CN115028632A - Fimsbactin A analogue-methotrexate antibacterial conjugate and application thereof - Google Patents

Fimsbactin A analogue-methotrexate antibacterial conjugate and application thereof Download PDF

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CN115028632A
CN115028632A CN202210643902.1A CN202210643902A CN115028632A CN 115028632 A CN115028632 A CN 115028632A CN 202210643902 A CN202210643902 A CN 202210643902A CN 115028632 A CN115028632 A CN 115028632A
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compound
conjugate
siderophore
antibacterial
methotrexate
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闫遥
崔雨婷
郭键
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Chongqing University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/552—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being an antibiotic
    • 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
    • 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

Abstract

A FilsbatinA analogue-methotrexate antibacterial conjugate and its application are disclosed. The invention provides a siderophore antibacterial conjugate, which takes dihydrofolate reductase inhibitor methotrexate as an active component in the antibacterial conjugate, takes a mixed siderophore Filsbastin A analogue as a bacteria targeting carrier, and is a compound shown as a formula (I) or a stereoisomer, a tautomer, a homolog, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown as the formula (I), wherein a linker is various connecting groups.

Description

Fimsbactin A analogue-methotrexate antibacterial conjugate and application thereof
Technical Field
The invention relates to a methotrexate antibacterial conjugate, in particular to a Finsbacin A analogue-methotrexate antibacterial conjugate and application thereof.
Background
The discovery of natural siderophore antibiotics provides a thought for the development of novel antibiotics. However, natural siderophore antibiotics are only in a few classes, so chemists develop a series of siderophore-antibiotic conjugates through an artificial synthesis way, and the classes of siderophore antibiotics are enriched.
In 1977, the first artificially synthesized siderophore-antibiotic conjugate was born, which used for reference of the structural characteristics of Ferrimycin and apramycin to link siderophore to sulfonamides. Antibacterial activity tests show that the antibacterial spectrum of the antibiotics is closely related to siderophores. The authors also found that the linker arm linking the siderophore to the drug plays a crucial role in antibacterial activity, requiring rational design of the linker arm to control the release of the antibiotic. The research opens up the field of the development of the siderophore-antibiotic conjugate to the antibiotic, and has good guiding value for the subsequent research.
In 2013, professor Miller reported the synthesis of a chain siderophore, Danoxamine, conjugate with ciprofloxacin (a fluoroquinolone antibiotic) and chlorocarbacephem (a β -lactam antibiotic) and tested its activity against staphylococcus aureus, respectively. The Danoxamine-chlorocarbacephem conjugate only shows weak anti-staphylococcus aureus activity, and the antibacterial activity is obviously reduced compared with that of the single chlorocarbacephem. The reason is that the cell wall mucopeptide synthetase serving as an action target of the chlorocarbacephem exists on the outer surface of staphylococcus aureus, and the Danoxamine-chlorocarbacephem conjugate carries the drug into the bacteria, so that the drug is far away from the action target, and the antibacterial activity is lost.
The MIC value of the Danoxamine-ciprofloxacin conjugate against Staphylococcus aureus SG511 was 1. mu.M, which is comparable to the antibacterial efficacy of ciprofloxacin. A relatively large siderophore modified on ciprofloxacin is likely to have reduced its affinity for DNA gyrase to some extent. And the active transport mode of the siderophore can enrich the drug in the bacterial body, thereby compensating the reduction of the affinity of the DNA gyrase, and the superposition of the two factors ensures that the Danoxamine-ciprofloxacin conjugate and the single ciprofloxacin show similar anti-staphylococcus aureus activity. From the antibacterial spectrum, ciprofloxacin is a broad-spectrum antibacterial drug and has obvious inhibition effect on gram-positive bacteria and gram-negative bacteria; the Danoxamine-ciprofloxacin conjugate only has an inhibition effect on gram-positive bacteria, and the antibacterial spectrum is obviously narrowed. This is because such siderophore conjugates enter the bacteria through siderophore transport systems in an active transport manner, different siderophores are recognized only by the corresponding siderophore transport systems, and since Danoxamine's transport systems are present only in some gram-positive bacteria, Danoxamine-ciprofloxacin conjugates have inhibitory activity only against the corresponding gram-positive bacteria.
