Application of compound in preparation of medicine for treating or preventing mycobacterium tuberculosis infection
Patent Information
- Application Number
- CN202380081652.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2022-11-28
- Filing Date
- 2023-11-27
- Publication Date
- 2025-07-04
AI Technical Summary
Mycobacterium tuberculosis is highly resistant to traditional anti-tuberculosis drugs, especially under hypoxic and hypometabolic conditions, resulting in long treatment cycles, low cure rates, and increased drug resistance. Existing drugs are difficult to effectively inhibit or kill latent bacteria. Tuberculosis infection.
It uses rifamycin-nitroimidazole coupling molecules to effectively inhibit and kill Mycobacterium tuberculosis, including multi-drug-resistant and hypoxic strains, through its synergistic inhibition of RNA, DNA, protein and cell wall synthesis pathways. , used to treat and prevent Mycobacterium tuberculosis infection.
Rifamycin-nitroimidazole coupling molecules significantly inhibit Mycobacterium tuberculosis and are superior to traditional anti-tuberculosis drugs. They have highly effective bactericidal activity against multi-drug-resistant and hypoxic strains, shortening the treatment cycle and reducing drug resistance. risk.
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Abstract
Description
Application of compound in preparing medicine for treating or preventing mycobacterium tuberculosis infection Technical Field
[0001] The invention relates to application of a rifamycin-nitroimidazole coupled molecule and belongs to the technical field of medicine. Background Art
[0002] The rifamycin-nitroimidazole conjugate is a new molecular entity formed by coupling two pharmacophores, rifamycin and nitroimidazole, through a stable covalent bond. The rifamycin-nitroimidazole conjugate has a unique multi-target antibacterial mechanism, achieving both antibacterial and bactericidal effects through synergistic inhibition of bacterial macromolecular synthesis pathways, such as RNA, DNA, protein, and cell wall. The rifamycin-nitroimidazole conjugate has a low frequency of spontaneous drug resistance, a rapid bactericidal rate, a prolonged post-antibiotic effect, and a post-antibiotic effect at subinhibitory concentrations. The antibacterial properties and applications of this molecule against anaerobic and microaerophilic bacteria are embodied in Chinese Patent CN104971061B. Chinese Patent CN106860451A discloses its application in inhibiting anaerobic bacteria. Chinese Patent CN108047250A discloses the antibacterial activity of this molecule against non-tuberculous mycobacteria. US Patent No. 7,678,791B2 discloses a rifamycin-nitroimidazole conjugate molecule having antibacterial activity against rifampicin-resistant or metronidazole-resistant Mycobacterium tuberculosis.
[0003] Mycobacterium tuberculosis is a unique aerobic, Gram-positive bacterium. Its growth cycle is 20-30 times longer than that of ordinary bacteria, placing higher demands on the effectiveness, safety, and prevention of drug resistance in therapeutic drugs. Tuberculosis (TB), caused by M. tuberculosis, is one of the most lethal diseases worldwide and currently the infectious disease with the highest mortality rate. 25% of the world's population is infected with M. tuberculosis, of which 10% may develop active TB, and 15% may develop latent TB. In 2016, there were 10.4 million TB cases worldwide, resulting in 1.7 million deaths. This included approximately 1 million children with TB, resulting in 250,000 deaths. Among HIV patients, 40% die from TB infection. In China, TB ranks second in both morbidity and mortality among infectious diseases, making it one of the ten major infectious diseases threatening public health. The treatment of drug-sensitive tuberculosis requires the combined use of four anti-tuberculosis drugs for 2 months, plus a 4-month combination of two drugs. The long treatment cycle and poor patient compliance often lead to increased drug resistance and reduced cure rates.
