WO2022121977A1 - 稠环酚类化合物的药学应用 - Google Patents
稠环酚类化合物的药学应用 Download PDFInfo
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- WO2022121977A1 WO2022121977A1 PCT/CN2021/136707 CN2021136707W WO2022121977A1 WO 2022121977 A1 WO2022121977 A1 WO 2022121977A1 CN 2021136707 W CN2021136707 W CN 2021136707W WO 2022121977 A1 WO2022121977 A1 WO 2022121977A1
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- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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Definitions
- the present invention relates to the use of a fused-ring phenolic compound, or a pharmaceutically acceptable salt or ester thereof, in the preparation of a medicament for treating, inhibiting or preventing bacterial infection.
- the present invention relates to a PPK inhibitor.
- Pseudomonas aeruginosa alias Pseudomonas aeruginosa, a Gram-negative bacterial pathogen
- Pseudomonas aeruginosa "alias Pseudomonas aeruginosa, a Gram-negative bacterial pathogen” was an urgently needed antibiotic. "First Class Priority" pathogens. Pseudomonas aeruginosa is one of the most important acquired pathogens in the hospital setting and is susceptible to infecting patients with compromised immune systems (eg, cystic fibrosis, cancer or AIDS patients, etc.) and those requiring medical equipment such as respiratory aids and catheters of patients.
- compromised immune systems eg, cystic fibrosis, cancer or AIDS patients, etc.
- Pseudomonas aeruginosa can also cause other very serious and fatal infections (such as pneumonia, urinary and gastrointestinal infections, etc.). Pseudomonas aeruginosa is resistant to many high-efficiency antibiotics currently used, such as carbapenems and cephalosporins. In the face of the rapid development of drug resistance in bacterial pathogens, the research and development of antibiotic drugs has been seriously lagging behind.
- Polyphosphate is a chain-like inorganic compound composed of several to hundreds of phosphoric acid groups connected by high-energy phosphoric anhydride bonds, and widely exists in all living organisms. Studies have shown that polyP will accumulate in bacteria under unfavorable living conditions, making bacteria highly tolerant to environmental stress. ), etc. together respond to stress and are considered to be global regulators of stress and toxicity response pathways in numerous bacterial species. Specifically, PPK is required for Pseudomonas aeruginosa quorum sensing, biofilm formation, toxin secretion, and virulence in animal infection models.
- Inorganic polyphosphate is a linear polymer formed by the polymerization of inorganic phosphate monomers through high-energy phosphoric acid bonds, and the length can reach 1000 monomers.
- polyphosphates are synthesized and consumed by polyphosphate kinases. These enzymes are further divided into two main families, polyphosphate kinase-1 (PPK1) and polyphosphate kinase-2 (PPK2).
- the PPK1 enzyme preferentially uses ATP as a phosphorylating agent to catalyze the synthesis of polyphosphates.
- PPK1 As a key virulence determinant of Pseudomonas aeruginosa, and demonstrated that after PPK1 gene knockout, Pseudomonas aeruginosa's quorum sensing, Motility, biofilm formation, and virulence are all severely affected (Polyphosphate kinase is essential for biofilm development, quorum sensing, and virulence of Pseudomonas aeruginosa. PNAS. 97, 9636–9641).
- PPK2 enzymes that do not have any similarity in sequence to PPK1, and their main function is to use polyP to synthesize GTP instead of polyP.
- PPK2 has been identified in many species, including major pathogens, as a determinant of virulence and persistence in Pseudomonas aeruginosa, highlighting the overall importance of polyP balance during bacterial infection.
- PPKs have been hailed as potential targets for antimicrobial therapy.
- the current screening effort has identified several inhibitors of the PPK1 and PPK2 enzymes, resulting in several compounds with relatively weak activity against PPK1 and PPK2 based on bisphosphonates (Burda-Grabowska, M. et al, Bisphosphonic acids and related compounds as inhibitors of nucleotide-and polyphosphate-processing enzymes: A PPK1and PPK2case study.Chem Biol Drug Des.10.1111/cbdd.13439).
- potent compounds low micromolar or nanomolar activity
- the technical problem mainly solved by this application is to provide potent compounds against PPK.
