Application of heterocyclic compound

Abstract

The invention relates to the technical field of medicine application, in particular to application of a heterocyclic compound. The compound shown in the formula I in the embodiment of the invention is applied to preparation of an inhibitor for inhibiting activity of methylenetetrahydrofolate reductase. Meanwhile, the compound shown in the formula I can be singly used or combined with p-aminosalicylic acid or combined with a beta-lactamase inhibitor, has good antibacterial activity on mycobacterium tuberculosis, and can be used for treating or preventing diseases caused by mycobacterium tuberculosis, such as tuberculosis and # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical applications, and more particularly, to the application of heterocyclic compounds. Background Art

[0002] Tuberculosis (TB) is a disease caused by infection with Mycobacterium tuberculosis (Mtb). It is mainly transmitted through the air and infects the lungs to form pulmonary TB; a small number are extrapulmonary TB, and the infection sites of extrapulmonary TB may appear in the larynx, lymph nodes, bones, gastrointestinal tract, central nervous system, urogenital system, etc. TB has a wide range of transmission. According to WHO estimates, about one-fourth of the world's population, that is, 2 billion people, are latent Mycobacterium tuberculosis carriers and will turn into active tuberculosis under suitable conditions. According to the latest WHO global tuberculosis report, about 10.6 million people were infected with tuberculosis in 2022, and the global tuberculosis death toll was 1.3 million.

[0003] Drug resistance is the most serious problem faced in the current treatment of tuberculosis. Drug-resistant tuberculosis requires a longer treatment cycle, higher treatment costs, and patients also need to endure longer pain, but the treatment success rate is lower. In 2022, the proportion of rifampicin-resistant / multidrug-resistant tuberculosis (RR / MDR-TB) among newly diagnosed tuberculosis cases globally was about 3.3%, and the proportion of RR / MDR-TB patients among retreated cases was about 17%. This is a very high proportion, because in 2022 alone, there were 410,000 newly diagnosed RR / MDR-TB patients, and the total number of RR-TB patients included in standardized treatment was only 175,000. According to the data that can be retrieved currently, the treatment success rate of sensitive pulmonary tuberculosis from 2012 to 2020 was above 80%, but the treatment success rate of drug-resistant tuberculosis during the same period was 50 - 60%. And the corresponding treatment cycle is at least 9 months, or even longer (more than 18 months); and the average treatment cost is about $20,000, that is, more than 100,000 yuan. China is both a high-burden country for tuberculosis and a high-burden country for drug-resistant tuberculosis. There is an urgent need to develop new treatment strategies or provide new alternative drugs for clinical treatment of tuberculosis to meet the urgent requirements of national tuberculosis prevention and control. Therefore, there is an urgent need to develop a new drug that can inhibit Mycobacterium tuberculosis.

[0004] In view of this, the present invention is specifically proposed. Summary of the Invention

[0005] The object of the present invention is to provide the application of heterocyclic compounds. The compound with the structural formula of Formula I provided by the embodiments of the present invention can not only inhibit the activity of methylenetetrahydrofolate reductase, but also have the effect of anti-Mycobacterium tuberculosis, and then have a good therapeutic effect on the diseases caused by Mycobacterium tuberculosis. At the same time, it can also be used in combination with β-lactamase inhibitors or para-aminosalicylic acid to anti-Mycobacterium tuberculosis and treat tuberculosis.

[0006] The present invention is implemented as follows:

[0007] In the first aspect, the present invention provides the application of a compound shown in Formula I, its pharmaceutically acceptable salt, hydrate of the salt or hydrate thereof in the preparation of an inhibitor for inhibiting the activity of methylenetetrahydrofolate reductase,

[0008] wherein, R 1 represents any one of H, carboxylic acid and alkyl, and R 2 represents any one of alkenyl substituted with heteroatom-containing heteroaryl, thioether group substituted with heteroatom-containing heteroaryl, alkyl substituted with heteroatom-containing heteroaryl and fused heteroaryl containing heteroatoms, and the heteroatoms include at least one of sulfur, oxygen, and nitrogen.