[0004] Mycobacterium tuberculosis possesses a robust array of drug resistance mechanisms, both intrinsic (due to a specialized cell wall structure with low drug permeability and multiple efflux pump systems) and acquired (through genetic mutations). Globally, tuberculosis cases caused by multidrug resistance (MDR, resistant to isoniazid and rifampicin) and extensively drug-resistant (XDR, resistant to isoniazid and rifampicin, as well as to quinolones and one second-line anti-TB drug) are increasing, posing a significant challenge to human health. In 2016, a conservative estimate of 500,000 cases of MDR-TB were reported worldwide, 64% of which occurred in India, Indonesia, China, Pakistan, Nigeria, and South Africa. Approximately 3.7% of new TB cases are MDR. XDR-TB has been reported in 84 countries, accounting for 9% of all MDR-TB cases. The WHO's recently recommended MDR-TB treatment regimen requires a combination of four second-line drugs for four months, followed by an additional five months of two second-line drugs, with a reported efficacy of 85%. However, 98% of XDR-TB patients remain untreated.
[0005] Another challenge in tuberculosis treatment is the tendency of Mycobacterium tuberculosis to transition from a highly metabolically active growth state to a low-metabolism, slow-growth state within lung granulomas or under hypoxic conditions after drug treatment, ultimately assuming a non-replicating persistence (NRP) state, a state known as latent tuberculosis infection. In the NRP state, M. tuberculosis is completely or partially insensitive to anti-TB drugs (such as isoniazid), a major factor in the prolonged duration of anti-TB treatment. Treatment cycles of six months or longer significantly reduce patient compliance and increase the likelihood of drug resistance due to discontinuous or incomplete treatment (Mitchison, D. and Davies, G., 2012; Alnimr, AM, 2015). Therefore, developing drugs that kill M. tuberculosis in the NRP state or in transition to the NRP state is crucial for shortening the duration of tuberculosis treatment.
[0006] On the other hand, 2-23% of patients with latent tuberculosis infection will develop active tuberculosis when their immune system weakens. Patients with latent tuberculosis and HIV infection develop active tuberculosis at a rate of 5-10% per year. Therefore, the development of drugs that kill Mycobacterium tuberculosis in or near the NRP state is crucial for the prevention of tuberculosis.
[0007] In summary, due to the particularity of Mycobacterium tuberculosis and its infection, the antibacterial properties of the compounds of this patent application (such as activity against Helicobacter pylori and Clostridium difficile) are not necessarily related to the activity against Mycobacterium tuberculosis, especially the activity against Mycobacterium tuberculosis under the low metabolism / slow growth state caused by hypoxia. According to the antibacterial activity against anaerobic bacteria and microaerophilic bacteria described in Chinese patent CN104971061B, it is impossible to infer its antibacterial activity against Mycobacterium tuberculosis. These characteristics of rifamycin-nitroimidazole conjugate molecules provide a basis for their application in anti-Mycobacterium tuberculosis infection. Pulmonary tuberculosis patients will form granulomas in the lungs and develop into caseous necrosis, and Mycobacterium tuberculosis grown in granulomas is in an oxygen-deficient state and is resistant to anti-tuberculosis drugs. Therefore, finding drugs that are active against an oxygen-deficient state is very important for treating tuberculosis, especially shortening the course of treatment or preventing latent tuberculosis infection from becoming active tuberculosis.
[0008] Summary of the Invention
[0009] In view of the above-mentioned defects in the prior art, the purpose of the present invention is to provide an application of a rifamycin-nitroimidazole conjugate molecule, which can effectively inhibit and kill the main pathogens that cause tuberculosis, and thus be used to treat tuberculosis.
[0010] The purpose of the present invention is achieved through the following technical solutions:
[0011] A rifamycin-nitroimidazole conjugate molecule, or a deuterated product, metabolite, pharmaceutically acceptable salt, or prodrug thereof, for use in preparing a drug for treating diseases caused by Mycobacterium tuberculosis infection. The rifamycin-nitroimidazole conjugate molecule has the structure shown in Formula I:
[0012] In some embodiments, the Mycobacterium tuberculosis is a drug-resistant Mycobacterium tuberculosis or multidrug-resistant Mycobacterium tuberculosis comprising one or more of the following types of resistance: rifamycin resistance, nitroimidazole resistance, isoniazid resistance, pyrazinamide resistance, macrolide resistance, fluoroquinolone resistance, aminoglycoside resistance, β-lactam resistance, tetracycline resistance, oxazolidinone resistance, nitrofuran resistance, glycopeptide resistance, and diarylquinoline resistance.