- the applicant found that a specific fused-ring phenolic compound, or a pharmaceutically acceptable salt or ester thereof, can effectively inhibit the production of PPK enzyme, thereby preparing a medicament for treating, inhibiting or preventing bacterial infection.
- the present invention provides the use of a fused-ring phenolic compound in the preparation of a medicament for treating, inhibiting or preventing bacterial infection, wherein the fused-ring phenolic compound comprises one or more compounds in Table 1 or its A pharmaceutically acceptable salt or ester.
- the bacterial infection comprises a bacterial infection caused by bacteria that produce one or more polyphosphokinases (PPKs).
- PPK includes, for example, PPK1, PPK2A, PPK2B, and PPK2C.
- the bacterial infection described above comprises infection by Pseudomonas aeruginosa, Klebsiella Pneumoniae, Escherichia coli, Staphylococcus aureus, salmonella, Bacillus subtilis Infections caused by Bacillus subtilis, Acinetobacter baumannii, Enterobacter cloacae or Enterococcus.
- the Enterococcus is a vancomycin-resistant Enterococcus
- the Staphylococcus aureus is a Methicillin-resistant Staphylococcus aureus.
- the above bacterial infection comprises a bacterial infection caused by Pseudomonas aeruginosa.
- C, H, O and S atoms in the above compounds are each independently selected from naturally abundant atoms and isotopically enriched atoms.
- the isotopically enriched atoms are selected from the group consisting of 12 C, 13 C and 14 C of carbon; 1 H, 2 H and 3 H of hydrogen; 16 O, 17 O and 18 O of oxygen; and 32S , 33S and 34S of sulfur.
- the compounds of the present invention may be the listed compounds as well as pharmaceutically acceptable salts or esters, and may also be pharmaceutically acceptable prodrug compounds.
- the present invention provides a medicament comprising one or more of the compounds of the present invention for the treatment, inhibition or prevention of bacterial infection, wherein the bacterial infection comprises a bacterial infection associated with a PPK enzyme-catalyzed reaction.
- the present invention relates to the use of a composition in the preparation of a medicament for the treatment, inhibition or prevention of bacterial infection, wherein the composition comprises a compound as defined in this application and at least one pharmaceutically acceptable carrier or thinner.
- the above-mentioned drug is a PPK inhibitor for the treatment, inhibition or prevention of bacterial infections caused by bacteria that produce one or more polyphosphokinases (PPKs); wherein the bacterial infections include green Infections caused by Pseudomonas, Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Salmonella, Bacillus subtilis, Acinetobacter baumannii, Enterobacter cloacae, or Enterococcus.
- the Enterococcus is a vancomycin-resistant Enterococcus
- the Staphylococcus aureus is a Methicillin-resistant Staphylococcus aureus.
- the above bacterial infection comprises a bacterial infection caused by Pseudomonas aeruginosa.
- the aforementioned pharmaceutically acceptable carriers or diluents include creams, emulsions, gels, liposomes, or nanoparticles.
- the present invention provides the use of a kit in the preparation of a medicament for treating, inhibiting or preventing bacterial infection, wherein the kit comprises a compound of the present application or a pharmaceutically acceptable salt or ester or the present invention composition; and diluents (eg, sterile water), buffers, pharmaceutically acceptable excipients.
- diluents eg, sterile water
- the present invention provides a method for inhibiting bacterial growth in vitro, wherein the bacteria are selected from Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Salmonella, Bacillus subtilis, and Acinetobacter baumannii , Enterobacter cloacae or Enterococcus, preferably Pseudomonas aeruginosa.
- the method comprises: administering a compound in Table 1 above, or a pharmaceutically acceptable salt or ester thereof, or a composition of the present application or a kit of the present application, to bacteria at an effective concentration or amount.
- the specific fused-ring phenolic compounds provided in this application, or their pharmaceutically acceptable salts or esters, can be used to effectively inhibit the production of PPK enzymes, especially for Pseudomonas aeruginosa and other bacteria that are regulated by PPK enzyme catalysis.
- the infection has a strong effect, so that a drug for treating, inhibiting or preventing bacterial infection can be prepared, and an excellent therapeutic, inhibiting or preventive effect can be obtained.
