CN112979732B - Furocoumarin compound and application thereof in mycobacterium tuberculosis detection - Google Patents
Furocoumarin compound and application thereof in mycobacterium tuberculosis detection Download PDFInfo
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- CN112979732B CN112979732B CN202110356587.XA CN202110356587A CN112979732B CN 112979732 B CN112979732 B CN 112979732B CN 202110356587 A CN202110356587 A CN 202110356587A CN 112979732 B CN112979732 B CN 112979732B
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- 238000001514 detection method Methods 0.000 title claims description 33
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Abstract
The invention discloses furocoumarin compounds capable of labeling mycobacterium tuberculosis single cells, which have structures shown in formula I, formula II or formula III, and can realize effective and real-time detection of clinical suspected tuberculosis patients through fluorescence microscopy.
Description
Technical Field
The invention relates to the technical field of mycobacterium tuberculosis detection, in particular to furocoumarin compounds and application of the furocoumarin compounds in mycobacterium tuberculosis detection.
Background
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is one of the most fatal infectious diseases in the world. According to WHO statistics, about 4000 people die from tuberculosis every day around the world, and 30000 people are infected with tubercle bacillus. Currently, about 1/3 people worldwide are Mtb infected people, 90% of which are clinically asymptomatic Latent Tuberculosis (LTB) infected people. Mtb is mainly transmitted through air droplets, and in recent years, drug-resistant tuberculosis is more and more, even full-drug-resistant strains appear, which brings great challenges to the prevention and treatment of TB.
The realization of the early diagnosis of tuberculosis and the development of individual and accurate treatment are key prerequisites for effectively reducing the morbidity and mortality of tuberculosis. The existing clinical diagnosis methods comprise imaging, pathology, molecular biology, bacteriology and immunology, wherein the bacteriology is the key basis for clinical diagnosis of tuberculosis.
Bacteriological diagnosis is divided into smear method and culture method, and the culture method has higher sensitivity and is the gold standard for tuberculosis diagnosis. The classical roche sputum culture method requires about 3 months, the improved sputum culture method requires 2 to several weeks for reporting positive and 8 weeks for reporting negative. Compared with a culture method, a smear method is suitable for rapid detection of mycobacterium tuberculosis, the clinical gold-amine-O fluorescence staining method has a higher detection rate than the common-nylon acid-fast staining positive detection rate, but the false positive condition caused by dye residues, hair, fibers, food residues and the like still exists, dead bacteria and non-tuberculous mycobacteria cannot be distinguished, meanwhile, the workload of actual operators is large, each sample needs to observe 100-300 visual fields under a microscope, and the influence of human factors is large.
At present, the research on the fluorescent diagnostic reagent of the tubercle bacillus is less, most of the tubercle bacillus is in the initial research stage, and five actual clinical application products are not available. Trehalose is an important component of the cell wall of actinomycetes, and has specificity. Bertozzi et al introduced trehalose into DMN's and developed as Solvatochromic probes, avoiding the extra step of washing excess dye. By utilizing the specificity of sulfatase or beta-lactamase in mycobacteria, people develop corresponding enzyme sensitive fluorescent diagnostic reagents, but all of them can realize clinical application for various reasons. For example, CDG-DNB3 developed by Rao et al, Stanford university, can rapidly and specifically image Mycobacterium tuberculosis, but the molecule has low signal-to-noise ratio and is unstable under clinical detection conditions (alkaline). Therefore, the development of novel fluorescent diagnostic reagents is an important scientific research content for increasing the diagnosis-confirming rate of bacteriological diagnosis.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide the furocoumarin compound and the application thereof in the detection of mycobacterium tuberculosis.
The inventor finds in research that Rv2466c is a nitroreductase inherent in Mycobacterium tuberculosis, Rv2466c is in an oxidation state and a reduction state equilibrium state in the Mycobacterium tuberculosis, namely Rv2466c in an oxidation state and Rv2466c in a reduction state are in a dynamic equilibrium state, under the condition that amino acid thiol (MSH) secreted by the Mycobacterium tuberculosis per se exists, the nitro in the compound shown in the formula I, the formula II or the formula III can be reduced by the Rv2466c in the reduction state, and active oxygen or an active nitrogen intermediate is released, so that Mtb is killed efficiently; and the reduced Rv2466c is oxidized into an oxidized state, so that the next catalytic cycle is continued. Moreover, the compound represented by the formula I, the formula II or the formula III shows a detectable difference in fluorescence spectrum properties before and after being reduced by the thioredoxin-like oxidoreductase Rv2466c inherent in Mycobacterium tuberculosis, is in a fluorescence quenching state before being reduced by Rv2466c, and can emit fluorescence under specific excitation light (320-400 nm) and emission light (420-530 nm) after being reduced by Rv2466c, that is, the compound represented by the formula I, the formula II or the formula III shows a significant difference in detectable fluorescence spectrum properties before and after being reduced by the thioredoxin-like oxidoreductase Rv2466c inherent in Mycobacterium tuberculosis. The on and off (off and on) effect (i.e. the difference of detectable fluorescence spectrum properties) of the fluorescence switch can also be realized under the condition of the existence of the mycobacterium tuberculosis (because the mycobacterium tuberculosis simultaneously contains reagents necessary for reducing the nitro group in the nitrofuran structure: Rv2466c and MSH), so the mycobacterium tuberculosis in the sample to be detected can be quickly and effectively detected by a fluorescence detection method by using the compound shown in the formula I, the formula II or the formula III based on the obvious difference of the detectable fluorescence spectrum properties, and the detection information can be effectively applied to the diagnosis of whether the suspected patient from which the sample to be detected is from has diseases related to the mycobacterium tuberculosis, thereby realizing the detection of the tuberculosis positive patient (active tuberculosis patient) and the tuberculosis carrier. Furthermore, the inventors have found that the derivatives of the compounds of formula I, formula II or formula III, such as nitro reduction products and corresponding hydrolysates, have detectable fluorescence changes before and after contact with Mycobacterium tuberculosis, and thus can be used for detecting Mycobacterium tuberculosis in a sample to be tested and further diagnosing diseases related to Mycobacterium tuberculosis.
In addition, the compound shown in the formula I, the formula II or the formula III provided by the invention comprises at least one trehalose group. The inventor finds that the specificity of the compound labeled mycobacterium tuberculosis can be further improved by introducing trehalose groups into the furocoumarin compound based on the characteristic that trehalose can be specifically recognized in the metabolic pathway of cell walls of actinomycetes. In addition, the introduction of the trehalose group can also improve the solubility of the furocoumarin compound in the detection environment, thereby further facilitating the detection.