[0013] For example, the rifamycin resistance may include resistance to rifampicin, resistance to rifapentine, and / or resistance to rifabutin.
[0014] For example, the nitroimidazole resistance may include resistance to metronidazole, resistance to tinidazole, resistance to ornidazole, and / or resistance to secnidazole.
[0015] For example, the macrolide resistance may include resistance to clarithromycin, resistance to azithromycin, and / or resistance to roxithromycin.
[0016] For example, the fluoroquinolone resistance may include resistance to ciprofloxacin, resistance to levofloxacin, and / or resistance to moxifloxacin.
[0017] For example, the aminoglycoside resistance may include resistance to streptomycin, resistance to amikacin, and / or resistance to ethambutol.
[0018] For example, the β-lactam resistance may include resistance to ampicillin and / or resistance to amoxicillin.
[0019] For example, the tetracycline resistance may include resistance to tetracycline, resistance to tigecycline, and / or resistance to minocycline.
[0020] For example, the oxazolidinone resistance may include resistance to linezolid and / or resistance to tedizolid.
[0021] For example, the nitrofuran resistance may include resistance to furazolidone.
[0022] For example, the glycopeptide resistance may include resistance to vancomycin.
[0023] For example, the diarylquinoline resistance may include resistance to bedaquiline and / or resistance to clofazimine.
[0024] In some embodiments, the drug resistance type does not include rifampicin monoresistance and metronidazole monoresistance.
[0025] In some embodiments, the Mycobacterium tuberculosis is a Mycobacterium tuberculosis that is sensitive or resistant under a hypoxic and / or hypometabolic state.
[0026] In some embodiments, the Mycobacterium tuberculosis is a Mycobacterium tuberculosis that is sensitive or contains the drug-resistant type under a hypoxic and / or hypometabolic state.
[0027] The outstanding effects of the present invention are:
[0028] The rifamycin-nitroimidazole conjugate molecule of the present invention, or its deuterated product, metabolite, pharmaceutically acceptable salt or prodrug, can effectively inhibit Mycobacterium tuberculosis, and thus be used to treat or prevent Mycobacterium tuberculosis infection, including infection caused by MDR / XDR strains; the rifamycin-nitroimidazole conjugate molecule of the present invention, or its deuterated product, metabolite, pharmaceutically acceptable salt or prodrug, can also effectively inhibit the NRP state or transform Mycobacterium tuberculosis to the NRP state, thereby preventing Mycobacterium tuberculosis infection or shortening the treatment of Mycobacterium tuberculosis infection. BRIEF DESCRIPTION OF THE DRAWINGS
[0029] The specific features of the inventions of this application are set forth in the appended claims. The features and advantages of the inventions of this application can be better understood by referring to the exemplary embodiments described in detail below and the accompanying drawings. A brief description of the drawings is as follows:
[0030] FIG1 is a bar graph showing the Log10 CFU±SEM values in the lungs of mice infected with Erdman's Mycobacterium tuberculosis (pFCA LuxAB) according to Example 3 of the present invention. DETAILED DESCRIPTION
[0031] To provide a clearer understanding of the technical features, objectives, and beneficial effects of the present invention, the following detailed description of the technical solution of the present invention is provided. However, this description should not be construed as limiting the scope of the present invention. The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.
[0032] Example
[0033] Example 1
[0034] This example provides an application of a rifamycin-nitroimidazole conjugate molecule in combating multidrug-resistant Mycobacterium tuberculosis, and simultaneously tests its in vitro antibacterial activity against clinical multidrug-resistant Mycobacterium tuberculosis.
