Antibacterial application of 3-phenyl-4h-benzopyran-4-one compound

Abstract

Provided is an antibacterial application of a 3-phenyl-4H-benzopyran-4-one compound. Specifically, provided is use of a 3-phenyl-4H-benzopyran-4-one compound represented by formula I in the preparation of a product for inhibiting the proliferation of mycobacteria or treating diseases or conditions mediated by the proliferation of mycobacteria, and in the preparation of an in vitro reagent for inhibiting cytochrome bcc-aa3 oxidase and cytochrome bd oxidase of mycobacteria. Further disclosed are use of a 3-phenyl-4H-benzopyran-4-one compound represented by formula I' in the preparation of a product for improving the sensitivity of mycobacteria to cytochrome bcc-aa3 oxidase inhibitors, and a related composition. The compound is used for targeting a new target, and provides a new direction for the inhibition of mycobacterium tuberculosis and the treatment of related diseases.

Description

Antibacterial applications of 3-phenyl-4H-benzopyran-4-one compounds Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the antibacterial application of 3-phenyl-4H-benzopyran-4-one compounds. Background Technology

[0002] Mycobacterium tuberculosis (MTB) is the primary pathogen causing tuberculosis. Tuberculosis (TB) is an infectious, chronic, and debilitating disease caused by Mycobacterium tuberculosis. It is one of the major infectious diseases that seriously threaten human health and a leading cause of death worldwide. It is a complex infectious disease that can be transmitted through the air. Although TB ​​is a preventable and curable disease, approximately 10 million people are infected with TB each year, and 1.5 million die from it. Drug-resistant and multidrug-resistant TB is a significant cause of death.

[0003] Currently, first-line drugs for treating drug-sensitive tuberculosis infections include isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), streptomycin (SM), and ethambutol (EMB), with treatment cycles lasting 6-8 months. The use of multiple drugs and significant side effects are common. This four-drug combination therapy not only severely impacts patient adherence and leads to adverse drug reactions, but also increases the risk of drug-resistant bacteria. Furthermore, drugs used to treat drug-resistant tuberculosis are often less effective, more toxic, and more expensive, with treatment cycles lasting 18-24 months, and a cure rate of only about 63%.

[0004] Mycobacterium tuberculosis (MTB) is the most prevalent mycobacterial bacterium causing human diseases, and there is a wealth of basic research on mycobacteria. In the energy respiratory chain of mycobacteria (such as MTB), cytochrome bcc-aa3 oxidase (cyt-bcc-aa3) and cytochrome bd oxidase (cyt-bd) are two important terminal oxidases involved in electron transport and energy generation. Their combined action helps mycobacteria survive and maintain energy metabolism in environments with varying oxygen concentrations. Cytochrome bcc-aa3 oxidase is one of the key enzymes in the tuberculosis respiratory chain, located on the bacterial inner membrane. It is part of the bacterial electron transport chain and participates in oxidative phosphorylation. This enzyme is mainly responsible for transferring electrons from cytochrome bc1 to oxygen (O2), thereby reducing oxygen to water, and accompanying the proton pump out of the membrane, forming a proton gradient, which in turn drives ATP synthesis. Due to its central role in energy metabolism, inhibiting cyt-bcc-aa3 can effectively prevent the growth of mycobacteria, thus making it a target for anti-tuberculosis drugs. Mycobacteria can flexibly adjust their energy metabolism pathways under different environments. Especially under hypoxic conditions or when cyt-bcc-AA3 is inhibited, the expression level of cytochrome BD oxidase increases to maintain electron transport and respiratory functions. Recent studies have shown that cyt-BD can serve as an alternative pathway in the presence of cyt-bcc-AA3 inhibitors. This discovery presents a new challenge to anti-tuberculosis drug research, as bacteria may evade drug inhibition through cyt-BD compensatory mechanisms. Future anti-tuberculosis drug development needs not only to target cyt-bcc-AA3 but also to consider simultaneously inhibiting cyt-BD or identifying drug targets that can block its compensatory effects to improve therapeutic efficacy.