One of the easily overlooked and very important aspects of the synthesis of siderophore-antibiotic conjugates is the choice of linker arm. Most conjugates now utilize conventional linking means such as amide linkages, ester linkages, copper-catalyzed Click reaction of azide and alkyne, or addition of thiol to maleimide, as the linker arm. Conjugates prepared from beta-lactam antibiotics and fluoroquinolone antibiotics can still exert antibacterial activity without breaking a connecting arm, but most antibiotics must be released from the connecting arm due to limited or well-conserved action site space. It is therefore necessary to explore and develop breakable connecting arms.
Much work has been done by the teachings of Miller in the development of disconnectable connecting arms. In 2012, they reported the synthesis of two conjugates of Desferrioxamine B-ciprofloxacin, with linkers cleaved by esterases and phosphatases selected respectively. Antibacterial activity studies found that the first conjugate exhibited some activity against the test strains, but did not work well with ciprofloxacin. The second conjugate showed no antibacterial activity against the test strain. Although the desired effect was not obtained, the authors did not give up on the linker arm. In 2015, they reported a new research result, namely synthesis of a third conjugate and antibacterial testing. The author selects the connecting arm which can be disconnected in a reduction mode to connect the siderophore with the ciprofloxacin, and an antibacterial activity test shows that the breakable connecting arm has better antibacterial effect than a conjugate prepared by the non-breakable connecting arm.
Most conjugates now utilize conventional linking means such as amide linkages, ester linkages, copper-catalyzed Click reaction of azide and alkyne, or addition of thiol to maleimide, as the linker arm. Conjugates prepared from beta-lactam antibiotics and fluoroquinolone antibiotics can still exert antibacterial activity without breaking a connecting arm, but most antibiotics must be released from the connecting arm due to limited or well-conserved action site space. It is therefore necessary to explore and develop breakable connecting arms.
The continuous emergence of multi-drug resistant bacteria and even 'super bacteria' makes bacterial infection form a new threat to human life health, and scientists are urgently required to develop novel antibiotics to resist the increasingly severe problem of bacterial drug resistance. The siderophore targeted delivery of antibiotics is a very promising antibiotic development strategy, which is to couple siderophore with the existing antibiotics, and the conjugate is identified and transported by an iron transport system, thus finally achieving the purpose of inhibiting or killing bacteria. Meanwhile, the artificially synthesized siderophore-antibiotic conjugate makes up the current situation of the shortage of natural siderophore antibiotics, and has great clinical development prospect.
Methotrexate (MTX) is a high-efficiency antitumor drug, and the action target is dihydrofolate reductase. The dihydrofolate reductase catalyzes the reduction of dihydrofolate to tetrahydrofolate, which is an important raw material for synthesizing thymine, purine and certain amino acids. Methotrexate competitively inhibits dihydrofolate reductase, blocks tetrahydrofolate synthesis, and ultimately blocks nucleic acid synthesis, thereby inhibiting tumor growth. Eukaryotic organisms such as human beings, animals and the like and prokaryotic organisms such as bacteria and the like all have dihydrofolate reductase, and can be used as a drug action target. Methotrexate has some antibacterial activity in addition to antitumor activity, in which MIC values for enterococcus and Streptococcus pneumoniae are 4. mu.M and 0.5. mu.M, respectively, but it cannot be used as an antibacterial agent because it is too toxic to normal cells of the human body.
The recognition and transport system of siderophores is present only in microorganisms such as bacteria, but not in mammals. Therefore, the conjugation of methotrexate with siderophores is expected to overcome the toxicity problem of methotrexate to normal cells and improve its antibacterial activity through a highly efficient iron transport system of bacteria.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art.
In a first aspect of the invention, the invention provides a coupling compound which is a compound of formula (I) or a stereoisomer, a tautomer, a homolog, a solvate, a metabolite, a pharmaceutically acceptable salt of the compound of formula (I) or a prodrug thereof, wherein a linker is a linker arm.
Figure BDA0003685167590000021
In a second aspect of the invention, the invention provides a conjugated compound which is a compound of formula (II) or a stereoisomer, a tautomer, a homolog, a solvate, a metabolite, a pharmaceutically acceptable salt of said compound, or a prodrug thereof.
Figure BDA0003685167590000031
In a third aspect of the invention, a pharmaceutical composition is provided. According to an embodiment of the invention, the pharmaceutical composition comprises a conjugate compound as described above. According to an embodiment of the invention, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
In a fourth aspect of the invention, the invention proposes the use of a conjugate compound as defined above or a pharmaceutical composition as defined above for the preparation of a medicament for the inhibition of a pathogenic bacterium.