- Figure 1 IC50 plot of compound 4 for inhibition of different PPKs (PPK1, PPK2A, PPK2B and PPK2C).
- Figure 2 Effect of compound 4 on biofilm formation in different Pseudomonas aeruginosa strains: A, absorbance; experimental concentration of compound 4 was 100 ⁇ M, "-" or "+” means no or addition of compound 4; WT, wild strain ; ⁇ ppk1 is the PPK1 knockout strain; ⁇ ppk2A ⁇ ppk2B ⁇ ppk2C is the PPK2A, PPK2B, PPK2C knockout strain; ⁇ ppk1 ⁇ ppk2A ⁇ ppk2B ⁇ ppk2C is the PPK1, PPK2A, PPK2B, PPK2C knockout strain.
- Figure 3 Effect of compound 4 on survival of Pseudomonas aeruginosa infected nematodes.
- Figure 4 Toxicity test of compound 4 and compound B on human embryonic kidney cells (HEK cells): relative viability of cells in the presence of DMSO (control), compound B (100 ⁇ M), and compound 4 (100 ⁇ M).
- derivative as used in the present invention should be understood as another compound which is similar in structure but differs in some fine structure.
- the present invention provides the use of a fused-ring phenolic compound, or a pharmaceutically acceptable salt or ester thereof, in the preparation of a medicament for treating, inhibiting or preventing bacterial infection, the fused-ring phenolic compound.
- the class of compounds is selected from, but not limited to, the compounds listed in Table 1.
- “Pharmaceutically acceptable salt” of a compound refers to a salt of a pharmaceutically acceptable compound. Salts of desired compounds (basic, acidic, or charged functional groups) can retain or improve the biological activity and properties of the parent compound as defined herein, and are not biologically undesirable.
- the compounds provided herein may contain unnatural proportions of isotopic atoms at one or more of the atoms that constitute such compounds.
- Unnatural proportions of isotopes can be defined as amounts ranging from those found in nature to those consisting of 100% of the atoms in question.
- compounds can incorporate radioactive isotopes such as tritium ( 3 H) or carbon-14 ( 14 C) or non-radioactive isotopes such as deuterium ( 2 H) or carbon-13 ( 13 C).
- radioactive isotopes such as tritium ( 3 H) or carbon-14 ( 14 C) or non-radioactive isotopes such as deuterium ( 2 H) or carbon-13 ( 13 C).
- isotopic changes may provide additional applications to those described elsewhere in this application.
- isotopic variants of the compounds of the present invention may find additional uses, including but not limited to, as diagnostic and/or imaging agents, or as cytotoxic/radiotoxic therapeutics.
- isotopic variants may have altered pharmacokinetic and pharmacodynamic profiles that may contribute to enhanced safety, tolerability or efficacy during treatment. All isotopic variations of the compounds provided herein, whether radioactive or not, are encompassed by the present invention.
- naturally abundant element or “naturally abundant atom” refers to the element or atom, respectively, of its most abundant atomic mass in nature.
- the natural abundance of hydrogen is 1 H
- the natural abundance of sulfur is 32 S
- the natural abundance of oxygen is 16 O
- the natural abundance of carbon is 12 C
- a "non-isotopically enriched" compound is one in which all atoms or elements in the compound are isotopes in natural abundance, ie all atoms or elements are most abundant in atomic mass in nature.
- the fused-ring phenolic compounds disclosed in the present application, or pharmaceutically acceptable salts or esters thereof, have a good inhibitory effect on one or both of PPK1 and PPK2, and are used for the preparation of therapeutic, inhibiting or preventing bacterial infections. drug.
- the bacterial infection includes PPK-related bacterial infection, which may be PPK1-related bacterial infection, PPK2-related bacterial infection, or both PPK1 and PPK2-related bacterial infection.
- PPK-associated bacterial infection and "PPK-mediated bacterial infection” are used interchangeably to refer to any bacterial infection, disease, disorder or condition that would benefit from treatment with a PPK inhibitor.
- PPK-related bacterial infections encompass those infections caused by bacteria/pathogens that carry at least one or more of the PPKs.