[0005] Many mycobacteria are pathogenic, including Mycobacterium tuberculosis, a persistent pathogen with a complex cell wall structure that resists various antibiotics and the host's immune response. It can remain dormant in the host for extended periods and reactivate when the immune system weakens, leading to relapse and spread of tuberculosis. Treatment for this pathogen requires long-term, multi-drug combination therapy to prevent the development of drug resistance.

[0006] Therefore, to alleviate the burden of tuberculosis infection and drug-resistant tuberculosis, a more precise and shorter treatment strategy is urgently needed. To prevent drug resistance and reduce the side effects of tuberculosis treatment, it is essential to actively explore and identify new protein targets, lead compounds for their drugs, and combination therapies. Summary of the Invention

[0007] The present invention aims to solve the above-mentioned problems and provides a 3-phenyl-4H-benzopyran-4-one compound and its pharmaceutically acceptable salt or stereoisomer or prodrug molecule for use in products targeting novel targets to inhibit the proliferation of mycobacteria and to improve the sensitivity of mycobacteria to cytochrome bcc-aa3 oxidase (Cyt-bc-aa3) inhibitors.

[0008] One aspect of the present invention provides the use of a 3-phenyl-4H-benzopyran-4-one compound of Formula I in the preparation of articles for inhibiting the proliferation of mycobacteria or for treating diseases or conditions mediated by the proliferation of mycobacteria;

[0009] Among them, R 11 R 12 R 13 R1 and R2 are both H, and R3 is CH3.

[0010] Where R4 is

[0011] Furthermore, the mycobacteria are Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium smegmatis, Mycobacterium leprae, Mycobacterium avium, Mycobacterium marineum, Mycobacterium occulta, Mycobacterium aureus, Mycobacterium sputum, Mycobacterium scrofula, Mycobacterium vesiculum, Mycobacterium intracellularum, Mycobacterium ulcerans, Mycobacterium Gordon, Mycobacterium Golden, Mycobacterium abscessus, Mycobacterium Kansas, Mycobacterium Malmo, Mycobacterium bufo, Mycobacterium scrofula, and Mycobacterium guilloché.

[0012] Furthermore, the products include medicines, disinfectants, antibacterial agents, personal antibacterial care products, medical antibacterial products, and household and environmental antibacterial products.

[0013] Furthermore, diseases or conditions mediated by mycobacterial proliferation are selected from tuberculosis, leprosy, swimming pool granuloma, chronic lung disease, cervical lymphadenopathy, skin ulcerative diseases, Crohn's disease (inflammatory bowel disease), and osteoarthritis.

[0014] Another aspect of the present invention provides the use of the 3-phenyl-4H-benzopyran-4-one compound of Formula I in the preparation of in vitro reagents that inhibit cytochrome bcc-aa3 oxidase and cytochrome bd oxidase.

[0015] Another aspect of the present invention provides the use of the 3-phenyl-4H-benzopyran-4-one compound of formula I' in the preparation of articles for improving the sensitivity of mycobacteria to cytochrome bcc-aa3 oxidase inhibitors;

[0016] in,

[0017] R 11 Selected from H and alkoxy groups;

[0018] R 12 Selected from H and alkoxy groups;

[0019] R 13 Selected from H, alkoxy, halogen, and phenyl;

[0020] R2 is selected from H or alkyl groups;

[0021] R3 is selected from H or alkyl groups;

[0022] R4 is selected from C4-C 10 Alkyl, C4-C 10 Alkyl, halogenated aromatic, olefinic, benzyl, carboxyl, carboxymethyl.

[0023] Furthermore, the halogens are F, Cl, Br, and I.

[0024] Furthermore, the alkoxy group is a C1-C6 alkoxy group, preferably a methoxy, ethoxy, or propoxy group.

[0025] Furthermore, the alkyl group is a C1-C6 alkyl group, preferably methyl, ethyl, or propyl.

[0026] Furthermore, R4 is selected from -COOH, -(CH2)n-CH3.

[0027] Furthermore, the products include pharmaceutical compositions, disinfectants, antibacterial agents, personal antibacterial care products, medical antibacterial products, and household and environmental antibacterial products.