According to an embodiment of the invention, the cocci are gram-negative bacteria. The inventors found that the inhibitory effect of the compounds according to the examples of the present invention against gram-negative bacteria was significant and further investigated.
The invention can artificially synthesize the siderophore-antibiotic conjugate, can expand antibiotic development approaches and provide more candidate drug molecules for clinic. The activity of the methotrexate is obviously improved, the toxicity is greatly reduced, the problem of toxicity of the methotrexate to normal cells is solved, and the antibacterial activity of the methotrexate is improved through a high-efficiency iron transport system of bacteria. The artificial siderophore antibiotic uses a natural siderophore antibiotic template structure for reference, and drug delivery is carried out through a special efficient active iron transfer system of bacteria, so that the antibacterial effect is exerted. And the application of the compound in the development of antibiotics can greatly broaden the research thought in the field and provide more candidate drugs for clinic. The artificially synthesized siderophore-antibiotic conjugate makes up the current situation of the shortage of natural siderophore antibiotics and has very large clinical development prospect.
Drawings
FIG. 1 shows the structural formula of the antibiotic conjugate of Fimsbactin A analogue-methotrexate
Detailed Description
Placing the compounds 2-29 and 2-30 in a flask filled with acetonitrile solvent, adding potassium carbonate for reaction under the condition of heating reflux for 6 hours, performing vacuum distillation as the post-treatment, washing with water, and filtering to obtain colorless oily substances 2-31.
Figure BDA0003685167590000041
Placing the compounds 2-31 in a flask filled with dry dichloromethane, adding methyl succinyl chloride and triethylamine to react for 4 hours at room temperature. The post-treatment comprises adding water for extraction, filtering, and purifying with silica gel column chromatography to obtain colorless oily substance 2-32.
Figure BDA0003685167590000042
Placing the compounds 2-32 into a flask filled with dichloromethane, adding trifluoroacetic acid for reaction, stirring at room temperature for 30 minutes, and carrying out vacuum distillation to obtain the compounds 2-33.
Figure BDA0003685167590000043
Placing compounds 2-26, CDI in a round bottom flask with dry dichloromethane, N 2 Under the protection condition, stirring is carried out for 1 hour at room temperature. Compound 5 is placed in another flask with dry dichloromethane, N 2 Protection, it was added to a solution of compound 6, and the reaction was carried out overnight at room temperature. The post-treatment is reduced pressure distillation, sodium hydroxide washing and silica gel column purification to obtain colorless oily substances 2-34.
Figure BDA0003685167590000044
Placing the compounds 2-34 in a flask containing 1, 4-dioxane, adding sodium hydroxide solution, reacting under the condition of vigorous stirring at room temperature for 24 hours, performing vacuum distillation, adjusting pH to 4, extracting, and purifying with silica gel chromatographic column to obtain colorless oily substances 2-7.
Figure BDA0003685167590000051
Place Compounds 2-44 in a flask of dry pyridine, N 2 Protection, standing at 0 ℃. Placing NpsCl in another flask with dry pyridine, N 2 Protecting, slowly dropping into the solution of the compounds 2-44, reacting for 1 hour at 0 ℃, and moving to room temperature for reacting for 4 hours. The post-treatment is that a high vacuum oil pump removes the solvent, and the white solid 2-45 is obtained after methanol recrystallization.
Figure BDA0003685167590000052
Placing compound 2-45 and compound 2-47 in a flask containing dry N, N-dimethylformamide, adding potassium carbonate, N 2 Protected under conditions of 70 ℃ heating overnight. And (4) carrying out post-treatment on the mixture by using a high vacuum oil pump to remove the solvent, and purifying the mixture by using a silica gel chromatographic column to obtain colorless oily substances 2-48.
Figure BDA0003685167590000053
Placing compounds 2-48 in a flask containing dry N, N-dimethylformamide, adding potassium carbonate, N 2 And (4) protecting, and reacting at room temperature for 3 hours. The post-treatment is that a high vacuum oil pump removes the solvent, and the colorless oily matter 2-49 is obtained after washing, reduced pressure distillation and silica gel chromatographic column purification.
Figure BDA0003685167590000054
Placing the compounds 2-49 in a flask filled with dry dichloromethane, adding methyl succinyl chloride, triethylamine and N 2 And (4) protecting, and reacting at room temperature for 4 hours. The post-treatment is extraction, reduced pressure distillation and silica gel chromatographic column purification to obtain colorless oily matter 2-51.
Figure BDA0003685167590000055
Placing the compounds 2-51 into a flask filled with dichloromethane, adding trifluoroacetic acid, stirring at room temperature for 30 minutes, performing vacuum distillation as the post-treatment, and removing the solvent by a high vacuum oil pump to obtain the compounds 2-8.