- infections or “bacterial infection” include the presence of bacteria in or on a subject that would benefit the subject if the growth of the bacteria was inhibited.
- infection or “bacterial infection” refers to the undesired normal flora in addition to the presence of bacteria.
- infection includes infections referred to by bacteria. Examples of such bacterial infections include many important bacterial pathogens such as P. aeruginosa, K.
- Pseudomonas aeruginosa can encode not only three PPK2 enzymes, namely PPK2A (PA14_01730), PPK2B (PA14_33240) and PPK2C (PA14_19410), but also PPK1 (PA14_69230).
- the bacterial infection may be an infection caused by Pseudomonas aeruginosa, or by Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Salmonella, Bacillus subtilis, Acinetobacter baumannii, Enterobacter cloacae Bacillus, vancomycin-resistant Enterococcus, or methicillin-resistant Staphylococcus aureus.
- growth refers to the growth of one or more microorganisms, and includes the reproduction or population expansion of microorganisms such as bacteria.
- the term also includes metabolic processes that maintain a microorganism on-going, including processes that keep the microorganism alive.
- the fused-ring phenolic compound provided by the present invention can be used as a PPK inhibitor, and the PPK inhibitor can simultaneously inhibit PPK1 and PPK2, or can inhibit either of them.
- the fused-ring phenolic compounds of the present invention function to inhibit PPK activity and/or anti-inflammatory activity, and are useful as therapeutic or prophylactic therapeutics when such inhibition is desired. Unless otherwise indicated, when the use of the compounds of the present invention is described herein, it is to be understood that these compounds may be in the form of a composition (ie, a pharmaceutical composition).
- PPK inhibitor As used herein, the terms “PPK inhibitor”, “PPK blocker”, “polyphosphokinase inhibitor”, “polyphosphokinase inhibitor” and all other related art acceptable terms are used interchangeably to represent compounds that directly or indirectly inhibit PPK receptors in in vitro assays, in vivo models, and/or in other assays that demonstrate PPK inhibition and potential therapeutic or prophylactic efficacy. The term also refers to compounds that exhibit at least some therapeutic or prophylactic benefit in human subjects.
- the present invention also provides a bacteriostatic agent/drug for treating, inhibiting or preventing bacterial infection, especially bacterial infection associated with PPK, comprising one or more of the above compounds, wherein the bacterial infection comprises a bacterial infection caused by Pseudomonas aeruginosa Bacillus, Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Salmonella, Acinetobacter baumannii, Bacillus subtilis, Enterobacter cloacae, or Enterococcus.
- bacteriostatic agent refers to the ability to inhibit, reduce or prevent the growth of bacteria, inhibit or reduce the ability of bacteria to cause infection in a subject, or inhibit or reduce the ability of bacteria to reproduce or maintain infection in the environment, or reduce the infectivity of bacteria or virulence of any substance, compound or combination thereof.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising: a compound disclosed in the present invention or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.
- a pharmaceutical composition comprising at least one of Compounds 1 to 10, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.
- the present invention provides the use of at least one PPK inhibitor compound or composition provided by the present invention for the treatment and/or prevention of immune-related diseases, disorders and conditions, diseases with an inflammatory component, and diseases associated with The above related methods of dissonance.
- treating refers to initiating action (eg, administration of a PPK inhibitor or a pharmaceutical composition comprising the same) after a disease, disorder or condition, or symptoms thereof, has been diagnosed, observed, to temporarily or permanently eliminate, alleviate, inhibit , alleviating or ameliorating at least one underlying cause of the disease, disorder, or condition afflicting the subject, or symptoms associated with the disease, disorder, or condition afflicting the subject.
- treatment includes inhibiting (eg, preventing or ameliorating the development or further development of a disease, disorder or condition or clinical symptoms associated therewith) active disease.
- treatment as used herein is used to specifically mean the administration of a therapeutic comprising a compound or composition according to the present invention to a patient already suffering from an infection.