Based on the above findings, in one aspect of the present invention, the present invention proposes a compound. According to an embodiment of the invention, the compound is a compound of formula I, formula II or formula III, or a stereoisomer, tautomer, deuterated, nitroxide, solvate, metabolite, or pharmaceutically acceptable salt thereof,
wherein,
R 1 and R 2 Each independently is hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl, phenyl, benzyl, benzoyl, 4-7 membered heterocyclic group or trehalose group, wherein amino, phenyl, benzyl, 4-7 membered heterocyclic group are optionally substituted by C 1-6 Alkyl radical, C 1-6 Alkoxy, hydroxyl, nitro, amino, nitrile or halogen;
R 3 is hydrogen, hydroxy, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Acyloxy group, phenyl group, benzyl group, 4-to 7-membered heterocyclic group, C 2-6 Alkenyl radical, C 2-6 Alkynyl or trehalose, wherein phenyl, benzyl, 4-to 7-membered heterocyclyl are optionally substituted by C 1-6 Alkyl radical, C 1-6 Alkoxy, hydroxyl, nitro, amino, nitrile or halogen;
R 4 is hydrogen, hydroxy, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Acyloxy group, phenyl group, benzyl group, 4-to 7-membered heterocyclic group, C 2-6 Alkenyl radical, C 2-6 Alkynyl or trehalose, wherein phenyl, benzyl, 4-to 7-membered heterocyclyl are optionally substituted by C 1-6 Alkyl radical, C 1-6 Alkoxy, hydroxyl, nitro, amino, nitrile or halogen;
R 1 、R 2 、R 3 、R 4 at least one of which is fucosyl;
R 5 is hydrogen, hydroxy, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Ester or mercapto group, wherein 1-6 Alkyl, mercapto optionally substituted by C 1-6 Alkyl alcohol, C 1-6 Alkyl mercaptan, C 1-6 Acyl oxygenRadicals, amino groups, nitrile groups, halogens or-L 4 -R 4 Substituted;
L 1 、L 2 、L 3 、L 4 are each independently a bond, C 1-4 Alkylene, or a mixture thereof,
n is 0,1, 2 or 3;
x is 1 or 2.
As described above, the compound represented by formula I, formula II or formula III and its derivatives, such as nitro reduction products and corresponding hydrolysis products, show detectable fluorescence changes before and after being reduced by thioredoxin-like oxidoreductase Rv2466c inherent in mycobacterium tuberculosis, so that the compound or its derivative is used as a detection reagent, a sample to be detected is contacted with the detection reagent, and based on the existence of fluorescence changes before and after the contact of the sample to be detected, the existence of mycobacterium tuberculosis in the sample to be detected can be effectively determined, and the result is accurate and reliable. And the detection information can be effectively used for diagnosing whether a suspected patient from which a sample to be detected is derived has a disease related to mycobacterium tuberculosis, so that detection of a tuberculosis positive patient (an active tuberculosis patient) and a tuberculosis carrier is realized.
When L is to be mentioned 1 、L 2 、L 3 Or L 4 When it is a bond, it represents L 1 、L 2 、L 3 Or L 4 The structural units on both sides are directly connected. For example, when L is 1 、L 2 、L 3 、L 4 When both are bonds, the structure shown in formula I can be represented as formula Ia, the structure shown in formula II can be represented as formula IIa, and the structure shown in formula III can be represented as formula IIIa.
Preferably, the fucosyl group is linked to the coumarin moiety by a linker. For example, when R is 1 In the case of trehalose, L 1 Not a bond, i.e. L 1 The trehalose group is connected with a coumarin structure as a linker. Similarly, when R is 2 In the case of trehalose, L 2 Is not a bond; when R is 3 In the case of trehalose, L 3 Is not a bond; when R is 4 In the case of trehalose, L 4 Not a bond.
In addition, the compounds according to the above embodiments of the present invention may also have the following additional technical features:
in some embodiments of the invention, said C 1-6 Alkyl is methyl, ethyl, propyl, butyl, pentyl or hexyl; the 4-to 7-membered heterocyclic group is
The trehalose group is 4-trehalose group or 6-trehalose group.
In some embodiments of the invention, it has the structure of one of the following (the following compounds are also referred to as class a compounds):
in some embodiments of the invention, the derivatives thereof have the structure of one of the following (the following compounds are also referred to as class B compounds):
the B-type compound is a nitro reduction product of the corresponding A-type compound, can generate fluorescence, and can be labeled after being contacted with the mycobacterium tuberculosis, so that the B-type compound can be used as a detection reagent, and after a sample to be detected is contacted with the B-type compound, whether the living mycobacterium tuberculosis exists in the sample to be detected can be effectively determined based on whether fluorescence change exists before and after the sample to be detected is contacted, and the result is accurate and reliable.
In some embodiments of the invention, the derivatives thereof have the structure of one of the following (the following compounds are also referred to as class C compounds):
the C-type compound is a nitro reduction product of the corresponding A-type compound, is similar to the B-type compound, can generate fluorescence, and can be labeled after being contacted with the mycobacterium tuberculosis, so that the C-type compound can be used as a detection reagent, and after a sample to be detected is contacted with the detection reagent, whether the living mycobacterium tuberculosis exists in the sample to be detected can be effectively determined based on whether fluorescence changes exist before and after the sample to be detected is contacted, and the result is accurate and reliable.
In addition, TFA in the above structure - Is trifluoroacetate anion, and Tre is 4-fucosyl (structure shown in formula 1 below) or 6-fucosyl (structure shown in formula 2 below).
In another aspect of the present invention, the present invention provides a kit for detecting mycobacterium tuberculosis, comprising the compound described in the above example as a detection reagent. Therefore, based on the difference of the detectable fluorescence spectrum properties of the compound shown in the formula I, the formula II or the formula III before and after the compound is reduced by the thioredoxin-like oxidoreductase Rv2466c inherent in the mycobacterium tuberculosis, the kit disclosed by the invention is utilized, the compound shown in the formula I, the formula II or the formula III or the derivative thereof is used as a detection reagent, a sample to be detected is contacted with the detection reagent, and whether the mycobacterium tuberculosis exists in the sample to be detected can be effectively determined based on whether the fluorescence change exists in the sample to be detected before and after the contact, and the result is accurate and reliable. And the detection information can be effectively used for diagnosing whether the suspected patient from which the sample to be detected is derived has the disease related to the mycobacterium tuberculosis, thereby realizing the detection of the tuberculosis positive patient (active tuberculosis patient) and the tuberculosis carrier.
In yet another aspect of the present invention, a method for detecting Mycobacterium tuberculosis is provided. According to an embodiment of the invention, the method comprises: contacting a sample to be tested with the compound of the embodiment; and determining whether the mycobacterium tuberculosis exists in the sample to be detected based on whether the sample to be detected has fluorescence change before and after the contact. Therefore, the method can realize effective, rapid and real-time detection of the mycobacterium tuberculosis by using the compound of the embodiment as a detection reagent. Moreover, the method is suitable for staining and detecting replicating and non-replicating mycobacterium tuberculosis.
According to some embodiments of the present invention, the detection of Mycobacterium tuberculosis using the compound of the present invention can be performed according to the following method: firstly, processing a sample to be detected, putting 5mL of the sample to be detected (such as sputum, cerebrospinal fluid, pleural effusion and the like) into a sterile 50mL plastic centrifuge tube, and adding an equal volume of NALC-NaOH solution, wherein the final concentration of NaOH in the centrifuge tube is 1%. The lid was closed, the mixture was inverted and shaken on a vortex for 20 s. The solution was allowed to stand at room temperature for 15min, after digestion was complete PBS (pH 6.8) was added to 50mL and centrifuged horizontally at 3000r/min for 15 min. The supernatant was discarded and 1mL of 7H9 medium was added, the compound of the present invention was incubated with the treated bacteria at a final concentration of 100. mu.M, smeared after 10min and counted under a fluorescence microscope. In addition to the above methods, a separate alkali treatment method may be employed. The method generally uses 2% NaOH solution, and the concentration can be increased to 3% -4% according to the digestion difficulty of the sample. After digestion with high concentration NaOH, HCl was added for neutralization, pH was adjusted to 7.0, and the number was counted under a fluorescent microscope after smearing. When the viscosity of the sample to be detected is large, the NALC concentration can be properly increased, but the increase of the NALC and the NAOH concentration can affect the detection rate of the mycobacteria, generally, the NaOH concentration is controlled below 2%, and the action time is controlled within 15 min.