[0009] In the second aspect, the present invention provides the application of a compound shown in Formula I, its pharmaceutically acceptable salt, hydrate of the salt or hydrate thereof in at least one of the following situations;

[0010] (1) Application in the preparation of an antibacterial agent for inhibiting the activity of Mycobacterium tuberculosis;

[0011] (2) Application in the preparation of a bactericide for killing Mycobacterium tuberculosis;

[0012] (3) Application in the preparation of a product for inhibiting the activity of Mycobacterium tuberculosis;

[0013] (4) Application in the preparation of a product for anti-Mycobacterium tuberculosis infection;

[0014] (5) Application in the preparation of a product for treating and / or preventing diseases caused by Mycobacterium tuberculosis;

[0015] (6) Application in the preparation of a drug for treating tuberculosis;

[0016] wherein, R 1 represents any one of H, carboxylic acid and alkyl, and R 2 represents any one of alkenyl substituted with heteroatom-containing heteroaryl, thioether group substituted with heteroatom-containing heteroaryl, alkyl substituted with heteroatom-containing heteroaryl and fused heteroaryl containing heteroatoms, and the heteroatoms include at least one of sulfur, oxygen, and nitrogen.

[0017] In a third aspect, the present invention provides a pharmaceutical composition, the active ingredients of which consist of the compound shown by formula I, its pharmaceutically acceptable salts, hydrates of the salts or hydrates thereof and para-aminosalicylic acid, or consist of the compound shown by formula I, its pharmaceutically acceptable salts, hydrates of the salts or hydrates thereof and a β-lactamase inhibitor,

[0018] wherein, R 1 represents any one of H, carboxylic acid and alkyl, and R 2 represents any one of an alkenyl substituted by a heteroatom-containing heteroaryl, a thioether group substituted by a heteroatom-containing heteroaryl, an alkyl substituted by a heteroatom-containing heteroaryl and a fused heteroaryl containing a heteroatom, and the heteroatom includes at least one of sulfur, oxygen, and nitrogen.

[0019] In a fourth aspect, the present invention provides an application of the pharmaceutical composition described in the foregoing embodiments in at least one of the following situations;

[0020] (1) Application in the preparation of an antibacterial agent for inhibiting the activity of Mycobacterium tuberculosis;

[0021] (2) Application in the preparation of a bactericide for killing Mycobacterium tuberculosis;

[0022] (3) Application in the preparation of a product for inhibiting the activity of Mycobacterium tuberculosis;

[0023] (4) Application in the preparation of a product for preventing and treating Mycobacterium tuberculosis infection;

[0024] (5) Application in the preparation of a product for treating and / or preventing diseases caused by Mycobacterium tuberculosis;

[0025] (6) Preparation of an inhibitor for inhibiting the activity of methylene tetrahydrofolate reductase;

[0026] (7) Application in the preparation of a drug for treating tuberculosis.

[0027] The present invention has the following beneficial effects: The compound shown by formula I provided in the embodiments of the present invention can inhibit the activity of methylene tetrahydrofolate reductase, has good antibacterial activity against Mycobacterium tuberculosis, and then has a certain therapeutic effect on diseases caused by Mycobacterium tuberculosis. At the same time, the compound can also have good antibacterial activity against Mycobacterium tuberculosis and a certain therapeutic effect on diseases caused by Mycobacterium tuberculosis when used in combination with para-aminosalicylic acid or a β-lactamase inhibitor. At the same time, multiple compounds having the structure shown by formula I, such as ceftobiprole, have been approved for marketing, with high safety, and "repurposing of old drugs" will greatly reduce the development cost. Description of the Drawings

[0028] To more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for use in the embodiments. It should be understood that the following drawings only show certain embodiments of the present invention and should not be regarded as limiting the scope. For those of ordinary skill in the art, without creative efforts, other relevant drawings can also be obtained based on these drawings.

