KR-102956078-B1 - Flavonoid derivatives(comp. no. 22099) and pharmaceutical compositions containing the same for the treatment of diseases caused by non-tuberculous mycobacterial infections

Abstract

The present invention relates to a composition for the prevention or treatment of non-tuberculosis mycobacterial infections or diseases caused by non-tuberculosis mycobacterial infection comprising a flavonoid derivative 22099. According to one aspect, the flavonoid derivative 22099 reduces mtROS and intracellular bacterial counts in macrophages infected with Mycobacterium abscessus ( M. abscessus ) and inhibits the growth of M. abscessus even upon direct treatment. Furthermore, it exhibits growth inhibitory activity against standard strains of M. abscessus subspecies such as abscessus , massiliense , and bolletii , M. abscessus derived from treatment-refractory patients, and mouse models of respiratory infections, and also exhibits synergistic effects with other antibiotics (clarithromycin and amikacin). Therefore, the flavonoid derivative 22099 can be effectively used alone or in combination for the prevention or treatment of diseases caused by M. abscessus infection.

Inventors

• 김범준
• 서혜준
• 오재훈
• 김남중
• 신정원

Assignees

• 서울대학교산학협력단
• 경희대학교 산학협력단

Dates

Publication Date

20260513

Application Date

20231130

Claims (14)

1. A pharmaceutical composition for the prevention or treatment of non-tuberculous mycobacterial infections or diseases caused by non-tuberculous mycobacterial infections, comprising as an active ingredient a compound represented by the following chemical formula 2 or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] .
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5. A pharmaceutical composition according to claim 1, wherein the compound represented by Chemical Formula 2 is prepared through a reaction represented by the following Reaction Scheme 1 over an organic solvent: [Reaction Equation 1] .
6. In claim 5, A pharmaceutical composition wherein the organic solvent is one or more selected from the group consisting of dimethyl sulfoxide, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, methyl ethyl ketone, acetone, acetonitrile, dimethylformamide, enmethylpyrrolidone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, and benzyl alcohol.
7. In claim 5, A pharmaceutical composition in which the above reaction is carried out by further adding palladium(II) trifluoroacetate and 2,2-bipyridine as catalysts.
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9. In claim 1, The above non-tuberculous mycobacteria are Mycobacterium avium , Mycobacterium intracellurare, Mycobacterium abscessus, Mycobacterium massiliense, Mycobacterium bolletii , Mycobacterium chimaera, Mycobacterium Scrofulaceum , Mycobacterium chelonae , Mycobacterium fortuitum , Mycobacterium peregrinum , Mycobacterium ulcerans , and Mycobacterium marinum ( A pharmaceutical composition comprising one or more selected from the group consisting of Mycobacterium marinum , Mycobacterium kansasii , Mycobacterium Genevans, Mycobacterium simiae, Mycobacterium terrae , Mycobacterium nonchromogenicum, Mycobacterium celatum, Mycobacterium gordonae , Mycobacterium szulgai , Mycobacterium mucogenicum, and Mycobacterium aubagnens .
10. In claim 9, A pharmaceutical composition in which the above-mentioned non-tuberculous mycobacterium is Mycobacterium abscessus .
11. In claim 1, A pharmaceutical composition wherein the above-mentioned nontuberculous mycobacterial infection or disease caused by nontuberculous mycobacterial infection is one or more selected from the group consisting of lung disease, lymphadenitis, skin disease and disseminated disease.
12. In claim 11, A pharmaceutical composition in which the above lung disease is pneumonia or bronchiectasis.
13. In claim 1, A pharmaceutical composition that further comprises an antibiotic.
14. A health functional food for the prevention or improvement of non-tuberculous mycobacterial infections or diseases caused by non-tuberculous mycobacterial infections, comprising as an active ingredient a compound represented by the following chemical formula 2 or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] .