[0028] In another aspect, the present invention provides a composition for inhibiting the proliferation of mycobacteria, the composition comprising, as an active ingredient, a 3-phenyl-4H-benzopyran-4-one compound of formula I, or a 3-phenyl-4H-benzopyran-4-one compound of formula I', and at least one Cyt-bcc-aa3 inhibitor.

[0029] Where R1 is

[0030] in,

[0031] R 11 Selected from H and alkoxy groups;

[0032] R 12 Selected from H and alkoxy groups;

[0033] R13 Selected from H, alkoxy, halogen, and phenyl;

[0034] R2 is selected from H or alkyl groups;

[0035] R3 is selected from H or alkyl groups;

[0036] R4 is selected from C4-C 10 Alkyl, C4-C 10 Alkyl, halogenated aromatic, olefinic, benzyl, carboxyl, carboxymethyl.

[0037] Furthermore, the halogens are F, Cl, Br, and I.

[0038] Furthermore, the alkoxy group is a C1-C6 alkoxy group, preferably a methoxy, ethoxy, or propoxy group.

[0039] Furthermore, the alkyl group is a C1-C6 alkyl group, preferably methyl, ethyl, or propyl.

[0040] Furthermore, R4 is selected from -COOH, -(CH2) n -CH3.

[0041] Furthermore, the Cyt-bcc-aa3 inhibitor is selected from lansoprazole, Q203 (Telacebec), IMB-133, TB47 and their related derivatives.

[0042] Furthermore, the composition is a pharmaceutical composition.

[0043] Furthermore, the composition is a disinfectant.

[0044] Furthermore, the composition is a reagent.

[0045] Furthermore, the composition is a pharmaceutical composition, and the composition further includes at least one pharmaceutically acceptable excipient.

[0046] Furthermore, the composition also includes at least one solvent.

[0047] Furthermore, the composition also includes at least one carrier.

[0048] In another aspect, the present invention provides the use of the above-described composition for inhibiting mycobacterial proliferation in the preparation of articles for inhibiting mycobacterial proliferation or for treating diseases or conditions mediated by mycobacterial proliferation.

[0049] Furthermore, the mycobacteria are Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium smegmatis, Mycobacterium leprae, Mycobacterium avium, Mycobacterium marineum, Mycobacterium occulta, Mycobacterium aureus, Mycobacterium sputum, Mycobacterium scrofula, Mycobacterium vesiculum, Mycobacterium intracellularum, Mycobacterium ulcerans, Mycobacterium Gordon, Mycobacterium Golden, Mycobacterium abscessus, Mycobacterium Kansas, Mycobacterium Malmo, Mycobacterium bufo, Mycobacterium scrofula, and Mycobacterium guilloché.

[0050] Furthermore, diseases or conditions mediated by mycobacterial proliferation are selected from tuberculosis, leprosy, swimming pool granuloma, chronic lung disease, cervical lymphadenopathy, skin ulcerative diseases, Crohn's disease (inflammatory bowel disease), and osteoarthritis.

[0051] In another aspect, the present invention provides a method for treating or preventing mycobacterial infection using the composition for inhibiting mycobacterial proliferation or the compound of formula I, comprising administering to a subject a therapeutically effective amount of the composition for inhibiting mycobacterial proliferation or the compound of formula I.

[0052] Furthermore, the therapeutically effective amount of the composition for inhibiting mycobacterial proliferation is administered in the form of a formulation, which further comprises a pharmaceutically acceptable carrier or excipient. Beneficial effects

[0053] This invention provides a 3-phenyl-4H-benzopyran-4-one small molecule inhibitor that can inhibit the proliferation of mycobacteria and enhance the inhibitory effect of Cyt-bcc-aa3 inhibitor on mycobacteria. The combined effect demonstrates that the two have a synergistic effect and have a very strong inhibitory effect on mycobacterial growth.

[0054] Specifically, when used alone, the 3-phenyl-4H-benzopyran-4-one small molecule inhibitors provided by this invention have an inhibition rate of over 80% against mycobacteria, while when used in combination with lansoprazole, the inhibition rate against Mycobacterium tuberculosis can reach up to 99%. It is also a novel skeleton for compounds that inhibit Mycobacterium tuberculosis.