As mentioned above, the compounds of the present invention also have the ability to stain and detect actinomycetes. When the compound contacts with the bacteria, fluorescence is generated, and the generated fluorescence can be detected by an enzyme-labeling instrument or a fluorescence spectrophotometer, or the bacteria can be observed under a fluorescence microscope.
In some embodiments of the invention, the fluorescence changes to at least one of: (a) the sample to be detected is in a fluorescence quenching state before the contact, and can be excited by exciting light with the wavelength of 320-400nm and emit fluorescence with the wavelength of 420-530 nm after the contact; (b) the sample to be detected is in a fluorescence quenching state before the contact, and can be excited by excitation light with the wavelength of 320-400nm and emit fluorescence with the wavelength of 420-530 nm after the contact, and the emitted fluorescence shows strong and weak changes. Therefore, the compound or the derivative thereof is contacted with a sample to be detected, fluorescence detection is carried out, and based on the fluorescence detection results before and after the contact, the sample can be effectively marked or whether the mycobacterium tuberculosis exists in the sample to be detected can be determined.
In some embodiments of the invention, the sample to be tested comprises at least one of sputum, cerebrospinal fluid, alveolar lavage, pleural effusion. It should be noted that the sample to be tested is a sample suspected of containing mycobacterium tuberculosis, including but not limited to a sputum sample. The source of the sample is not particularly limited, and the sample may be derived from human or other animals such as livestock.
In a further aspect of the invention, the invention provides the use of a compound of the above examples in screening for drugs, testing for drug sensitivity or detection of dead/live bacteria for the treatment or prevention of human or animal diseases associated with mycobacterium tuberculosis. The compound of the invention can be used for tracking and detecting bacteria in cells, and can selectively mark bacteria in cells with phagocytic function. The cell sources include cultured cell lines, living cells of animal origin, isolated cells in clinical samples, and the like, and can be observed under a fluorescence microscope after incubation with the NFCs class compounds.
According to some embodiments of the present invention, the screening of drugs using the compounds of the present invention can be performed as follows: contacting (e.g., incubating for a certain period of time) a test drug with mycobacterium tuberculosis, adding a compound of the invention, and comparing the fluorescence intensity of the compound of the invention after addition with a control group (without the test drug, and under otherwise identical conditions), wherein a significant decrease in fluorescence generated by the compound of the invention after addition relative to the fluorescence of the control group (as described above, mycobacterium tuberculosis not contacted with the test drug but contacted with the compound of the invention) is indicative of the effect of the test drug in preventing or treating a disease associated with mycobacterium tuberculosis infection.
The method for detecting the drug sensitivity by using the compound of the invention can also be carried out according to the method, but the drug to be detected is provided with a series of concentration gradients, during the experiment, the drug to be detected with the series of concentrations is respectively contacted with the mycobacterium tuberculosis (for example, the drug to be detected is incubated for a certain time) under the condition of the same mycobacterium tuberculosis amount, then the compound of the invention is added, the fluorescence intensity of the treated drug group to be detected and the control group (without the drug to be detected) after the compound of the invention is added is compared, when the fluorescence of the treated group after the compound of the invention is added is just unchanged compared with the control group, the mycobacterium tuberculosis amount in the system can be judged to be lower than the lowest detection limit of the compound, and correspondingly, the drug concentration to be detected corresponding to the mycobacterium tuberculosis amount is MIC (minimum inhibitory concentration of the drug to be detected).
In some embodiments of the invention, the disease associated with mycobacterium tuberculosis infection is pediatric tuberculosis, pulmonary tuberculosis, intestinal tuberculosis, lymphoid tuberculosis, bone tuberculosis, renal tuberculosis, tuberculous peritonitis, tuberculous meningitis, drug-sensitive tuberculosis, multi-drug resistant tuberculosis, extensively drug resistant tuberculosis, latent tuberculosis, or HIV-co-infected tuberculosis.
In some embodiments of the invention, the disease associated with mycobacterium tuberculosis infection is a disease associated with tuberculosis in an animal.
In some embodiments of the invention, the drug is an anti-tuberculosis lead compound or an anti-tuberculosis drug.
In addition, for ease of understanding, reference will now be made to the terms referred to herein:
the terms "comprising", "including" and "comprises" are open-ended expressions that include what is stated in the invention, but do not exclude other aspects.
"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.
"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to designate the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configurations.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); PrinciplesofAsymmetric Synthesis (2) nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention include each and every member of each of these groups in the classes and rangesA separate sub-combination. For example, the term "C 1-6 Alkyl "means in particular independently disclosed methyl, ethyl, C 3 Alkyl radical, C 4 Alkyl radical, C 5 Alkyl and C 6 An alkyl group.
In each of the sections of the present invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl," it is to be understood that the "alkyl" represents a linked alkylene group.
In the present invention, alkyl means a straight-chain and branched-chain saturated aliphatic group having a specific number of carbon atoms.
Alkoxy refers to an alkyl-O-group having the indicated number of carbon atoms.
"halogen" or "halo" refers to fluoro, chloro, bromo, or iodo as a substituent. When a halogen atom is used as a substituent, the number of substitution may be one, two or three.
Aryl includes phenyl, substituted phenyl (where substituted phenyl includes one, two or three groups: C 1-6 Alkyl radical, C 1-6 Alkoxy, nitrile, nitro, amino or halogen).
The term "heterocycle" as used herein denotes a stable 4 to 7 membered monocyclic ring, which may be saturated or unsaturated, aromatic or non-aromatic, and consists of carbon atoms and optionally 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulfur heteroatoms may be selectively oxidized and the nitrogen heteroatom may be selectively quaternized, preferably a6 membered heterocycle, such as pyridine, piperidine, pyrazine, piperazine, morpholine or thiomorpholine, and the like.
In the present invention, when the structural formula has
Or the like, means that the covalent bond is in a position above or below the paper, but it is to be noted that this configuration has a relative meaning only, unless otherwise specified. Also, whenReferences to "cis" or "trans" are, unless otherwise specified, merely relative positions of groups.
The solvate means an inclusion solvent formed by the compound of the general formula with a reaction organic solvent or water, etc., or a form of molecules of water or solvent contained in the molecular formula obtained by instrumental analysis, or water or solvent contained in the crystal lattice. Pharmaceutically acceptable solvents useful in the present invention include those that do not interfere with the biological activity of the compounds of the present invention (e.g., water, ethanol, acetic acid, N-dimethylformamide, dimethylsulfoxide, and solvents known or readily determined by those skilled in the art). The compounds of the present invention may form hydrates or other solvates. Methods are known to those skilled in the art for forming hydrates when the compounds are lyophilized with water or solvates when concentrated in solution with a suitable organic solvent. Thus, hydrates and solvates of the compounds of the invention are also encompassed within this invention.
