WO2021169661A1 - Composés bodipy à double substitution cationique en position 4, leurs procédés de préparation et leur utilisation - Google Patents

Composés bodipy à double substitution cationique en position 4, leurs procédés de préparation et leur utilisation 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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PCT/CN2021/072158
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English (en)
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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte au domaine de la technologie antimicrobienne photodynamique et concerne des composés BODIPY de formule (I) ou (II), en particulier des composés BODIPY à double substitution cationique en position 4, leur procédé de préparation et leur utilisation dans la préparation de médicaments antimicrobiens. Les composés de la présente invention peuvent se fixer à des micro-organismes au moyen d'une action électrostatique, et peuvent considérablement inhiber la croissance de micro-organismes après l'action photodynamique. Selon des résultats d'essai, les composés présentent une bonne activité antimicrobienne photodynamique et peuvent en outre être préparés en de nouveaux médicaments antimicrobiens aux fins d'une utilisation clinique, d'une hygiène alimentaire et d'un élevage.
PCT/CN2021/072158 2020-02-28 2021-01-15 Composés bodipy à double substitution cationique en position 4, leurs procédés de préparation et leur utilisation WO2021169661A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202010127505 2020-02-28
CN202010127505.X 2020-02-28
CN202010592762.0A CN113402535B (zh) 2020-02-28 2020-06-25 4位阳离子双取代bodipy类化合物及其制备方法和用途
CN202010592762.0 2020-06-25

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114230595A (zh) * 2021-12-22 2022-03-25 中国科学院长春应用化学研究所 带正电的bodipy光敏剂及其制备方法与应用
CN114940691A (zh) * 2022-05-31 2022-08-26 扬州大学 一种含荧光基团的双官能化顺铂衍生物及其杀灭细菌的应用

Citations (8)

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JP2000029213A (ja) * 1998-07-15 2000-01-28 Kansai Paint Co Ltd ポジ型可視光感光性樹脂組成物及びその用途
JP2000029205A (ja) * 1998-07-15 2000-01-28 Kansai Paint Co Ltd ポジ型可視光感光性樹脂組成物及びその用途
TW494275B (en) * 1997-08-12 2002-07-11 Mitsui Chemicals Inc Photosensitizer and visible light curable resin composition comprising the same
CN102300868A (zh) * 2008-12-29 2011-12-28 国家科学研究中心 二吡咯亚甲基-硼亲水性荧光化合物
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CN106565760A (zh) * 2016-11-11 2017-04-19 深圳市声光动力生物医药科技有限公司 氟硼二吡咯衍生物及其制备方法和在医药上的应用
CN108752401A (zh) * 2018-06-27 2018-11-06 西南大学 一种含bodipy杀菌材料及其制备方法和应用

Patent Citations (8)

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Publication number Priority date Publication date Assignee Title
TW494275B (en) * 1997-08-12 2002-07-11 Mitsui Chemicals Inc Photosensitizer and visible light curable resin composition comprising the same
JP2000029213A (ja) * 1998-07-15 2000-01-28 Kansai Paint Co Ltd ポジ型可視光感光性樹脂組成物及びその用途
JP2000029205A (ja) * 1998-07-15 2000-01-28 Kansai Paint Co Ltd ポジ型可視光感光性樹脂組成物及びその用途
CN102300868A (zh) * 2008-12-29 2011-12-28 国家科学研究中心 二吡咯亚甲基-硼亲水性荧光化合物
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114230595A (zh) * 2021-12-22 2022-03-25 中国科学院长春应用化学研究所 带正电的bodipy光敏剂及其制备方法与应用
CN114940691A (zh) * 2022-05-31 2022-08-26 扬州大学 一种含荧光基团的双官能化顺铂衍生物及其杀灭细菌的应用
CN114940691B (zh) * 2022-05-31 2023-10-31 扬州大学 一种含荧光基团的双官能化顺铂衍生物及其杀灭细菌的应用

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