[0035] The drug sensitivity test in this example was performed using the broth dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI; M24-A2) guidelines. The culture medium used was Difco TM Middlebrook 7H9 medium. Clinical isolates were obtained from Beijing Chest Hospital.
[0036] The control drugs were isoniazid, rifampicin, and metronidazole, commonly used anti-tuberculosis drugs in clinical practice. The rifamycin-nitroimidazole conjugate (Formula I) and metronidazole were solubilized with dimethyl sulfoxide (DMSO), while rifabutin was solubilized with anhydrous ethanol. The remaining drugs were dissolved in sterile water. The concentrations of DMSO and anhydrous ethanol in the final test solution did not exceed 2%.
[0037] Each clinical isolate was cultured in 7H9 medium in a 5% CO2 incubator at 37°C for 2-3 weeks until the logarithmic growth phase. The Mycobacterium tuberculosis clinical isolate was removed from the 37°C incubator and 200 μL of each bacterial solution was pipetted into a 96-well plate in a biosafety cabinet. 200 μL of blank 7H9 medium without bacterial solution was then pipetted into the 96-well plate as a background control. The 96-well plate was placed in a multifunctional microplate reader and the OD value of the bacterial solution was measured at a wavelength of 570 nm. An OD value of 0.1 is equivalent to 1×10 8 The concentration of each strain was calculated by CFU / mL and the concentration of each strain was diluted to 10 6 Drugs and bacterial solutions were added to sterile 96-well plates, and the plates were incubated at 37°C in a 5% CO2 incubator for 7 days. Bacterial growth was then recorded.
[0038] After 7 days, add 20 μL of a mixture of 10× Alamar Blue and 50 μL of 5% Tween 80 to the drug-free growth control wells and incubate at 37°C for 24 hours. If the color changes from blue to pink (indicating bacterial growth), add the aforementioned amount of Alamar Blue and Tween 80 mixture to the wells containing each experimental drug and incubate at 37°C for 24 hours. Record the color of each well and measure the fluorescence values at 530 nm and 590 nm using a microplate reader to calculate the minimum inhibitory concentration (MIC).
[0039] The results showed that under 5% CO₂-containing air culture conditions, the rifamycin-nitroimidazole conjugate (Formula I) exhibited similar activity to two first-line anti-TB drugs, isoniazid and rifampicin, against susceptible TB strains, with MICs of 0.016, 0.039, and 0.039 μg / mL, respectively. Notably, the rifamycin-nitroimidazole conjugate (Formula I) exhibited excellent antibacterial activity against all TB strains resistant to the drugs comprising Formula I (rifampicin and metronidazole), surpassing both isoniazid and rifampicin, with MICs ranging from 0.5 to 2 μg / mL (Table 1). Metronidazole was inactive against the tested strains.
[0040] Table 1 Antibacterial activity of rifamycin-nitroimidazole conjugates against drug-resistant Mycobacterium tuberculosis (MIC, μg / mL)
[0041] Example 2
[0042] This embodiment provides an application of a rifamycin-nitroimidazole conjugate molecule in combating Mycobacterium tuberculosis under hypoxic conditions.
[0043] Mycobacterium tuberculosis H37Rv (ATCC 27294) was obtained from the American Type Culture Collection (ATCC, Manassas, VA).
[0044] The rapid anaerobic dormancy (RAD) model used in this experiment was based on the “Wayne model” (Infect. Immun. 1996, 64, 2062; Pathogens, 2018, 7, 88.) and was improved accordingly.
[0045] Test compound concentration: rifamycin-nitroimidazole conjugate (Formula I), control drugs rifampicin (RIF), rifapentine (RPT) and rifabutin (RBT) were tested at concentrations of 5 and 20 μg / mL, other control drugs are isoniazid (INH) at 10 μg / mL, and metronidazole (MET) at 20 and 50 μg / mL).