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such asAcetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or these salts can be obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl radical) 4 A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulphonates and aromatic sulphonates.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
FIG. 1 is a graph showing the results of the test that Compound A1-A6 was reduced under the action of Rv2466c to generate fluorescence;
FIG. 2 is the fluorescence spectrum of Compound A1-A6;
FIG. 3 is a graph showing the results of specific staining of Mycobacterium tuberculosis with Compound A6;
FIG. 4 is a graph showing the results of gram-negative and gram-positive staining of intermediate 12;
FIG. 5 is a graph showing the results of testing the ability of compound A1-A6 to label Mtb;
FIG. 6 is a graph showing the results of Compound A6 labeling non-replicating Mycobacterium tuberculosis;
FIG. 7 is a graph showing the staining of intracellular bacteria with Compound A6;
FIG. 8 is a graph showing the results of bacterial staining of sputum samples with Compound A6.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are conventional products which are commercially available, and are not indicated by manufacturers.
Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the present invention, "a plurality" means at least two, e.g., two, three, etc., unless specifically limited otherwise.
EXAMPLE 1 fluorescent response of Compounds of the invention to the Rv2466c enzyme
The instrument comprises the following steps: multifunctional microplate reader: (
Flash，Thermo Scientific)。
Reagents and materials: compound (A1-A6), Rv2466c, MSH, Tris-Cl (pH 7.5), DMSO, 96-well plate (Corning, 3603).
The operation is as follows: 1) 50mM Tris-Cl (pH 7.5) buffer containing 0.5mM MSH was prepared, and 20mL of each buffer was taken in two sterile tubes. 2) To one tube was added an amount of Rv2466c to give a final concentration of 200. mu.g/mL, which was an enzyme-containing working solution, and to the other tube was added an equal amount of Tris-Cl buffer as an enzyme-free control solution. 3) The compounds of the present invention were dissolved in DMSO separately to prepare 25 μ g/mL solutions, and 20 μ L of each compound was added to four wells of a 96-well plate, two wells were used as enzyme-free control groups, and the other two wells were used as enzyme-containing working groups, and each group was tested in duplicate. 4) mu.L of the enzyme-containing working solution and 180. mu.L of the enzyme-free control solution were added to the wells, respectively. 5) And 3h later, detecting the fluorescence intensity on a microplate reader.
As a result, as shown in fig. 1 and 2, the inventors found that: compounds a1 to a6 all showed detectable differences in fluorescence intensity before and after reduction by Rv2466 c: the compounds are in a fluorescence quenching state before being reduced by Rv2466C, and recover fluorescence after being reduced by Rv2466C (corresponding to compounds B8 to B14 and C15 to C20), i.e., are capable of emitting fluorescence under excitation light of a specific wavelength. Wherein FIG. 2 shows the results of Fluorescence enhancement of compounds A1 to A6 under the action of Rv2466c (RFU: relative Fluorescence units in FIG. 1; wavelength: wavelength, Fluorescence Intensity: Fluorescence Intensity in FIG. 2).
EXAMPLE 2 specificity assay of Compound A6 of the invention
The instrument comprises: fluorescence microscopy (high resolution live cell imaging system Delta Vision).
Reagents and materials: compound a6, intermediate 12, Bacillus subtilis (Bs), Escherichia coli (Ec), Enterococcus faecalis (Ef), Listeria monocytogenes (Lm), Staphylococcus aureus (Sa), Mycobacterium smegmatis (m.smeg), LB medium, THY medium, 7H9 medium.
The operation is as follows: a6 and an intermediate 12 compound are prepared to be 10mM, after the bacteria are cultured to a logarithmic growth phase, 200 mu L of bacteria liquid is respectively added with 2 mu LA6 and the intermediate 12, after incubation for 30min at 37 ℃, a slide sample is prepared and observed under a fluorescence microscope. The results show that the compounds of the invention are specific for mycobacteria, do not stain other gram-negative or gram-positive bacteria (figure 3), whereas intermediate 12 lacks specificity for staining bacteria (figure 4).
Note: bs, Ec, Ef, Lm medium LB, Sa medium THY, m.smeg medium 7H 9.
EXAMPLE 3 Mtb staining ability of Compound A6 of the present invention
The instrument comprises the following steps: fluorescence microscopy.
Reagents and materials: compound a1, a6, Mycobacterium tuberculosis (Mtb), 7H9 medium.
The operation is as follows: a1 and A6 compounds are respectively prepared to be 10mM concentration, after the bacteria are cultured to logarithmic growth phase, 200 mu L of bacteria liquid is taken and added with the ebselen (Eb, the final concentration is 50 mu g/mL), incubation is carried out for 3H, centrifugation is carried out to remove the ebselen, 200 mu L of 7H9 culture medium and 2 mu L of 1, A6 are respectively added, incubation is carried out for 30min at 37 ℃, slide samples are prepared and observed under a fluorescence microscope, and the result is shown in figure 5.
EXAMPLE 4 labeling ability of Compound A6 of the present invention to non-replicating Mycobacterium tuberculosis
The instrument comprises the following steps: fluorescence microscopy.
Reagents and materials: compound a6, BCG, PBS.
The operation is as follows: the A6 compound was formulated at a concentration of 10mM, and M.tuberculosis BCG was cultured in PBS under non-replicating conditions for 14 days, and the bacteria were confirmed to enter a non-replicating state after the change in cell morphology. 200 mu L of the bacterial solution was added with 2 mu LA6, incubated at 37 ℃ for 1 hour, and then a slide sample was prepared and observed under a fluorescence microscope.
The results are shown in FIG. 6, and show that the compounds of the present invention can label non-replicating Mycobacterium tuberculosis.
EXAMPLE 5 detection ability of Compound A6 of the present invention for intracellular bacteria
RAW cells (1X 10) 5 Perwell) and BMDM cells (2X 10) 5 Per well) were inoculated onto a 35mm four-section confocal dish and incubated at 37 ℃ for 18 hours for adherent growth. After 18h, the supernatant was discarded and washed with PBS. Complete culture in DMEM at a cell: bacteria ratio of 1:3 and 1:5, respectivelyBCG or m.smeg was added to the medium and cells were incubated with the medium for 4h at 37 ℃. After 4h, the supernatant was discarded and stained with Dil membrane red dye (4X, 37 ℃ C., 10 min). After the staining was completed, the supernatant was discarded and washed with DMEM complete medium (1 mL. times.3). 1mL of the complete medium containing Compound A6 (100. mu.M) was added to the treated cells, and the cells were cultured at 37 ℃ for 15 min. After 15min, wash with PBS (1 mL. times.3). Then, 1mL of 4% paraformaldehyde was added for fixation, and after fixation for 30min, a cell nucleus staining solution (2 drops/mL) was added for staining, and the cells were observed under a rotary confocal microscope.
The results are shown in FIG. 7, and show that the compound of the present invention can stain M.intracellulare.
Example 6 test of the ability of the Compounds of the present invention to detect Mycobacterium tuberculosis in clinical specimens Using Compound A6 as an example
5mL of sample to be detected is put into a sterile 50mL plastic centrifuge tube, and an equal volume of NALC-NaOH solution is added, wherein the final concentration of NaOH in the centrifuge tube is 1%. The lid was closed, the mixture was inverted and shaken on a vortex for 20 s. The solution was allowed to stand at room temperature for 15 min. After digestion was complete PBS (pH 6.8) was added to 50 mL. Centrifuging at 3000r/min for 15min, discarding the supernatant, adding 1mL of 7H9 culture medium, incubating compound A6 with the treated bacteria, and observing the smear 10min later with a fluorescence microscope, wherein the final concentration of compound A6 is 100. mu.M.
The results are shown in FIG. 8, and show that the compound of the present invention can stain Mycobacterium tuberculosis in clinical specimens.