[0029] Figure 1 It is a conservation analysis diagram of the homologous protein of mycobacterial methylenetetrahydrofolate reductase provided by the embodiment of the present invention;

[0030] Figure 2 It is a schematic diagram of the molecular docking of the compound shown in Formula I provided by the embodiment of the present invention with mycobacterial methylenetetrahydrofolate reductase;

[0031] Figure 3 It is a schematic diagram of the molecular docking of ceftaroline with mycobacterial methylenetetrahydrofolate reductase provided by the embodiment of the present invention;

[0032] Figure 4 It is a schematic diagram of the molecular docking of ceftobiprole with mycobacterial methylenetetrahydrofolate reductase provided by the embodiment of the present invention;

[0033] Figure 5 It is a schematic diagram of the molecular docking of ceftozopran with mycobacterial methylenetetrahydrofolate reductase provided by the embodiment of the present invention;

[0034] Figure 6 It is a schematic diagram of the molecular docking of cefozopran with mycobacterial methylenetetrahydrofolate reductase provided by the embodiment of the present invention;

[0035] Figure 7 The half-inhibitory concentration IC of the activity of ceftaroline or ceftobiprole on mycobacterial methylenetetrahydrofolate reductase provided by the embodiment of the present invention 50 The measured result diagram;

[0036] Figure 8 It is a result diagram of the bactericidal effect detection of ceftaroline on mycobacterium tuberculosis provided by the embodiment of the present invention;

[0037] Figure 9 It is a result diagram of the pharmacokinetic detection of subcutaneous injection of 50 mg / kg ceftaroline in mice provided by the embodiment of the present invention;

[0038] Figure 10 It is a result diagram of the anti-tuberculosis activity detection of ceftaroline in mice provided by the embodiment of the present invention;

[0039] Figure 11The figure shows the results of detecting the synergistic anti-tuberculosis effect of ceftobiprole and para-aminosalicylic acid provided by the embodiments of the present invention;

[0040] Figure 12 The figure shows the results of detecting the synergistic anti-tuberculosis effect of ceftobiprole and para-aminosalicylic acid provided by the embodiments of the present invention. Specific embodiments

[0041] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. For those not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments without indicating the manufacturer can be obtained as conventional products available on the market.

[0042] Folic acid is a nutrient essential for the life activities of organisms, providing a one-carbon carrier for the synthesis of purines and deoxythymidine monophosphate (dTMP), and participating in the synthesis and transformation of methionine, serine, and glycine. Mammalian cells cannot synthesize folic acid and need to obtain this nutrient from food; while bacteria lack a folic acid transport system and must synthesize folic acid from scratch. This characteristic makes the synthesis and metabolic pathway of folic acid an ideal target for the development of antibacterial drugs. For example, para-aminosalicylic acid (PAS), which is currently used to treat drug-resistant tuberculosis, targets bacterial folic acid synthesis.

[0043] Among them, the key enzyme of folic acid metabolism, methylenetetrahydrofolate reductase (MTHFR), catalyzes the generation of 5-methyltetrahydrofolate from 5,10-methylenetetrahydrofolate, which is essential for bacteria to synthesize methionine and S-adenosylmethionine and is an ideal target for antibacterial drug design. In many species such as Escherichia coli, MTHFR has been identified, annotated, and the crystal structure has been successfully resolved. And for the MTHFR of these species, its reductase activity depends on both reduced coenzyme I (NADH) and flavoprotein cofactors (FAD / FMN). However, MTHFR has not been identified and annotated on the genome of Mycobacterium tuberculosis. The inventors found through research that the Rv2172c protein is the MTHFR of Mycobacterium tuberculosis, and it was confirmed that the reductase activity of Rv2172c only depends on NADH and not on FAD (see: DOI: 10.1128 / AAC.01465-21. Epub 2021 Nov 15.). At the same time, the protein structures of MTFHR in Mycobacterium smegmatis and Mycobacterium thermoresistibile were resolved. The primary amino acid sequences and tertiary structures of these two proteins are highly similar to Rv2172c, and their reductase activities do not depend on FAD. Therefore, it is considered that the MTHFR of mycobacteria is a special type of methylenetetrahydrofolate reductase with a catalytic mechanism that depends on NADH but not on FAD.