[0055] The 3-phenyl-4H-benzopyran-4-one small molecule inhibitors, their pharmaceutically acceptable salts, stereoisomers, or prodrugs proposed in this invention, which can be used in combination with Cyt-bcc-aa3 inhibitors, have multiple modifiable chemical sites and can serve as lead compounds for the treatment of Mycobacterium tuberculosis in combination with Cyt-bcc-aa3 inhibitors, showing broad clinical application prospects. Detailed Implementation

[0056] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below, but should not be construed as limiting the scope of the present invention.

[0057] This invention is based on research on Mycobacterium tuberculosis Cyt-bd oxidase and its existing inhibitors, revealing the binding mode of the heterodimeric protein Cyt-bd oxidase and its inhibitors, as well as its important amino acid residues. Building upon this, starting from the structure of the protein and the structures of existing inhibitors, a series of small molecules were selected through structural analysis of the heterodimeric protein Cyt-bd oxidase. This was achieved using ligand-based and protein-based virtual screening methods, combined with molecular similarity screening, molecular docking, molecular dynamics simulation, and binding energy calculation and prediction. These small molecules were then used alone or in combination with Cyt-bcc-aa3 inhibitors such as Lansoprazole for in vitro bioactivity testing, yielding novel 3-phenyl-4H-benzopyran-4-one compounds with good inhibitory activity against Mycobacterium smegma and Mycobacterium tuberculosis. The 3-phenyl-4H-benzopyran-4-one compounds, their pharmaceutically acceptable salts, stereoisomers, or prodrug molecules, proposed in this invention as small-molecule inhibitors of Cyt-bd oxidase, possess multiple modifiable chemical sites and can serve as lead compounds for combination therapy in the prevention and / or treatment of tuberculosis. The combination therapies of this invention show great promise for clinical application in the treatment of tuberculosis. This invention is based on the above findings.

[0058] the term

[0059] "Pharmaceutical acceptable carriers or excipients" include, but are not limited to, any adjuvant, carrier, excipient, gliding agent, sweetener, diluent, preservative, dye / coloring agent, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the Food and Drug Administration for acceptable use in humans or livestock.

[0060] "Pharmaceutical composition" refers to the compounds of the present invention and formulations of agents commonly accepted in the art for delivering bioactive compounds to mammals (e.g., humans). Such agents include all pharmaceutically acceptable excipients for this purpose.

[0061] "Effective amount" or "therapeutic effective amount" means an amount of the compound according to the invention that, when administered to a patient in need, is sufficient to achieve treatment against mycobacteria or the disease caused therefrom. Such an amount would be sufficient to elicit a biological or medical response in the tissue system or patient sought by the researcher or clinician. The amount of the compound according to the invention constituting a therapeutic effective amount will vary depending on factors such as: the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of compound excretion, the duration of treatment, the type and severity of the disease state or symptom being treated, the drugs used in combination with or in conjunction with the compound of the invention, and the patient's age, weight, general health, sex, and diet. Such a therapeutic effective amount can be conventionally determined by those skilled in the art based on their own knowledge, the prior art, and this disclosure.

[0062] Unless otherwise stated, the term "treating" as used herein means reversing, alleviating, inhibiting the progression of, or preventing the impairment or condition to which the term applies, or one or more symptoms of such impairment or condition. The term "treatment" as used herein refers to the act of treatment, as "treatment" is as immediately stated above.

[0063] "Prevention" (or "preventing") refers to any treatment that prevents the development of clinical symptoms of a disease or condition. The term "prevention" also includes administering a therapeutically effective amount of a compound or composition according to the invention (e.g., pre-exposure prophylaxis) before an individual is exposed to mycobacteria to prevent the development of symptoms of disease and / or to prevent mycobacteria from reaching detectable levels in the body or in the in vitro environment.

[0064] The terms "subject" or "patient" refer to an animal, such as a mammal (including a human), that has been or will be a subject of treatment, observation, or experimentation. The methods described herein can be used for human treatment and / or veterinary applications. In some embodiments, the subject is a mammal (or patient). In some embodiments, the subject (or patient) is a human, livestock (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats, and pigs), and / or laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, and monkeys). In some embodiments, the subject (or patient) is a human. "A person in need (or patient)" means a person who may have or is suspected of having a disease or condition that would benefit from certain treatments.