EXAMPLE 8 preparation of Compound A1
Reagents and conditions:(a)ethanol,phloroglucinol,BF 3 ·C 2 H 5 OC 2 H 5 ,reflux,overnight,90％；(b)DCM,DMF,POCl 3 ,rt,overnight,55％；(c)toluene,1,1-Diethoxy-3-methyl-2-butene,pyridine,reflux,3h,35％；(d)(I)Ac 2 O,IR-120,rt,overnight(II)methanol,H 2 ,Pd/C,50℃,1h(III)methanol，K 2 CO 3 ,rt,2h,80％；(e)(I)acetone,BrCH 2 NO 2 ,K 2 CO 3 ,3h(II)acetic anhydride,reflux,overnight,60％；(f)6N HCl,reflux,1h,50％；(g)DCM,propargulamine,EDCI,HOBt,DIPEA,rt,2h,55-65％；(h)DMF,Vc-Na,CuSO 4 ,H 2 O,rt,30min,50％.
The experimental steps are as follows:
1) phloroglucinol (12.6g, 100mmol) and diethyl 3-oxoadipate (23.8g, 110mmol) were dissolved in 300mL of ethanol at 0 deg.C, then boron trifluoride ether (21.3g, 150mmol) was added slowly, and the solution was heated to reflux temperature and reacted overnight. After the reaction was complete and cooled to room temperature, 600mL of water were added, a large amount of solid precipitated, filtered with suction, and the filter cake was washed with 5% aqueous sodium bicarbonate. After air-drying, 25g of intermediate 1(Ethyl 3- (5,7-dihydroxy-2-oxo-2H-chromen-4-yl) propanoate) was obtained, and the crude product was used directly in the following reaction.
2) Phosphorus oxychloride (12.2mL, 15mmol) was added dropwise to DMF (10.5mL, 15mmol) under ice-bath conditions, with stirring. After the dropwise addition, stirring was continued for 30 min. Intermediate 1(20.8g, 7.5mmol) was dissolved in 200mL of anhydrous dichloromethane and added dropwise to DMF-POCl as above 3 The mixture was stirred at room temperature overnight. The reaction was complete, the dichloromethane was evaporated, the solution was cooled to 0 ℃, quenched by the slow addition of 400mL ice water, and the mixture was stirred vigorously for 30 min. The precipitate formed was filtered and washed with water and Ethyl acetate to give 2.5g of intermediate 2(Ethyl 3- (8-formyl-5,7-dihydroxy-2-oxo-2H-chromen-4-yl) propanoate). 1 H NMR(400MHz,DMSO)δ12.25(s,1H),10.16(s,1H),6.27(s,1H),6.07(s,1H),4.15–3.98(m,2H),3.17(t,J＝7.5Hz,2H),2.63(t,J＝7.6Hz,2H),1.18(t,J＝7.1Hz,3H). 13 C NMR(101MHz,DMSO)δ190.7,172.3,165.6,164.7,159.2,158.8,157.0,110.7,103.7,102.3,99.1,60.5,33.6,31.1,14.6.
3) Intermediate 2(8g, 26mmol) was dissolved in 100mL of toluene and added dropwise to a mixture of 1, 1-diethoxy-3-methyllbut-2-ene (6.2g, 39mmol) and pyridine (320. mu.L, 4mmol) and stirred at reflux for 3 h. After completion of the reaction, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (petroleum: Ethyl acetate 4:1) to give 3.4g of intermediate 3(Ethyl3- (6-formyl-5-hydroxy-2,2-dimethyl-8-oxo-2H,8H-pyrano [2,3-f ] chromen-10-yl) propanoate).
4) Intermediate 3(3g, 8mmol) was dissolved in 30mL of acetic anhydride, 3g of Amberlite IR-120 was added, and the reaction mixture was stirred overnight. The reaction was complete with acetic anhydride distilled off, monitored by LC-MS. To the residue were added 60mL of methanol and 1g of 10% Pd/C, and the mixture was stirred in H 2 Stirred at 50 ℃ for 1h under an atmosphere. After completion of the reaction, Pd/C was removed by passing through celite, and then potassium carbonate (5.6g, 40mmol) was added to the solution and stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was filtered and concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum: Ethyl acetate 4:1) to obtain intermediate 4(Ethyl3- (6-formyl-5-hydroxy-2,2-dimethyl-8-oxo-3,4-dihydro-2H,8H-pyrano [2, 3-f)]chromen-10-yl)propanoate)，2.39g。 1 H NMR(400MHz,CDCl 3 )δ12.82(s,1H),10.39(s,1H),6.68(d,J＝10.1Hz,1H),6.07(s,1H),5.61(d,J＝10.1Hz,1H),4.31–4.06(m,2H),3.25(dd,J＝9.5,5.9Hz,2H),2.73–2.52(m,2H),1.55(s,6H),1.29(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ192.1,172.0,161.5,158.7,158.2,157.9,155.7,126.8,115.0,111.8,105.5,104.0,102.3,80.6,60.8,34.0,31.7,28.2,14.3.
5) Intermediate 4(2.4g, 6.4mmol) was dissolved in 20mL acetone and K was added 2 CO 3 (2.7g, 19.2mmol) and BrCH 2 NO 2 (672. mu.L, 9.6mmol), after stirring at room temperature for 1.5h the reaction mixture is filtered and concentrated in vacuo. The residue was dissolved in 30mL of acetic anhydride and stirred at 140 ℃ overnight. The reaction mixture was then cooled and the solvent was distilled off, and the residue was purified by silica gel column chromatography to give intermediate 5(Ethyl3- (9,9-dimethyl-2-nitro-5-oxo-10,11-dihydro-5H,9H-furo [2, 3-f)]pyrano[2,3-h]chromen-7-yl)propanoate)1.59g。 1 H NMR(400MHz,CDCl 3 )δ12.96(s,1H),10.41(s,1H),6.07(s,1H),4.28–4.10(m,2H),3.34–3.14(m,2H),2.73(t,J＝6.8Hz,2H),2.67–2.55(m,2H),1.88(t,J＝6.8Hz,2H),1.46(s,6H),1.30(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ192.0,172.0,164.5,159.2,158.8,157.2,156.2,111.6,105.1,103.4,102.4,78.7,60.8,34.3,32.0,31.0,26.6,15.9,14.3.
6) Intermediate 5 was dissolved in 30mL of 6N hydrochloric acid, heated to 100 ℃ and reacted overnight. After completion of the reaction, the reaction mixture was filtered and washed with methanol to give intermediate 6(3- (9,9-dimethyl-2-nitro-5-oxo-10,11-dihydro-5H,9H-furo [2, 3-f)]pyrano[2,3-h]chromen-7-yl)propanoic acid)348mg。 1 H NMR(400MHz,CDCl 3 )δ7.93(s,1H),6.24(s,1H),4.30–4.14(m,2H),3.43–3.27(m,2H),3.06(t,J＝6.8Hz,2H),2.76–2.61(m,2H),1.98(t,J＝6.8Hz,2H),1.50(s,6H),1.31(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ172.0,159.2,156.4,153.9,153.7,152.6,149.5,114.1,108.8,107.7,106.1,102.1,78.3,60.8,34.3,32.1,30.6,26.5,16.5,14.3.