- treatment also relates to administering a compound or composition according to the invention, optionally together with one or more antibacterial agents, to: alleviate or alleviate a bacterial infection or one or more symptoms associated with a bacterial infection; or slowing the development of a bacterial infection or one or more symptoms associated with a bacterial infection; or reducing the severity of a bacterial infection or one or more symptoms associated with a bacterial infection; or inhibiting the clinical manifestations of a bacterial infection; or Suppresses the manifestation of adverse symptoms of bacterial infection.
- prevention refers to initiating action (e.g., administration of a PPK inhibitor or a pharmaceutical composition comprising the same) in a manner (e.g., prior to the onset of a disease, disorder, condition, or symptoms thereof), thereby temporarily or permanently preventing, inhibiting , suppress or reduce a subject's risk of developing a disease, disorder or condition, etc. (as determined by, eg, lack of clinical symptoms) or delay the onset of a particular disease, condition or condition in the case of a subject predisposed to it.
- the term also refers to slowing the progression of a disease, disorder or condition or inhibiting its progression into a deleterious or other undesirable state.
- the term “prophylaxis” as used herein is used to refer to the administration of a compound or composition according to the present invention to prevent infection caused by bacteria or to prevent the occurrence of related infections and/or diseases.
- prevention also encompasses the prevention of at least one bacterial infection by administration of a compound or composition according to the invention by administering to a patient susceptible to or at risk of bacterial infection.
- the present invention further provides the use of the PPK inhibitor compounds and compositions described herein in combination with one or more additional agents.
- the one or more additional agents may have some PPK-modulating activity and/or they may act through different mechanisms of action.
- such agents comprise radiation (eg, local radiation therapy or systemic radiation therapy) and/or other treatment modalities that are not pharmacological in nature.
- the PPK inhibitor and one additional agent may be in a single composition or in multiple compositions, and the treatment modality may be administered simultaneously, sequentially or by some other regimen.
- the radiation phase is followed by a chemotherapy phase.
- Combination therapy can have additive or synergistic effects.
- compositions containing the active ingredient may be in a form suitable for oral use, such as tablets, capsules, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions , hard or soft capsules, or syrup, solution, microbeads, or elixir.
- Pharmaceutical compositions for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as sweetening, flavoring, coloring and a preservative to provide a pharmaceutically acceptable formulation.
- Tablets, capsules and the like generally contain the active ingredient in admixture with non-toxic pharmaceutically acceptable carriers or excipients which are suitable for the manufacture of tablets.
- carriers or excipients can be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binders, such as starch, gelatin Or gum arabic and lubricants such as magnesium stearate, stearic acid or talc.
- the composition is an injectable formulation. In other embodiments, the composition is formulated for oral administration to a subject.
- compositions are contained in single-use containers (eg, single-use vials, ampoules, syringes, or auto-injectors), while in other embodiments, multiple-use containers (eg, multiple used vials).
- single-use containers eg, single-use vials, ampoules, syringes, or auto-injectors
- multiple-use containers eg, multiple used vials
- the formulations may also include carriers to protect the composition from rapid degradation or disappearance from the body, such as controlled release formulations, including liposomes, hydrogels, and microencapsulated delivery systems.
- controlled release formulations including liposomes, hydrogels, and microencapsulated delivery systems.
- time delay materials such as glyceryl monostearate or glyceryl stearate alone or in combination with waxes can be used.
- Any drug delivery device can be used to deliver the PPK inhibitor, including implants (eg, implantable pumps) and catheter systems, slow infusion pumps and devices. All of these are well known to those skilled in the art.
- compositions may also be in the form of sterile injectable aqueous or oily suspensions.
- This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned herein.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
- solvents and dispersion media that may be used are water, Ringer's solution, isotonic sodium chloride solution, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyol Alcohols such as glycerol, propylene glycol and liquid polyethylene glycols and suitable mixtures thereof.
- sterile fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables. Prolonged absorption of the specific injectable formulations can be brought about by the inclusion of agents which delay absorption, for example, aluminum monostearate or gelatin.
- the PPK inhibitor compounds and compositions provided herein can be administered to a subject in any suitable manner known in the art.
- Suitable routes of administration include, but are not limited to, oral; parenteral, eg, intramuscular, intravenous, subcutaneous (eg, injection or implantation), intraperitoneal, intracisternal, intraarticular, intracerebral (intraparenchymal and intraventricular; nasal cavity ; vaginal; sublingual; intraocular; rectal; topical (eg, transdermal); buccal and inhalation.