[0065] pharmaceutical preparations

[0066] The compounds of the present invention are formulated using conventional carriers and excipients, which will be selected according to conventional practice. Tablets will contain excipients, flow aids, fillers, binders, etc. Aqueous formulations are prepared aseptically and are intended for delivery, typically isotonic, other than orally.

[0067] Although the active ingredients can be administered alone, they may be preferably presented as pharmaceutical formulations. The formulations of the present invention for veterinary and human use comprise at least one active ingredient as defined above (the active ingredient being a compound of formula I or I' combined with a Cyt-bcc-aa3 inhibitor and a composition thereof, hereinafter the same) and one or more acceptable carriers; or mixtures thereof.

[0068] The formulations of the present invention suitable for oral administration can be presented in discrete unit form, such as capsules, flat capsules, or tablets, each containing a predetermined amount of the active ingredient; as powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. Alternatively, they can be prepared into oral administration formulations using other known techniques.

[0069] Tablets are prepared by compression or molding, optionally containing one or more excipients. Compressed tablets can be prepared by compressing a free-flowing form of active ingredient, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored and optionally formulated to provide a slow or controlled release of the active ingredient therefrom.

[0070] The pharmaceutical compositions of the present invention can be topical formulations such as ointments for local administration. For infections of the eyes or other external tissues such as the mouth and skin, the formulation is preferably a topical ointment or cream containing an active ingredient. When formulated as an ointment, the active ingredient can be used with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with an oil-in-water cream base. If desired, the topical formulation may include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues. The oil phase of the emulsions of the present invention can be composed of known ingredients in a known manner. The oil phase may contain only emulsifiers, but it may also contain at least one emulsifier with fats or oils, or with a mixture of both fats and oils. Preferably, hydrophilic emulsifiers are included together with lipophilic emulsifiers that act as stabilizers. Oils and fats are also preferred.

[0071] The pharmaceutical compositions of the present invention may be in the form of sterile injectable formulations, such as sterile aqueous or oily suspensions for injection.

[0072] The pharmaceutical compositions of the present invention may be formulations suitable for topical ocular administration, including eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient.

[0073] The pharmaceutical compositions of the present invention can be formulations suitable for topical oral administration, including tablets containing an active ingredient in a flavoring matrix, typically sucrose and gum arabic or tragacanth; tablets containing an active ingredient in an inert matrix such as gelatin and glycerin or sucrose and gum arabic; and mouthwashes containing an active ingredient in a suitable liquid carrier.

[0074] The pharmaceutical compositions of the present invention can be formulations for rectal administration, which can be presented as suppositories with a suitable matrix having the active ingredient.

[0075] The pharmaceutical compositions of the present invention can be formulations suitable for intrapulmonary or intranasal administration. Such formulations typically have a particle size in the range of 0.1-500 micrometers, such as 0.5, 1, 30, 35 micrometers, etc., and are administered via rapid inhalation through the nasal passage or oral inhalation to reach the alveoli. The active ingredients of the present invention have a size suitable for intrapulmonary or intranasal administration, and can be used for intrapulmonary or intranasal administration, for example, as inhalers.

[0076] The pharmaceutical compositions of the present invention may be formulations suitable for parenteral administration, including aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, antibacterial agents and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners.

[0077] The pharmaceutical compositions of the present invention are formulated in single-dose or multi-dose containers (e.g., sealed ampoules and vials) and can be stored under freeze-drying (lyophilization) conditions, requiring only the addition of a sterile liquid carrier (e.g., water for injection) immediately before use. Immediate-use solutions and suspensions are prepared from the aforementioned types of sterile powders, granules, and tablets. Preferred single-dose formulations are those containing the active ingredient at the daily dose or a unit daily sub-dose or a suitable portion thereof as described above.

[0078] The pharmaceutical composition of the present invention may be a veterinary composition comprising at least one active ingredient as defined above and a veterinary carrier.

[0079] The compounds of the present invention are used to provide controlled-release pharmaceutical formulations containing one or more of the active ingredients of the present invention as active ingredients, wherein the release of the active ingredient is controlled and modulated to allow for less frequent administration or to improve the pharmacokinetic or toxicological characteristics of a given active ingredient.

