于，所述的抗菌药物用于抑制革兰氏阳性菌如金黄色葡萄球菌、革兰氏阴性菌如大肠杆菌、真菌(白色念珠菌或临床耐药菌的活性。The use according to claim 17, wherein the antibacterial drug is used to inhibit Gram-positive bacteria such as Staphylococcus aureus, Gram-negative bacteria such as Escherichia coli, fungi (Candida albicans or clinically resistant The activity of bacteria.
  20. 按权利要求17所述的用途，其特征在于，所述的抗菌药物的应用途径包括和其他种类消毒剂如过氧化氢或医用酒精联用。The use according to claim 17, characterized in that the application route of the antibacterial drug includes combined use with other kinds of disinfectants such as hydrogen peroxide or medical alcohol.
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