Figure BDA0003685167590000056
Placing the compound 2-7 in a flask filled with N, N-dimethylformamide, adding the compound 2-8, HATU and DIPEA, reacting at room temperature overnight, performing aftertreatment with a high vacuum oil pump to remove the solvent, performing reduced pressure distillation, and purifying with a silica gel chromatographic column to obtain colorless oily substance 2-52.
Figure BDA0003685167590000057
Placing compound 2-52 in flask containing 1, 4-dioxane, adding sodium hydroxide solution, stirring at room temperature for 24 hr, distilling under reduced pressure, adjusting pH to 4, and purifying with silica gel column chromatography to obtain white solid 2-5.
Figure BDA0003685167590000061
Compounds 2-53 were placed in a flask containing sodium bicarbonate solution with stirring at room temperature. Fmoc-Osu was placed in a flask containing 1, 4-dioxane and added portionwise to a solution of compounds 2-53 in sodium bicarbonate with vigorous stirring at room temperature for 12 hours. The post-treatment is reduced pressure distillation, pH is adjusted to be neutral, extraction is carried out, and colorless oily substances 2-54 are obtained after purification by a silica gel chromatographic column.
Figure BDA0003685167590000062
Placing the compounds 2-54 into a flask filled with dichloromethane, adding trifluoroacetic acid, stirring at room temperature for 30 minutes, performing vacuum distillation as a post-treatment, and removing the solvent by a high vacuum oil pump to obtain the compound 2-1 a.
Figure BDA0003685167590000063
The compounds 2 to 60 were placed in a flask containing methylene chloride, and dibromotriphenylphosphine was added thereto, and the mixture was stirred at room temperature for 20 hours. 4-Methylaminobenzoic acid was added to the reaction flask and DIPEA was added, with stirring at room temperature for three days. The post-treatment is filtration, the pH is adjusted to 4.5, solid is separated out, and orange solid 2-62 is obtained by filtration.
Figure BDA0003685167590000064
The compounds 2 to 62 and BOP are placed in a flask filled with dimethyl sulfoxide, triethylamine is added, and the mixture is stirred for 2 hours at room temperature. Adding L-glutamic acid into a reaction bottle, adding potassium carbonate, reacting for 15 minutes at 50 ℃, moving to room temperature, and stirring for 18 hours. After-treatment, solid is separated out, filtered and washed to obtain yellow products 2-6.
Figure BDA0003685167590000065
The compound 2-6 was placed in a flask containing N, N-dimethylformamide, the compound 2-1a was added, HATU was added, and DIPEA was added, under the conditions of room temperature overnight. The post-treatment is to remove the solvent by a high vacuum oil pump, distill under reduced pressure and purify by a silica gel chromatographic column to obtain a yellow oily substance 2-1 b.
Figure BDA0003685167590000066
Compound 2-1b was placed in a flask containing 20% piperidine in N, N-dimethylformamide with stirring at room temperature for 30 minutes and worked up by high vacuum oil pump to remove the solvent. Adding N, N-dimethylformamide again for dissolving, adding compound 2-5, adding HATU, adding DIPEA, reacting at room temperature overnight, performing aftertreatment with high vacuum oil pump to remove solvent, distilling under reduced pressure, and purifying with silica gel column chromatography to obtain yellow oily substance 2-1 c.
Figure BDA0003685167590000071
Placing the compound 2-1c in a flask filled with dichloromethane, slowly adding trifluoroacetic acid, adding water, stirring at room temperature overnight, performing after-treatment, namely removing the solvent under reduced pressure by using a high vacuum oil pump, and recrystallizing methanol and diethyl ether to obtain a yellow solid product 2-1.
Figure BDA0003685167590000072
Summary of the invention
The development of siderophore antimicrobial conjugates of intracellular target drugs is a difficult point and bottleneck in the current field of "trojan horse" antimicrobial strategies. The siderophores are various in types, different siderophores are transported by different types of transport proteins and cooperative proteins, and the structural information and characteristics of most transport proteins are unclear, so that difficulty is increased for the reasonable design of siderophore antibacterial conjugates. In the future, when other siderophores and antibacterial conjugates thereof are researched, siderophore fluorescent conjugates should be constructed first, and whether the siderophores are located in periplasm or cytoplasm is confirmed through imaging research, so that the siderophore fluorescent conjugates can help to reasonably select proper active drugs for constructing siderophore conjugates. At present, most of antibacterial drugs applied to intracellular targets by a 'Trojan horse' antibacterial strategy have poor effects, but the drugs targeting the intracellular targets of bacteria are numerous, and breakthrough in the field can greatly help to overcome the drug resistance of the bacteria and promote the discovery of novel antibacterial drugs.