[0080] Example 1: In vitro bioactivity test

[0081] Experimental methods: The in vitro anti-tuberculosis activity of lansoprazole in combination with the compound described in Formula I or II of this invention was determined by resazurin microtiter assay (REMA).

[0082] Experimental procedure: Mycobacterium tuberculosis was grown in Middlebrook 7H9 broth for 3-4 weeks, and a suspension OD was prepared. 600 =0.003. All compounds used in the experiment, including lansoprazole, were dissolved in DMSO to prepare an initial solution with a concentration of 10 mM. The concentrations of each compound (compounds 1-14 have structures shown below, and refer to Table 1; all are known compounds) were calculated based on their molecular weights and then distributed in 96-well plates at consecutive 2-fold dilutions (10 mM - 5 μM). Mycobacterium tuberculosis was inoculated into these wells, with two growth control wells (without antibiotics) on each plate. After static incubation at 37°C and 5% CO2 for 7 days, 40 μl of freshly prepared resazurin solution (0.1 mg / ml) was added to the growth control wells, and incubation continued for 48 hours. Fluorescence values ​​(ex = 544 nm, em = 590 nm) were read using a microplate reader, and the growth inhibition rate was calculated. Lansoprazole was selected as the positive control drug.

[0083] Experimental results:

[0084] Table 1. In vitro anti-tuberculosis activity of some compounds of the present invention.

[0085] As shown in Table 1, when the compounds provided in this invention are used in combination with lansoprazole, all compounds exhibit a synergistic effect with lansoprazole, enhancing the inhibition rate of lansoprazole against Mycobacterium tuberculosis, with the highest inhibition rate reaching 99%. These experimental results demonstrate that the 3-phenyl-4H-benzopyran-4-one compounds of this invention, when used in combination with lansoprazole, exhibit significantly better inhibitory effects than lansoprazole alone, showing great potential for the treatment and / or prevention of infectious pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis, while also possessing significant potential to overcome problems related to drug resistance in Mycobacterium tuberculosis.

[0086] Meanwhile, this invention unexpectedly discovered that among a variety of compounds, several compounds can exert significant effects individually, such as compounds 2 and 11, whose inhibitory effects can exceed 80%. This phenomenon may be due to the fact that these compounds can inhibit not only cytochrome bcc-aa3 oxidase but also cytochrome bd oxidase. This invention is the first to screen compounds with two inhibitory activities simultaneously, providing new research ideas and directions for the treatment of mycobacterial diseases.

[0087] The above examples are for illustrative purposes only and are not intended to limit the scope of the invention. The protection of the invention is not limited to the above embodiments. All variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of the inventive concept are included in this invention. Therefore, all equivalent technical solutions should also fall within the scope of this invention and are defined by the appended claims.