7) Intermediate 6(0.6g, 1.5mmol) was dissolved in 20mL of anhydrous dichloromethane and EDCI (385mg, 2mmol), HOBt (270mg, 2mmol) were added and stirred for 0.5h, followed by propargylamine (110mg, 2mmol) and DIPEA (774mg, 6mmol) and stirring continued for 2 h. After completion of the reaction, the reaction mixture was concentrated by vacuum pump. The residue was purified by silica gel column chromatography to give intermediate 7(3- (9,9-dimethyl-2-nitro-5-oxo-10,11-dihydro-5H,9H-furo [2, 3-f)]pyrano[2,3-h]chromen-7-yl)-N-(prop-2-yn-1-yl)propanamide)413mg。 1 H NMR(400MHz,DMSO)δ8.31(s,1H),6.30(s,1H),3.32(s,2H),3.17(t,J＝7.7Hz,3H),2.93(t,J＝6.7Hz,2H),2.59–2.51(m,2H),1.92(t,J＝6.7Hz,2H),1.41(s,6H). 13 C NMR(101MHz,DMSO)δ173.7,158.8,157.0,154.0,153.6,152.6,149.3,114.2,108.7,107.6,107.4,102.4,78.7,49.1,34.4,31.9,30.2,26.4,16.4.
8) Intermediate 7(98mg, 0.23mmol) and trehalose azide (90mg, 0.23mmol) were dissolved in 3mL of DMF and stirred for 10 min. Vc-Na (20mg, 0.1mmol) and copper sulfate (37.5mg, 0.15mmol) were then dissolved in 100. mu.L of water, respectively, and then added to the solution in order. After the reaction, the mixture was concentrated by positive vacuum pump, and the residue was purified by C18 column chromatography to give Compound A1(NFC-Tre)91 mg. 1 H NMR(400MHz,DMSO)δ8.34(s,1H),8.32(s,1H),6.25(s,1H),3.89(dd,J＝5.3,2.3Hz,2H),3.18(dd,J＝10.3,4.8Hz,2H),3.10(t,J＝2.3Hz,1H),2.94(t,J＝6.6Hz,2H),2.45(t,J＝7.6Hz,2H),1.93(t,J＝6.6Hz,2H),1.43(s,6H). 13 C NMR(101MHz,DMSO)δ170.8,158.9,157.6,154.2,153.7,152.7,149.4,114.1,108.6,107.7,107.5,102.4,81.6,78.8,73.4,35.4,32.2,30.3,28.3,26.5,16.4.
EXAMPLE 9 preparation of Compounds A3, A4
Reagents and conditions:(a)THF,PPh 3 ,DIAD,rt,overnight,30％；(b)acetone,BrCH 2 NO 2 ,K 2 CO 3 ,rt,3h；(c)6N HCl,reflux,overnight,50％；(d)DCM,Boc 2 O,DIPEA,rt,3h,65％；(e)DCM,propargulamine,EDCI,HOBt,DIPEA,rt,2h,55-65％；(f)DMF,Vc-Na,CuSO 4 ,H 2 O,rt,30min,50％；(j)DCM,TFA,rt,1h,80-90％；
The experimental steps are as follows:
1) intermediate 2(8g, 26mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (5.3g, 26mmol) were added to THF, PPh added at 0 deg.C 3 (10.2g, 39mmol) and diisopropyl azodicarboxylate (8.9g, 44 mmol). After the reaction mixture was stirred overnight, the reaction mixture was concentrated under vacuum pump, and the residue was purified by silica gel column chromatography to give 4.4g of intermediate 8(Tert-butyl4- ((4- (3-ethoxy-3-oxopropyl) -8-formyl-7-hydroxy-2-oxo-2H-chromen-5-yl) oxy) piperidine-1-carboxylate). 1 H NMR(400MHz,CDCl 3 )δ12.65(s,1H),10.40(s,1H),6.30(s,1H),6.08(s,1H),4.69–4.56(m,1H),4.25–4.10(m,2H),3.99–3.87(m,2H),3.31–3.22(m,2H),3.21–3.11(m,2H),2.67–2.51(m,2H),2.18–2.07(m,2H),1.85–1.70(m,2H),1.48(s,9H),1.28(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ192.0,171.8,166.8,162.0,159.0,158.6,155.7,154.5,111.6,104.3,103.1,96.6,80.1,75.9,60.9,33.8,31.8,30.4,28.4,14.3.
2) The synthetic procedure for intermediate 9 refers to intermediate 6.
3) Intermediate 9(1.5g, 3.7mmol) was dissolved in dichloromethane and Boc was added sequentially 2 O (1.2g, 5.5mmol) and DIPEA (900mg, 7 mmol). Mixing the reaction mixtureStirring for 3 h. After completion of the reaction, the reaction mixture was vacuum-concentrated, and the residue was purified by silica gel column chromatography to give intermediate 10(3- (5- ((1- (tert-butoxycarbonyl) piperidine-4-yl) oxy) -8-nitro-2-oxo-2H-furo [2, 3-H)]chromen-4-yl)propanoic acid)1.2g。 1 H NMR(400MHz,DMSO+CDCl 3 )δ7.94(s,1H),7.60(s,1H),6.26(s,1H),4.91–4.68(m,1H),4.09–3.84(m,2H),3.42–3.30(m,2H),3.29–3.16(m,2H),2.69–2.59(m,2H),2.36–2.11(m,2H),1.94–1.69(m,2H),1.48(s,9H). 13 C NMR(101MHz,DMSO+CDCl 3 )δ173.7,158.7,158.0,156.6,155.2,154.4,152.4,151.1,113.8,109.6,108.2,105.8,92.7,79.7,75.9,33.7,32.0,30.3,28.4.
4) See intermediate 7 for the synthetic procedure for intermediate 11. 1 H NMR(400MHz,DMSO)δ8.35(s,1H),8.33(s,1H),7.65(s,1H),6.27(s,1H),4.92–4.77(m,1H),3.85(dd,J＝11.3,9.2Hz,4H),3.24–3.17(m,2H),3.06(t,J＝2.2Hz,2H),2.46(t,J＝7.6Hz,2H),2.16–2.03(m,2H),1.72–1.57(m,2H),1.43(s,9H). 13 C NMR(101MHz,DMSO)δ170.8,158.6,158.2,157.5,155.5,154.3,152.7,151.0,113.9,109.6,108.0,107.0,93.5,81.5,79.4,75.8,73.3,35.0,32.3,30.3,28.6,28.3.
5) Synthetic procedure for compound A3 reference compound a 1. 1 H NMR(400MHz,DMSO)δ8.44–8.32(m,2H),7.79(s,1H),7.65(s,1H),6.26(s,1H),5.28(d,J＝5.1Hz,1H),4.94(d,J＝4.5Hz,1H),4.88–4.81(m,2H),4.78–4.73(m,2H),4.67(d,J＝6.1Hz,1H),4.62–4.52(m,2H),4.43(dd,J＝14.4,7.7Hz,1H),4.33–4.27(m,2H),4.11(t,J＝8.2Hz,1H),3.81(d,J＝13.3Hz,2H),3.66–3.48(m,4H),3.46–3.39(m,1H),3.25–3.17(m,4H),3.15–3.04(m,3H),3.02–2.92(m,1H),2.46(d,J＝7.5Hz,2H),2.08(d,J＝10.3Hz,2H),1.65(d,J＝9.2Hz,2H),1.41(s,9H). 13 C NMR(101MHz,DMSO)δ170.6,158.2,157.8,157.2,155.1,153.9,152.3,150.6,144.6,123.2,113.4,109.1,107.6,106.6,93.3,93.1,78.9,75.3,72.8,72.6,71.5,71.4,71.3,70.1,69.8,60.8,50.7,34.58,34.2,31.9,29.9,28.1.