- Depot injection typically by subcutaneous or intramuscular administration, can also be used to release the PPK inhibitors disclosed herein over a defined period of time .
- kits comprising PPK inhibitor compounds or compositions.
- the kits are generally in the form of physical structures containing the various components, and can be used, for example, to practice the methods provided herein.
- a kit can include one or more PPK inhibitors disclosed herein (e.g., provided in a sterile container) in the form of a pharmaceutical composition suitable for administration to a subject.
- the PPK inhibitor may be provided in ready-to-use (eg, tablet or capsule) form or in a form that requires reconstitution or dilution (eg, powder), eg, prior to administration.
- the kit may also include diluents (eg, sterile water), buffers, pharmaceutically acceptable excipients, etc.
- diluents eg, sterile water
- the kit may contain several therapeutic agents independently, or they may already be combined in the kit.
- Each component of the kit can be packaged in a separate container, and all of the various containers can be in a single package.
- the kits of the present invention can be designed to properly maintain the conditions required (eg, refrigerated or frozen) for the components contained therein.
- Compound 1 was synthesized using 2-bromo-3,4,5-trimethoxybenzoic acid (2.67 g, 9.17 mmol) as starting material.
- Compound 6 was a commercial product purchased from Shanghai Yuanye Biotechnology Co., Ltd.
- Compound 7 was a commercial product purchased from Shanghai Yuanye Biotechnology Co., Ltd.
- Compound 8 is a commercial product purchased from Bailingwei.
- Compound 9 is a commercial product from Aldrich.
- compound 10 was synthesized starting from thiophen-3-ylboronic acid.
- Compound A is a commercial product purchased from Bailingwei.
- This compound can also be purchased from commercial channels, and the compound used in this application is synthesized according to the following reaction:
- the compound was synthesized from 2-methoxybenzene-1,3-diol as the starting material.
- the compound was synthesized from 6-bromo-2,3-dimethoxybenzoic acid as starting material.
- the compound was synthesized using resorcinol as the starting material.
- the compound was synthesized from 1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid as starting material.
- Compound F is a commercial product from Aldrich.
- Compound G is a commercial product from Aldrich.
- Compound H is a commercial product from TCI.
- Pseudomonas aeruginosa can produce biofilms in the culture medium.
- group A was inoculated with wild Pseudomonas aeruginosa (WT)
- group B was inoculated with PPK1 knockout Pseudomonas aeruginosa ( ⁇ ppk1)
- group C was inoculated with knockout PPK2A
- Pseudomonas aeruginosa ⁇ ppk2A, ⁇ ppk2B, ⁇ ppk2C
- group D was inoculated with Pseudomonas aeruginosa ( ⁇ ppk1, ⁇ ppk2, A ⁇ ppk2B, ⁇ ppk2C) that knocked out PPK1 and PPK2A, PPK2B, and PPK2C at the same time.
- each group was divided into two groups, one of which was added with DMSO (-) as a control, and the other was added with 100 ⁇ m of compound 4 (+).
- the bacteria were cultured at 37°C for 24 hours, and a layer of biofilm would grow in the medium.
- the biofilms in the four groups of medium A, B, C, and D were analyzed with 570 nm visible light, and the results showed: Compound 4 It has a good inhibitory effect on wild Pseudomonas aeruginosa and can reduce the formation of biofilm; and the compound can not only inhibit PPK1, but also has a good inhibitory effect on PPK2.
- the specific results are shown in Figure 2.
- C. elegans were divided into five groups, A, B, C, D, and E, and then modeled respectively.
- groups A and B were infected with wild-type (WT) Pseudomonas aeruginosa, in which group A was the DMSO control group, and group B was the compound 4 treatment group;
- groups C and D received knockout of all PPK ( ⁇ polyP, namely ⁇ ppk1 ⁇ ppk2A ⁇ ppk2B ⁇ ppk2C) Infection of Pseudomonas aeruginosa, group C was the DMSO control group, group D was the compound 4 treatment group;
- group E was the control group to receive Escherichia coli (OP50E.coli) infection.