[0046] Anaerobic growth control: Methylene blue was added to an untreated control culture. Under oxygen-free conditions, the blue dye gradually faded and eventually disappeared. Wayne et al. directly measured O₂ concentrations and linked the fading of the dye to oxygen consumption. Their results will be used graphically in our experiments to determine oxygen consumption.
[0047] Preculture: Throughout the experiment, Dubois Tween-albumin broth was used to culture Mycobacterium tuberculosis H37Rv (wild type), RMP-R (rifampicin-resistant strain), and RPT-R (rifapentine-resistant strain). Precultures were grown as 20 mL broth cultures, supplemented with 2.0 mL of frozen working stock (H37Rv, 4.61 × 10 7 CFU / mL; RMP-R, 4.29×10 6 CFU / mL; RPT-R, 3.88×10 6 The culture was incubated aerobically at 37°C for 7 days (with vigorous stirring) to obtain bacteria in the exponential growth phase.
[0048] Anaerobic culture establishment: In a 15 mm × 125 mm stoppered test tube, the culture medium was divided into 9 mL aliquots. 1 mL of 10% bacterial suspension (OD 600=0.5-0.6 H37Rv) (final dilution of bacterial culture was 1:100). A sterile rubber septum was used to ensure anaerobic growth of the bacteria and to allow injection of the drug under continuous anaerobic conditions. The test tubes were incubated on a stirring platform at a speed of "8" (medium stirring to ensure thorough mixing). 30 μL of methylene blue stock solution (concentration of 500 μg / mL) was added to three test tubes, including a control (final concentration of 1.5 mg / L), and anaerobic bacterial growth was visually confirmed (methylene blue fades with oxygen depletion).
[0049] Inoculation: Serially dilute the bacterial culture at a 1:5 ratio using PBS. Plate one to eight dilutions onto 7H11 / OADC agar. Incubate the culture at 37°C in an atmosphere of normal air. Count the bacterial colonies three weeks after inoculation.
[0050] The results showed that compared with the drug-free group, the rifamycin-nitroimidazole conjugate molecule (Formula I) reduced the bacterial count of wild tuberculosis bacteria by nearly >4Log at two test concentrations (20μg / mL and 5μg / mL). 10 CFU (Table 2). This shows that the Formula I molecule has a strong inhibitory effect on tuberculosis bacteria in a hypoxia-induced dormant state in vitro, which is much better than the single drugs rifabutin and metronidazole that make up the Formula I molecule and other anti-tuberculosis control drugs. Studies have also found that metronidazole has a certain inhibitory effect on the growth of rifamycin-sensitive or resistant tuberculosis strains under anaerobic conditions. Therefore, it is speculated that the synergistic activity of the dual pharmacophores of rifamycin and metronidazole may be one of the reasons for the efficient and rapid bactericidal activity of the rifamycin-nitroimidazole coupled molecule (Formula I).
[0051] Table 2 Antibacterial activity of rifamycin-nitroimidazole conjugates and control drugs against wild-type tuberculosis strains
[0052] Example 3
[0053] This example provides the activity of a rifamycin-nitroimidazole conjugate molecule in a BALB / c mouse acute Mycobacterium tuberculosis infection model.
[0054] Bacterial strain: A working solution of Erdman's Mycobacterium tuberculosis (pFCA LuxAB) was aliquoted into 1.5 mL and stored at -80°C (pFCA LuxAB strain provided by Dr. S. Franzblau, University of Illinois at Chicago). For infection, the aliquot was thawed, mixed 20 times with a 1 mL Luer lock syringe equipped with a 26 G needle, and diluted in sterile deionized water.
[0055] The control drugs were rifampicin, PA-824, linezolid, and metronidazole. The rifamycin-nitroimidazole conjugate (Formula I) was prepared in an aqueous solution containing 0.5% sodium carboxymethylcellulose (CMC-Na) (w / v) and 0.5% Tween 80 (v / v), vortexed, and sonicated until uniformly dispersed. PA-824 was prepared in an aqueous solution containing 10% 2-hydroxypropyl-β-cyclodextrin. Linezolid was prepared in an aqueous solution containing 0.5% methylcellulose. Rifampicin and metronidazole were dissolved in water.