6) To a solution of compound A3(20mg, 0.02mmol) in DCM (1mL) was added TFA (0.5mL) at room temperature, and the solution was stirred for 1 h. The reaction mixture was concentrated on a vacuum pump and dried on a high vacuum pump for 1h to give compound a 415.6mg。 1 H NMR(400MHz,DMSO)δ4.87–4.77(m,2H),7.83(s,1H),7.66(s,1H),6.29(s,1H),5.32(d,J＝4.7Hz,1H),5.01(d,J＝4.0Hz,1H),4.93(s,1H),4.87–4.77(m,4H),4.71(d,J＝5.6Hz,1H),4.62–4.54(m,2H),4.43(dd,J＝14.6,7.8Hz,1H),4.37–4.30(m,2H),4.14–4.07(m,1H),3.66–3.47(m,5H),3.46–3.40(m,1H),3.26–3.17(m,4H),3.10(d,J＝8.4Hz,3H),3.01–2.93(m,1H),2.30–2.20(m,2H),2.02–1.92(m,4H). 13 C NMR(101MHz,DMSO)δ170.7,158.2,157.5,157.1,155.0,152.4,150.6,123.4,113.3,109.4,107.6,106.5,93.3,93.2,79.3,79.0,78.7,72.9,72.6,72.3,71.5,71.4,71.3,70.1,69.8,60.7,56.1,50.8,41.2,34.5,34.2,32.0,26.9,18.6.
EXAMPLE 10 preparation of Compound A5
Reagents and conditions:(a)DCM,Succinic anhydride,Et 3 N,rt,3h,85％；(b)DMF,Tre-NH 2 ,EDCI,HOBt,DIPEA,rt,87％
The experimental steps are as follows:
1) intermediate 12(744mg, 2mmol) was dissolved in dichloromethane and Succinic anhydride (250mg, 2.5mmol) and Et were added sequentially 3 N (404mg, 4 mmol). The reaction mixture was stirred for 3 h. After completion of the reaction, the reaction mixture was concentrated under a vacuum pump, and the residue was purified by silica gel column chromatography to give intermediate 13.
2) Intermediate 13(472g, 1mmol) was dissolved in 5mL anhydrous DMF and EDCI (385mg, 2mmol), HOBt (270mg, 2mmol) were added and stirred for 0.5h, followed by the addition of amino trehalose (110mg, 1.1mmol) and DIPEA (774mg, 6mmol) and stirring continued for 2 h. After completion of the reaction, the reaction mixture was concentrated by vacuum pump. The residue was purified by C18 silica gel column chromatography to give Compound A5. 1 H NMR(400MHz,DMSO)δ8.33(s,1H),7.77(s,1H),7.67(s,1H),6.30(s,1H),4.95–4.89(m,3H),4.85(d,J＝12.0Hz,2H),4.79–4.75(m,2H),4.71–4.61(m,3H),4.37–4.31(m,1H),4.14(d,J＝13.3Hz,1H),3.86(d,J＝11.5Hz,1H),3.76–3.70(m,1H),3.67–3.62(m,1H),3.58–3.44(m,5H),3.30–3.21(m,3H),3.17–3.04(m,3H),3.99–3.89(m,3H),2.63–2.55(m,2H),2.42–2.31(m,2H),2.16(dd,J＝25.8,11.4Hz,2H),1.69(d,J＝9.1Hz,1H),1.64–1.53(m,3H),0.96(t,J＝6.5Hz,3H). 13 C NMR(101MHz,DMSO)δ172.2,172.1,170.0,158.3,158.0,157.8,155.0,152.3,150.7,113.3,109.2,107.7,106.6,93.4,93.3,93.1,75.2,72.7,72.5,71.7,71.6,71.4,70.5,70.1,60.8,42.5,38.1,30.6,30.4,30.0,27.9,22.5,13.6.
EXAMPLE 11 preparation of Compound A6
Reagents and conditions:(a)DCM,propargulamine,EDCI,HOBt,DIPEA,rt,2h,84％；(b)DMF,Vc-Na,CuSO 4 ,H 2 O,rt,30min,89％
The experimental steps are as follows:
1) synthesis of intermediate 14 reference example 10.
2) Synthesis of compound a6 reference compound a 1. 1 H NMR(400MHz,DMSO)δ8.28(s,1H),7.78(s,1H),7.62(s,1H),6.27(s,1H),5.31(d,J＝5.2Hz,1H),4.97(d,J＝4.6Hz,1H),4.90(s,1H),4.83(d,J＝3.5Hz,1H),4.81–4.77(m,3H),4.59–4.52(m,2H),4.42–4.34(m,2H),4.19–4.08(m,2H),3.85(d,J＝13.1Hz,1H),3.64–4.52(m,5H),3.26–3.16(m,3H),3.12–3.06(m,2H),3.03–2.96(m,1H),2.95–2.89(m,2H),2.87–2.82(m,2H),2.71(d,J＝7.4Hz,2H),2.22–2.09(m,2H),1.66(d,J＝7.1Hz,1H),1.58(dt,J＝14.8,7.4Hz,4H),0.95(t,J＝7.3Hz,3H).
EXAMPLE 12 preparation of Compound C15
The experimental steps are as follows: a1(1eq) was dissolved in ethanol and reduced iron powder (10eq) was added. Ammonium chloride (10eq) dissolved in water was then added and stirred overnight. After completion of the reaction, the iron sludge was removed by filtration, and the filtrate was separated and purified by HPLC. 1 H NMR(800MHz,DMSO)δ10.21(s,1H),8.36(s,1H),7.80(s,1H),5.95(s,1H),5.28(s,1H),4.95–4.88(m,1H),4.84(s,1H),4.81–4.66(m,4H),4.60–4.5(m,2H),4.43(dd,J＝14.0,7.4Hz,1H),4.29(d,J＝4.4Hz,2H),4.13–4.10(m,1H),3.84(s,2H),3.64–3.61(m,1H),3.59–3.56(m,1H),3.54–3.50(m,2H),3.45–3.42(m,2H),3.21(d,J＝7.3Hz,2H),3.14–3.08(m,4H),2.98(t,J＝8.8Hz,1H),2.64–2.61(m,2H),2.44–2.41(m,2H),1.80–1.76(m,2H),1.30(s,6H). 13 C NMR(201MHz,DMSO)δ170.8,159.3,157.6,156.5,152.2,152.0,144.7,144.7,123.2,118.5,109.9,105.6,102.5,97.5,93.3,93.3,75.9,72.8,72.6,71.5,71.3,71.3,70.0,69.7,60.7,50.7,35.1,34.2,31.9,30.6,25.9,17.4,11.5.
EXAMPLE 13 preparation of Compound C17
The experimental steps are as follows: reference is made to the synthesis of C15. 1 H NMR(400MHz,DMSO)δ8.37(s,1H),7.80(s,1H),6.55(s,1H),5.94(s,1H),5.29(s,1H),4.95(s,1H),4.84(s,1H),4.81–4.73(m,3H),4.71–4.66(m,1H),4.62–4.55(m,3H),4.48–4.39(m,1H),4.31–4.25(m,2H),4.16–4.00(m,2H),3.77(s,2H),3.73–3.67(m,2H),3.66–3.49(m,6H),3.46–3.43(m,1H),3.23–3.19(m,2H),3.15–3.11(m,3H),3.01–2.05(m,1H),2.45–2.40(m,2H),2.02–1.94(m,2H),1.68–1.58(m,2H),1.41(s,9H). 13 C NMR(201MHz,DMSO)δ170.8,159.1,157.4,155.5,154.4,153.8,144.6,123.2,118.3,109.2,105.4,102.4,97.5,96.6,93.3,91.3,87.9,78.9,73.8,72.8,72.6,72.6,71.5,71.3,71.3,70.1,69.7,60.8,50.7,40.0,34.7,34.2,31.7,29.8,28.1,11.0.
