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CN-121987613-A - Antibacterial application of 3-phenyl-4H-benzopyran-4-one compounds

CN121987613ACN 121987613 ACN121987613 ACN 121987613ACN-121987613-A

Abstract

The invention provides an antibacterial application of a 3-phenyl-4H-benzopyran-4-ketone compound, in particular to an application of the 3-phenyl-4H-benzopyran-4-ketone compound shown in a formula I in preparing an article for inhibiting proliferation of mycobacteria or treating diseases or symptoms mediated by proliferation of mycobacteria and an in vitro reagent for inhibiting cytochrome bcc-aa3 oxidase and cytochrome bd oxidase of mycobacteria, and also discloses an application of the 3-phenyl-4H-benzopyran-4-ketone compound shown in a formula I' in preparing an article for improving sensitivity of mycobacteria to cytochrome bcc-aa3 oxidase inhibitor, and a related composition. The compound provided by the invention is used for targeting a new target, and provides a new direction for inhibiting mycobacterium tuberculosis and treating related diseases.

Inventors

  • ZHANG ZENGHUI
  • WU XUE
  • ZHOU BING
  • ZHANG XU
  • WANG JIAN
  • XIA WEI

Assignees

  • 华东师范大学
  • 深圳联星生物技术有限公司

Dates

Publication Date
20260508
Application Date
20241107

Claims (10)

  1. 1. Use of a 3-phenyl-4H-benzopyran-4-one compound of formula I in the manufacture of a product for inhibiting mycobacterial proliferation or treating a disease or condition mediated by mycobacterial proliferation; Wherein R 11 、R 12 、R 13 、R 3 is H, R2 is CH 3 , R 4 is Preferably, the articles are medicines, disinfectants, antibacterial agents, personal antibacterial care products, medical antibacterial products, household and environmental antibacterial products.
  2. 2. The use according to claim 1, wherein the mycobacterium is mycobacterium tuberculosis, mycobacterium bovis, mycobacterium smegmatis, mycobacterium leprae, mycobacterium avium, mycobacterium marinum, mycobacterium fortuitum, mycobacterium aureus, mycobacterium phlegm, mycobacterium scrofula, mycobacterium chromes, mycobacterium intracellulare, mycobacterium ulcerans, mycobacterium gordonae, mycobacterium abscessus, mycobacterium kansasii, mycobacterium macerans, mycobacterium bufonis, mycobacterium scrofula, mycobacterium tortoise; preferably, the mycobacterial proliferation mediated disease or condition is selected from tuberculosis, leprosy, swimming pool granuloma, chronic lesions of the lung, cervical lymphadenectasis, skin ulceration diseases, crohn's disease (inflammatory bowel disease), osteoarthritis.
  3. 3. Use of a 3-phenyl-4H-benzopyran-4-one compound of formula I as defined in claim 1 or 2 for the preparation of an in vitro reagent for inhibiting cytochrome bcc-aa 3 oxidase and cytochrome bd oxidase of mycobacterium.
  4. 4. Use of a 3-phenyl-4H-benzopyran-4-one compound of formula I' for the preparation of an article for increasing the sensitivity of mycobacteria to cytochrome bcc-aa 3 oxidase inhibitor; Wherein, the R 11 is selected from H, alkoxy; r 12 is selected from H, alkoxy; R 13 is selected from H, alkoxy, halogen, phenyl; r 2 is selected from H, alkyl; r 3 is selected from H, alkyl; R 4 is selected from the group consisting of C 4 -C 10 alkyl, C 4 -C 10 alkenyl, halogenated aryl, alkylene, benzyl, carboxyl, and carboxymethyl; preferably, the product is a pharmaceutical composition, a disinfectant, an antibacterial agent, a personal antibacterial care product, a medical antibacterial product, a household and environmental antibacterial product.
  5. 5. The method according to claim 4, wherein, Halogen is F, cl, br, I; Alkoxy is C 1 -C 6 alkoxy, preferably methoxy, ethoxy, propoxy; alkyl is C 1 -C 6 alkyl, preferably methyl, ethyl, propyl; Preferably, R 4 is selected from -COOH,-(CH 2 )n-CH 3 。
  6. 6. A composition for inhibiting proliferation of Mycobacteria, which comprises as an active ingredient a 3-phenyl-4H-benzopyran-4-one compound represented by formula I as described in claim 1, or A 3-phenyl-4H-benzopyran-4-one compound of formula I' as defined in any one of claims 4 to 5 and at least one Cyt-bcc-aa 3 inhibitor; Preferably, the composition is a pharmaceutical composition; Preferably, the composition is a disinfectant; preferably, the composition is an agent; More preferably, the composition is a pharmaceutical composition, the composition further comprising at least one pharmaceutically acceptable excipient; preferably, the composition further comprises at least one solvent; Preferably, the composition further comprises at least one carrier.
  7. 7. The composition of claim 6, wherein the Cyt-bcc-aa 3 inhibitor is selected from lansoprazole, Q203 (Telacebec), IMB-133, TB47, and related derivatives thereof.
  8. 8. Use of a composition according to claim 6 or 7 for the manufacture of a product for inhibiting mycobacterial proliferation or for treating a disease or condition mediated by mycobacterial proliferation; preferably, the articles are medicines, disinfectants, antibacterial agents, personal antibacterial care products, medical antibacterial products, household and environmental antibacterial products.
  9. 9. The use according to claim 8, wherein the mycobacterium is mycobacterium tuberculosis, mycobacterium bovis, mycobacterium smegmatis, mycobacterium leprae, mycobacterium avium, mycobacterium marinum, mycobacterium fortuitum, mycobacterium aureus, mycobacterium phlegm, mycobacterium scrofula, mycobacterium chromes, mycobacterium intracellulare, mycobacterium ulcerans, mycobacterium gordonae, mycobacterium abscessus, mycobacterium kansasii, mycobacterium macerans, mycobacterium bufonis, mycobacterium scrofula, mycobacterium tortoise; Preferably, the disease or condition mediated by mycobacterial proliferation is selected from tuberculosis, leprosy, granuloma in swimming pool, chronic lesions in the lung, enlargement of the cervical lymph node, skin ulceration diseases, crohn's disease (inflammatory bowel disease), osteoarthritis.
  10. 10. A method of treating or preventing a mycobacterial infection according to claim 6 or 7 or 3-phenyl-4H-benzopyran-4-one compound of formula I in claim 1, comprising administering to a subject a therapeutically effective amount of a composition according to claim 6 or 7 or a therapeutically effective amount of a 3-phenyl-4H-benzopyran-4-one compound of formula I in claim 1; Preferably, the composition for inhibiting mycobacterial proliferation in a therapeutically effective amount or the 3-phenyl-4H-benzopyran-4-one compound of formula I in claim 1 in a therapeutically effective amount is administered, and the preparation further comprises a pharmaceutically acceptable carrier or excipient.