Claims (9)

1. A conjugate compound which is a compound represented by formula (I) or a stereoisomer, tautomer, homolog, solvate, metabolite, pharmaceutically acceptable salt of the compound represented by formula (I) or a prodrug thereof, wherein a linker is a linker,
Figure FDA0003685167580000011
。
2. the coupling compound of claim 1, wherein the linker arm comprises at least one member selected from the group consisting of alkanes, alkenes, alkynes, aromatics, heteroatom-containing alkanes, alkenes, alkynes, aromatics, amino acids, ketones, esters, amides, sulfonamides, ureas, enamines;
optionally, the coupled compound is protium substituted or deuterium substituted.
3. The coupling compound of claim 2, wherein the linking group further comprises one or more of an aromatic ring compound, an alkane ring compound, and a heterocyclic compound.
4. The coupling compound of claim 3, wherein the linking group has the structure shown below:
Figure FDA0003685167580000012
。
5. a conjugated compound, which is a compound represented by the following formula or a stereoisomer, tautomer, homolog, solvate, metabolite, pharmaceutically acceptable salt of said compound, or a prodrug thereof,
Figure FDA0003685167580000021
。
6. a pharmaceutical composition comprising a conjugate compound according to any one of claims 1 to 4.
7. The pharmaceutical composition of claim 5, further comprising a pharmaceutically acceptable excipient.
8. Use of a conjugate compound as claimed in any one of claims 1 to 4 or a pharmaceutical composition as claimed in claim for the manufacture of a medicament for use in the inhibition of a pathogenic bacterium.
9. Use according to claim 7, wherein the cocci are resistant to gram-negative bacteria.
CN202210643902.1A 2022-06-09 2022-06-09 Fimsbactin A analogue-methotrexate antibacterial conjugate and application thereof Pending CN115028632A (en)

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