- the cytotoxicity of the compounds was evaluated in cultured human embryonic kidney cells (HEK 239T) by trypan blue viability assay, and the blank solvent DMSO, compound B and compound 4 were tested respectively.
- the test results are shown in Figure 4. The results showed that Compound 4 was not cytotoxic (close to 100% relative viability) at concentrations up to 100 ⁇ M, while Compound B caused substantial cell death (approximately 35% relative viability).
- fused-ring phenolic compounds disclosed in this application not only have strong activity, but also have safety (low or no cytotoxicity); and have good inhibitory effects on both PPK1 and PPK2. Therefore, it is feasible for such compounds to be used in the preparation of medicaments for the treatment, inhibition or prevention of bacterial infections associated with PPK.
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Abstract
Description
化合物编号 | PPK1 | PPK2A | PPK2B | PPK2C |
2 | 20 | N/A | 59 | N/A |
3 | 20 | 50 | 48 | N/A |
4 | 17 | 16 | 20 | 165 |
5 | 26 | 24 | 31 | 273 |
B | 120 | N/A | N/A | N/A |
Claims (13)
- 根据权利要求1所述的用途,其中,所述细菌感染包括由产生一种或多种多磷酸激酶(PPK)的细菌所引起的细菌感染,所述PPK例如包括PPK1和PPK2A、PPK2B、PPK2C。
- 根据权利要求1或2所述的用途,其中,所述细菌感染包括由绿脓杆菌、肺炎克雷伯菌、大肠杆菌、金黄葡萄球菌、沙门氏菌、枯草芽孢杆菌、鲍曼不动杆菌、阴沟肠杆菌或肠球菌引起的感染。
- 根据权利要求1所述的用途,其中,所述化合物中的C、H、O和S原子各自独立选自天然丰度的原子和同位素丰度富集的原子。
- 根据权利要求4所述的用途,其中,所述同位素富集的原子选自碳的 12C、 13C和 14C;选自氢的 1H、 2H和 3H;选自氧的 16O、 17O和 18O;以及选自硫的 32S、 33S和 34S。
- 一种用于治疗、抑制或预防细菌感染的药物,其中,包括如权利要求1至5中任一项所限定的化合物中的一种或多种,其中所述细菌感染包括与PPK相关的细菌感染。
- 组合物在制备用于治疗、抑制或预防细菌感染的药物中的用途,其中,所述组合物包括一种或多种权利要求1至5中任一项所限定的化合物以及至少一种可药用的载体或稀释剂。
- 根据权利要求7所述的用途,其中,所述细菌感染包括由产生一种或多种多磷酸激酶(PPK)的细菌所引起的细菌感染。
- 根据权利要求7或8所述的用途,其中,所述细菌感染包括由绿脓杆菌、肺炎克雷伯菌、大肠杆菌、金黄葡萄球菌、沙门氏菌、鲍曼不动杆菌、枯草芽孢杆菌、阴沟肠杆菌或肠球菌引起的感染。
- 根据权利要求7所述的用途,其中,所述可药用的载体或稀释剂包括乳膏、乳剂、凝胶、脂质体或纳米颗粒。
- 根据权利要求7至10中任一项所述的用途,其中,所述组合物适用于口服施用或者可用于注射施用。
- 试剂盒在制备用于治疗、抑制或预防细菌感染的药物中的用途,其中,所述试剂盒包括根据权利要求1至5中任一项所限定的化合物或药学上可接受的盐或酯或者根据权利要求7至11中任一项所限定的组合物;以及稀释剂(例如无菌水)、缓冲液、药学上可接受的赋形剂。
- 化合物或组合物或试剂盒在抑制PPK酶产生中的用途,其中所述PPK例如包括PPK1和PPK2A、PPK2B、PPK2C,所述化合物为根据权利要求1至5中任一项所限定的化合物或药学上可接受的盐或酯;所述组合物为根据权利要求7至11中任一项所限定的组合物;所述试剂盒为根据权利要求12所限定的试剂盒。
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EP21902682.0A EP4260854A1 (en) | 2020-12-09 | 2021-12-09 | Pharmaceutical application of fused-ring phenolic compound |
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