Description

Antibacterial application of 3-phenyl-4H-benzopyran-4-one compounds Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to an antibacterial application of a 3-phenyl-4H-benzopyran-4-one compound. Background Mycobacterium Tuberculosis (MTB) is the primary pathogen responsible for tuberculosis. Tuberculosis (TB), an infectious chronic wasting disease caused by invasion of mycobacterium tuberculosis into the human body, is one of the major infectious diseases seriously jeopardizing human health, and is also a major infectious disease killer worldwide. It is an infectious disease that can be airborne, complex. Although tuberculosis is a preventable and curable disease, about 1000 tens of thousands of people still infect tuberculosis each year, 150 tens of thousands of people die from tuberculosis. Among them, drug-resistant and multi-drug-resistant tuberculosis is an important cause of death. At present, the first-line medicine capable of treating the drug-sensitive tuberculosis infection mainly comprises Isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), streptomycin (SM), ethambutol (EMB) and the like, the treatment period is as long as 6-8 months, the variety of the used medicine is large, and the side effect is huge. The four-drug combination therapy not only can seriously affect the compliance of patients, and cause adverse reactions of drug treatment, but also can increase the risk of drug-resistant bacteria. The medicine for treating drug-resistant tuberculosis has poorer effect, higher toxicity and more expensive, and the treatment period is as long as 18-24 months, and the cure rate of the drug-resistant tuberculosis is only about 63%. Mycobacterium tuberculosis is taken as the mycobacterium which causes the most human diseases in mycobacterium genus, and basic research on mycobacteria is numerous, and in the energy respiratory chain of mycobacteria (such as mycobacterium tuberculosis, MTB), cytochrome bcc-aa 3 oxidase (cyt-bcc-aa 3) and cytochrome bd oxidase (cyt-bd) are two important terminal oxidases, and participate in respiratory chain electron transfer and energy generation. Their combined action helps to survive and maintain energy metabolism in environments of varying oxygen concentration. Cytochrome bcc-aa 3 oxidase is one of the key enzymes in the respiratory chain of tubercle bacillus and is located on the bacterial inner membrane. It is part of the bacterial electron transfer chain, which is involved in the oxidative phosphorylation process. The enzyme is mainly responsible for transferring electrons from cytochrome bc1 to oxygen (O 2), thereby reducing the oxygen to water and with proton pumping out of the membrane, creating a proton gradient, driving ATP synthesis. Because of its central role in energy metabolism, inhibition of cyt-bcc-aa 3 is effective in preventing mycobacteria growth, and therefore it becomes a target for antitubercular drugs. Mycobacteria are able to flexibly modulate their energy metabolic pathways in different environments. In particular, under conditions where hypoxia or cyt-bcc-aa 3 is inhibited, the expression level of cytochrome bd oxidase is increased to maintain electron transfer and respiratory function. In recent years, research has shown that cyt-bd can become an alternative pathway in the presence of cyt-bcc-aa 3 inhibitors, and this discovery presents a new challenge for anti-tubercular drug research, since bacteria may evade the inhibitory effect of drugs through the compensatory mechanism of cyt-bd. In the future, development of antitubercular drugs is not only required to target cyt-bcc-aa 3, but also is required to consider simultaneous inhibition of cyt-bd or search for drug targets capable of blocking the compensatory effect thereof so as to improve the therapeutic effect. There are a variety of pathogenic bacteria among them, including mycobacterium tuberculosis, a refractory pathogenic bacteria that has a complex cell wall structure and is resistant to the immune response of a variety of antibiotics and hosts, which causes human diseases. It can remain latent in the host for long periods of time and re-activate when the immune system is weakened, resulting in recurrence and spread of tuberculosis. Treatment against such pathogenic bacteria requires long-term multi-drug combination therapy to prevent the development of drug resistance. Therefore, in order to alleviate the burden of tuberculosis infection and drug-resistant tuberculosis, a more accurate and short-period treatment strategy is urgently needed. In order to prevent the occurrence of drug resistance and reduce the side effects of tuberculosis patient treatment, new protein targets, lead compounds of their drugs, and drug combination therapies must be actively explored and determined. Disclosure of Invention The invention aims to solve the problems and provides an application of a 3-phenyl-4H-benzopyran-4-ketone compound, a ph