[0056] Experimental animals: 6-8 week old female Balb / c mice were purchased from Charles River Laboratories (Wilmington, MA) and rested for at least one week before infection.
[0057] Aerosol infection: Balb / c mice were infected by aerosol on day 0 using an inhalation exposure system (Glas-col Inc, Terre Haute, IN) to a lung bacterial load of ∼100 CFU / mouse. Balb / c mice were infected with Erdman tuberculosis aerosolized Erdman tuberculosis bacilli (pFCA LuxAB) and then randomly assigned to treatment groups (6 mice per group). Three mice were euthanized on day 1 post-infection, and the whole lungs were aseptically removed, homogenized in 4 mL of 1× PBS, and plated undiluted on 150×15 mm 7H11 / OADC agar plates. The plates were placed in a 37°C dry air incubator for approximately 3–4 weeks, after which CFU counts were performed and maintained for approximately 6 weeks.
[0058] Antibiotic treatment: Starting on day 7 after aerosol infection, oral administration was continued once daily (QD) for 12 consecutive days. Treatment drugs and dosages were as follows: Control drug: 10 mg / kg rifampicin (RIF), 50 mg / kg PA-824, 100 mg / kg linezolid (LZD), 200 mg / kg metronidazole (MTZ). Experimental drug: 100 mg / kg rifamycin-nitroimidazole conjugate (Formula I).
[0059] Bacterial load determination by CFU: To determine the bacterial load at the start of treatment, 6 untreated mice were euthanized using CO2 and the pre-treatment CFU counts in the lungs and spleens were determined. All lung lobes and spleens were removed aseptically. The left lung lobe and spleen were homogenized in 4.5 mL of 1× PBS and serially diluted at 1:5. Dilutions 0-7 were plated on 7H11 / OADC agar plates and incubated at 37°C in a dry air incubator for 3-4 weeks, and then the CFU were counted and kept for approximately 5 weeks. The right upper lobe (upper and inner) and right lower lobe (lower and posterior cavity) were stored at -80°C as a backup.
[0060] Evaluation of therapeutic efficacy: Three days after the last treatment (day 21), mice were euthanized using CO2, and the lung lobes and spleens were aseptically removed. The left lung lobe and spleen were homogenized in 4.5 mL of 1× PBS and serially diluted 1:5. Dilutions 0-7 were plated on 7H11 / OADC agar plates and incubated at 37°C in a dry air incubator for 3-4 weeks, after which CFU were counted and maintained for approximately 5 weeks.
[0061] Bacterial load was determined by luciferase readout (RLU): In addition to determining the CFU in the lungs before and after treatment, the number of bacterial cells can be quickly measured by "indirect" measurement of the luminescence of luciferase-expressing bacteria from lung homogenates. For this purpose, 1 mL of organ homogenate was taken out and placed in a 15 mL conical tube for luminometer determination. 2 mL of Geye solution (8.3 g / L NH4Cl, 1 g / L KHCO3 in H2O) was added to the homogenate, mixed, and incubated at room temperature for 5 minutes to lyse red blood cells (RBCs). 5 mL of phosphate-buffered saline (PBS) was then added to each tube to neutralize the cell lysis solution. The homogenate was then centrifuged at 3000 RPM for 10 minutes at 4°C. The supernatant was poured out and the homogenate was suspended in 1 mL of cold PBS. 100 μL of homogenate without RBC was then mixed with 900 μL of cold PBS in a luminometer tube. Three copies of each organ sample were prepared. The samples were run on a luminometer (Berthold AutoLumatPlus LB 953). The injector volume was 100 μL and the injection solution was anhydrous ethanol containing 1% N-decanal (a substrate for luciferase). The measurement time was 1 second, and 10 measurements were taken per tube and summed to obtain the cumulative relative light unit (RLU) reading for each sample. The data point for each organ was calculated as the average of 3 RLU readings (organ samples were prepared in triplicate) and converted to log 10 RLU was used for data analysis.