Claims

Use of a 3-phenyl-4H-benzopyran-4-one compound of Formula I in the preparation of articles for inhibiting the proliferation of mycobacteria or for treating diseases or conditions mediated by the proliferation of mycobacteria; in, R 11 R 12 R 13 R1 and R2 are both H, and R3 is CH3. R4 is Preferably, the products are medicines, disinfectants, antibacterial agents, personal antibacterial care products, medical antibacterial products, and household and environmental antibacterial products. The use according to claim 1, characterized in that, The mycobacteria mentioned are Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium smegmatis, Mycobacterium leprae, Mycobacterium avium, Mycobacterium marineum, Mycobacterium occulta, Mycobacterium aureus, Mycobacterium sputum, Mycobacterium scrofula, Mycobacterium vesiculum, Mycobacterium intracellularum, Mycobacterium ulcerans, Mycobacterium Gordon, Mycobacterium Golden, Mycobacterium abscessus, Mycobacterium Kansas, Mycobacterium Malmo, Mycobacterium bufo, Mycobacterium scrofula, and Mycobacterium guilloché. Preferably, the diseases or conditions mediated by mycobacterial proliferation are selected from tuberculosis, leprosy, swimming pool granuloma, chronic lung disease, cervical lymphadenopathy, skin ulcerative diseases, Crohn's disease (inflammatory bowel disease), and osteoarthritis. Use of a 3-phenyl-4H-benzopyran-4-one compound of Formula I as described in claim 1 or 2 in the preparation of an in vitro reagent for inhibiting mycobacterial cytochrome bcc-aa3 oxidase and cytochrome bd oxidase. Use of a 3-phenyl-4H-benzopyran-4-one compound of Formula I' in the preparation of articles for improving the sensitivity of mycobacteria to cytochrome bcc-aa3 oxidase inhibitors; in, R 11 Selected from H and alkoxy groups; R 12 Selected from H and alkoxy groups; R 13 Selected from H, alkoxy, halogen, and phenyl; R2 is selected from H or alkyl groups; R3 is selected from H or alkyl groups; R4 is selected from C4-C 10 Alkyl, C4-C 10 Alkyl, halogenated aromatic, olefinic, benzyl, carboxyl, carboxymethyl; Preferably, the product is a pharmaceutical composition, disinfectant, antibacterial agent, personal antibacterial care product, medical antibacterial product, or household and environmental antibacterial product. The use according to claim 4 is characterized in that, Halogens are F, Cl, Br, and I; The alkoxy group is a C1-C6 alkoxy group, preferably a methoxy, ethoxy, or propoxy group; The alkyl group is a C1-C6 alkyl group, preferably methyl, ethyl, or propyl; Preferably, R4 is selected from -COOH, -(CH2)n-CH3. A composition for inhibiting the proliferation of mycobacteria, characterized in that, The composition comprises, as an active ingredient, a 3-phenyl-4H-benzopyran-4-one compound of formula I as described in claim 1, or The 3-phenyl-4H-benzopyran-4-one compound of formula I' as described in any one of claims 4-5, and at least one Cyt-bcc-aa3 inhibitor; Preferably, the composition is a pharmaceutical composition; Preferably, the composition is a disinfectant; Preferably, the composition is a reagent; More preferably, the composition is a pharmaceutical composition, and the composition further includes at least one pharmaceutically acceptable excipient; Preferably, the composition further includes at least one solvent; Preferably, the composition further includes at least one carrier. The composition according to claim 6, characterized in that, Cyt-bcc-aa3 inhibitors are selected from lansoprazole, Q203 (Telacebec), IMB-133, TB47 and their related derivatives. Use of the composition of claim 6 or 7 in the preparation of articles for inhibiting mycobacterial proliferation or for treating diseases or conditions mediated by mycobacterial proliferation; Preferably, the products are medicines, disinfectants, antibacterial agents, personal antibacterial care products, medical antibacterial products, and household and environmental antibacterial products. The use according to claim 8 is characterized in that, The mycobacteria mentioned are Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium smegmatis, Mycobacterium leprae, Mycobacterium avium, Mycobacterium marineum, Mycobacterium occulta, Mycobacterium aureus, Mycobacterium sputum, Mycobacterium scrofula, Mycobacterium vesiculum, Mycobacterium intracellularum, Mycobacterium ulcerans, Mycobacterium Gordon, Mycobacterium Golden, Mycobacterium abscessus, Mycobacterium Kansas, Mycobacterium Malmo, Mycobacterium bufo, Mycobacterium scrofula, and Mycobacterium guilloché. Preferably, the diseases or conditions mediated by mycobacterial proliferation are selected from tuberculosis, leprosy, swimming pool granuloma, chronic lung disease, cervical lymphadenopathy, skin ulcerative diseases, Crohn's disease (inflammatory bowel disease), and osteoarthritis. A method of treating or preventing mycobacterial infection using the composition of claim 6 or 7 or the 3-phenyl-4H-benzopyran-4-one compound of formula I of claim 1, comprising administering to a subject a therapeutically effective amount of the composition of claim 6 or 7 or the 3-phenyl-4H-benzopyran-4-one compound of formula I of claim 1; Preferably, the therapeutically effective amount of the composition for inhibiting mycobacterial proliferation or the formulation of a 3-phenyl-4H-benzopyran-4-one compound of Formula I as described in claim 1 is given, the formulation further comprising a pharmaceutically acceptable carrier or excipient.

Images