Description

Flavonoid derivatives (comp. no. 22099) and pharmaceutical compositions containing the same for the treatment of diseases caused by non-tuberculous mycobacterial infections The present invention relates to a flavonoid derivative (comp. no. 22099) and a pharmaceutical composition containing the same for treating non-tuberculous mycobacterial infections or diseases caused by non-tuberculous mycobacterial infections, and specifically may be useful for treating diseases caused by Mycobacterium abscessus infection. Non-tuberculosis mycobacteria (NTM) refer to acid-fast bacteria excluding Mycobacterium tuberculosis complex and Mycobacterium leprae . Unlike Mycobacterium tuberculosis, which is found only in animal hosts, NTMs exist normally in environments such as soil and water systems as well as in the animal kingdom, and currently, more than 150 species are known. Diseases caused by NTMs are classified clinically into lung diseases, lymphadenitis, skin diseases, and disseminated diseases, with lung diseases accounting for more than 90% of these cases. The incidence and prevalence of NTM lung disease are on the rise globally, and in Korea, the frequency of NTM isolation from clinical specimens, as well as its incidence and prevalence, are all increasing rapidly. Infections caused by NTM show differences in incidence rates by country and pathogen. In the United States and Japan, the most common causative agent of NTM lung disease is known to be the Mycobacterium avium complex ( MAC ), a mixture of Mycobacterium avium and Mycobacterium intracellulare . In Korea, infection by MAC is also the most common, and an important epidemiological characteristic of NTM-infected lung disease in Korea is that the rapidly growing bacterium, specifically the Mycobacterium abscessus complex, which is relatively rare abroad, is the second most common causative agent. The Mycobacterium abscessus complex consists of three subspecies: Mycobacterium abscessus subsp. abscessus , Mycobacterium abscessus subsp. massiliense , and Mycobacterium abscessus subsp. bolletii , and holds significant clinical importance due to high antibiotic resistance. Among the NTMs, M. abscessus is particularly clinically important in patients with cystic fibrosis. In patients with cystic fibrosis , M. abscessus infection is associated with a faster decline in lung function and can impede subsequent lung transplantation, leading to poor clinical outcomes or lifelong asymptomatic infection. It is surprising that while M. abscessus is the most commonly isolated and rapidly growing mycobacterium in lung infections, the average treatment success rate is only 45.6%. None of the currently available treatments have been shown to be effective in curing patients with chronic lung disease or achieving long-term sputum turnover. M. abscessus is known to be the most antibiotic-resistant bacterium among Mycobacteria genera, possessing resistance genes such as β-lactamases, aminoglycoside phosphotransferases, and aminoglycoside acetyltransferases, and is congenitally resistant to first-generation antituberculosis drugs (isoniazid, rifampin, pyrazinamide, and ethambutol). Currently, current treatment recommendations for M. abscessus lung infection include combination therapy of one or two oral antibiotics, including macrolides, linezolid, clofazimine, and sometimes quinolone-derived drugs, and two or more intravenous drugs (e.g., amikacin, tigecycline, imipenem, and cefoxitin). Long-term multi-antibiotic therapy is often limited by drug-induced toxicities, such as bone marrow suppression by linezolid, hepatotoxicity by tigecycline, and the development of hypersensitivity to β-lactams. Despite strict regimens, treatment failure rates remain high, whether relapsed or chronic. In addition to these characteristics, M. abscessus infection, which requires long-term drug treatment, has limitations when treated with antibiotic monotherapy alone and tends to rely heavily on surgical treatment; therefore, there is an urgent need to develop new drugs to complement this and to identify new therapeutic approaches. However, while research on experimental antibiotics and new treatments with potential activity against M. abscessus through various mechanisms is rapidly increasing, their efficacy against M. abscessus has not been sufficiently studied. Figure 1 is a schematic diagram of an experiment to confirm the safety and efficacy of 22099 in vitro . Figure 2 is a schematic diagram of an experiment to confirm the efficacy of 22099 against bacteria derived from treatment-resistant patients. Figure 3 is a schematic diagram of an experiment to confirm the efficacy of 22099 in vivo . Figure 4 is a graph showing the mitochondrial reactive oxygen species inhibitory ability of mitoSOX™ and 22099 via flow cytometry in vitro . Figure 5 is a graph showing the growth inhibitory activity of 22099 against M. abscessus strains infected with macrophages J774A.1 in vitro . Figure 6 is a graph showing the