[0062] Efficacy data analysis: The CFU counts in the lungs and spleens were log-transformed and then evaluated by one-way ANOVA (Kruskal-Wallis one-way ANOVA if the data did not pass the normality test). Differences were considered significant at the 95% confidence level.
[0063] Table 3 Log in the lungs of mice infected with Erdman's Mycobacterium tuberculosis (pFCA LuxAB) 10 CFU count *n = number of mice with CFU / number of mice at time of plating; N / A = not applicable; # mice were removed from the study due to lack of RLU signal
[0064] Results: This example tested the activity of the rifamycin-nitroimidazole conjugate molecule (Formula I) and four control drugs (rifampicin, PA-824, linezolid, and metronidazole) in an acute pharmacodynamic model of Mycobacterium tuberculosis in BALB / c mice. Treatment was continued for 12 days starting 7 days after low-dose aerosol infection with the Erdman Mycobacterium tuberculosis pFCA LuxAB strain. As shown in Table 3 and Figure 1, the orally administered rifamycin-nitroimidazole conjugate molecule had high antibacterial activity against tuberculosis lung infection in mice in this model. Compared with the vehicle group, the rifamycin-nitroimidazole conjugate molecule I treatment group reduced CFU by 4 log and 0.69 log compared to pre-treatment; while the rifampicin and metronidazole single-dose groups only reduced CFU by 0.65 and 0.09 log, respectively, compared to the vehicle group. The rifamycin-nitroimidazole conjugate showed significantly better activity than the untreated control group, rifampicin control group, metronidazole control group, linezolid control group, and PA-824 control group. There were no drug-related tolerability issues after 12 consecutive days of administration.
[0065] The results of the study indicate that the rifamycin-nitroimidazole conjugate molecule (Formula I) of the present invention has the activity of inhibiting Mycobacterium tuberculosis in vitro (under air and anaerobic / hypoxic conditions) and in vivo, and thus can be used to treat Mycobacterium tuberculosis infection.
[0066] In addition, the deuterated products, metabolites, pharmaceutically acceptable salts or prodrugs of the rifamycin-nitroimidazole conjugate molecules described in the embodiments of the present invention can also be used to prepare drugs for treating or preventing diseases caused by Mycobacterium tuberculosis infection in humans.
[0067] It should be understood that the examples and embodiments described herein are for illustrative purposes only, and various modifications or changes based thereon will be suggested to those skilled in the art, and these modifications or changes are included within the spirit of the present application and the scope of the appended claims.
Claims
1. A rifamycin-nitroimidazole conjugate molecule, or a deuterated product, metabolite, pharmaceutically acceptable salt, or prodrug thereof, for use in the preparation of a medicament for treating or preventing diseases caused by Mycobacterium tuberculosis infection, wherein the rifamycin-nitroimidazole conjugate molecule has the structure shown in Formula I:
2. The use according to claim 1, wherein the Mycobacterium tuberculosis is a drug-resistant Mycobacterium tuberculosis or a multidrug-resistant Mycobacterium tuberculosis comprising one or more of the following drug resistance types: resistance to rifamycins, nitroimidazoles, isoniazid, pyrazinamide, macrolides, fluoroquinolones, aminoglycosides, beta-lactams, tetracyclines, oxazolidinones, nitrofurans, glycopeptides, and diarylquinolines.
3. The use according to claim 2, wherein the drug resistance type does not include rifampicin single resistance and metronidazole single resistance.
4. The use according to claim 1, wherein the Mycobacterium tuberculosis is sensitive or resistant Mycobacterium tuberculosis under hypoxic and / or low metabolic state.
5. The use according to claim 2 or 3, wherein the Mycobacterium tuberculosis is sensitive or contains the drug-resistant type under a hypoxic and / or low metabolic state.