EXAMPLE 14 preparation of Compound C18
The experimental steps are as follows: reference is made to the synthesis of C15. 1 H NMR(400MHz,DMSO)δ8.41(s,1H),7.82(s,1H),6.67(s,1H),5.79(s,1H),4.83(s,1H),4.68–4.49(m,3H),4.48–4.38(m,1H),4.30(s,2H),4.12(t,J＝9.1Hz,1H),3.72(s,2H),3.65–3.40(m,7H),3.22(d,J＝6.4Hz,3H),3.14–3.03(m,4H),3.01–2.91(m,2H),2.44–2.24(m,4H),2.16–1.97(m,2H),1.79–1.62(m,2H). 13 C NMR(201MHz,DMSO)δ170.9,160.0,159.9,159.9,158.1,157.9,157.7,155.4,155.4,144.7,123.2,93.3,93.3,72.8,72.6,72.6,71.5,71.4,71.3,70.0,69.7,60.7,56.7,56.0,55.9,50.7,45.1,35.1,34.2,31.8,15.7,11.0.
EXAMPLE 15 preparation of Compound C19
The experimental steps are as follows: reference is made to the synthesis of C15. 1 H NMR(400MHz,DMSO)δ7.72(d,J＝4.4Hz,1H),6.51(s,1H),5.91(s,1H),4.91(d,J＝3.4Hz,1H),4.87–4.85(m,1H),4.76(dd,J＝19.7,3.4Hz,2H),4.68–4.63(m,1H),4.62–4.58(m,1H),4.03–3.91(m,1H),3.82–3.70(m,3H),3.69–3.61(m,1H),3.60–3.42(m,4H),3.42–3.37(m,1H),3.18–3.09(m,3H),3.00–2.93(m,1H),2.90–2.82(m,2H),2.59–2.54(m,1H),2.41–2.31(m,3H),2.11–2.00(m,2H),1.71–1.52(m,4H),0.94(t,J＝7.3Hz,3H).
EXAMPLE 16 preparation of Compound C20
The experimental steps are as follows: reference is made to the synthesis of C15. 1 H NMR(400MHz,DMSO)δ8.41–8.39(m,1H),7.77(s,1H),6.26(s,1H),5.67(s,1H),5.29(s,1H),4.86–4.74(m,3H),4.63–4.50(m,3H),4.43–4.34(m,1H),4.16–4.08(m,1H),4.02–3.91(m,1H),3.75–3.66(m,3H),3.64–3.56(m,2H),3.56–3.48(m,3H),3.15–3.06(m,3H),3.03–2.92(m,2H),2.87–2.77(m,4H),2.66(dd,J＝10.5,4.6Hz,2H),2.07–1.93(m,2H),1.61–1.46(m,4H),0.93(t,J＝6.2Hz,3H). 13 C NMR(101MHz,DMSO)δ169.7,156.0,158.6,155.5,155.2,146.1,122.4,119.3,99.6,98.6,98.1,98.1,98.0,93.6,93.3,78.6,72.9,72.7,72.6,71.6,71.5,71.3,70.1,69.8,60.8,50.7,42.3,38.1,32.1,30.8,30.1,22.9,21.0,13.8,11.1.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (9)
1. A compound of formula I or formula II, or a stereoisomer, tautomer, deuteride, nitroxide, or pharmaceutically acceptable salt thereof,
wherein,
R 1 and R 2 Each independently hydrogen, methyl, ethyl or propyl;
R 3 is trehalose base;
R 4 is hydrogen;
R 5 is hydrogen or C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted by-L 4 -R 4 Substituted;
L 1 is a bond;
L 2 is composed of
L 3 Is a bond, C 1-4 Alkylene or
L 4 Is a bond,
n is 0,1, 2,3 or 4;
the trehalose group is 4-trehalose group or 6-trehalose group.
2. A compound having the structure of one of:
wherein Tre is 4-fucosyl or 6-fucosyl.
3. A compound having the structure of one of:
wherein Tre is 4-mycosyl or 6-mycosyl.
4. A compound having the structure of one of:
wherein Tre is 4-fucosyl or 6-fucosyl.
5. A kit for detecting Mycobacterium tuberculosis, comprising the compound of any one of claims 1 to 4 as a detection reagent.
6. A method for detecting Mycobacterium tuberculosis for the purpose of non-disease diagnosis and treatment, comprising:
contacting a test sample with a compound according to any one of claims 1 to 4; and
and determining whether the mycobacterium tuberculosis exists in the sample to be detected based on whether the sample to be detected has fluorescence change before and after the sample to be detected is contacted.
7. The method of claim 6, wherein the fluorescence changes to at least one of:
the sample to be detected is in a fluorescence quenching state before the contact, and can be excited by exciting light of 320-400nm and emit fluorescence of 420-530 nm after the contact;
the sample to be detected is in a fluorescence quenching state before the contact, and can be excited by excitation light of 320-400nm and emit fluorescence of 420-530 nm after the contact, and the emitted fluorescence shows intensity change;
optionally, the sample to be tested comprises at least one of sputum, cerebrospinal fluid, alveolar lavage fluid, pleural effusion.
8. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for use in the detection of viable/dead bacteria, the treatment or prevention of mycobacterium tuberculosis-related diseases in humans and animals;
optionally, the drug is an anti-tuberculosis lead compound or an anti-tuberculosis drug.
9. The use according to claim 8, wherein the disease associated with mycobacterium tuberculosis infection is pediatric tuberculosis, pulmonary tuberculosis, intestinal tuberculosis, lymphoid tuberculosis, bone tuberculosis, renal tuberculosis, tuberculous peritonitis, tuberculous meningitis, drug-sensitive tuberculosis, multi-drug resistant tuberculosis, extensively drug resistant tuberculosis, latent tuberculosis, or HIV co-infected tuberculosis;
optionally, the disease associated with mycobacterium tuberculosis infection is a disease associated with tuberculosis in an animal.
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| CN106279083A (en) * | 2016-08-02 | 2017-01-04 | 浙江大学 | A kind of furocoumarin analog derivative and preparation method thereof |
| CN107266463A (en) * | 2017-07-17 | 2017-10-20 | 清华大学 | Compound and its purposes in mycobacterium tuberculosis detection |
| CN109942523A (en) * | 2017-12-20 | 2019-06-28 | 华东师范大学 | A kind of benzofuran and benzofuran coumarin derivative and its preparation method and application |
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| CN106279083A (en) * | 2016-08-02 | 2017-01-04 | 浙江大学 | A kind of furocoumarin analog derivative and preparation method thereof |
| CN107266463A (en) * | 2017-07-17 | 2017-10-20 | 清华大学 | Compound and its purposes in mycobacterium tuberculosis detection |
| CN109942523A (en) * | 2017-12-20 | 2019-06-28 | 华东师范大学 | A kind of benzofuran and benzofuran coumarin derivative and its preparation method and application |
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