[0044] The inventors have found through research that the compound shown in Formula I, its medicinal salts, hydrates of the salts or hydrates thereof are used in the preparation of an inhibitor for inhibiting the activity of methylenetetrahydrofolate reductase.

[0045] Among them, R 1 represents any one of H, carboxylic acid and alkyl, and R 2 represents any one of an alkenyl substituted with a heteroatom-containing heteroaryl, a thioether group substituted with a heteroatom-containing heteroaryl, an alkyl substituted with a heteroatom-containing heteroaryl, and a fused heteroaryl containing a heteroatom, and the heteroatom includes at least one of sulfur, oxygen, and nitrogen.

[0046] Preferably, R 1 represents any one of H, C1-C7 carboxylic acid and C1-C8 alkyl, preferably any one of H, C1-C5 carboxylic acid and C1-C5 alkyl, more preferably any one of H, C3-C5 carboxylic acid and C1-C3 alkyl, and more preferably any one of hydrogen, n-butyric acid, isobutyric acid, methyl and ethyl; R 2 represents any one of a C2-C5 alkenyl substituted with a C3-C10 heteroaryl containing oxygen and nitrogen, a thioether group substituted with a C3-C10 heteroaryl containing sulfur and nitrogen, a C1-C3 alkyl substituted with a heteroaryl containing a nitrogen atom, and a C4-C8 fused heteroaryl containing a single atom;

[0047] Preferably, R 2 represents any one of

[0048] Specifically, the compound shown in Formula I is selected from any one of ceftaroline, ceftaroline fosamil, ceftobiprole, ceftobiprole medocaril, ceftozopran and cefozopran hydrochloride.

[0049] Among them, ceftaroline (also known as T-91825, PPI-0903M), CAS No. 189345-04-8, molecular formula: C 22 H 20 N 8 O 5 S 4 , and the structural formula is as follows:

[0050]

[0051] The prodrug of ceftaroline, ceftaroline fosamil (also known as TAK-599, PPI-0903), is currently on the market in the form of acetate, CAS No. 400827-46-5, molecular formula: C 24 H 25 N8 O 10 PS 4 , the structural formula is as follows:

[0052] Ceftolozane pivoxil was developed by Takeda Pharmaceutical Company of Japan and was first approved by the US FDA for marketing in October 2010 for the treatment of adult community-acquired bacterial pneumonia and acute bacterial skin and soft tissue infections. As the N-phosphonoamino water-soluble prodrug of ceftolozane, ceftolozane pivoxil is rapidly hydrolyzed by phosphatase in the blood into the biologically active compound ceftolozane in vivo.

[0053] Ceftobiprole (also known as: Ro 63-9141, BAL 9141; also called: ceftobip, cefpirome, cefotoro), CAS No. 209467-52-7, molecular formula: C 20 H 22 N 8 O 6 S 2 , the structural formula is as follows:

[0054]

[0055] The prodrug of ceftobiprole, ceftobiprole medocaril (also known as: BAL5788; also called: ceftobiprole ester, cefpirome ester, cefotoro ester), CAS No. 376653-43-9, molecular formula: C 26 H 26 N 8 O 11 S 2 , the structural formula is as follows:

[0056] Since the free form of ceftobiprole medocaril is unstable, the commonly available form on the market is the stable sodium salt form, ceftobiprole medocaril sodium (CAS No.: 252188-71-9), which was developed by Basilea Pharmaceutica of Switzerland and was first approved for marketing in Canada in March 2018 for the treatment of community-acquired pneumonia and hospital-acquired pneumonia. Ceftobiprole medocaril is rapidly decomposed by plasma esterase in plasma into the active form ceftobiprole.

[0057] Ceftolozane (also known as: FR-264205, CXA-101), CAS No. 689293-68-3, molecular formula: C 23 H 30 N 12 O 8 S2 ; The structural formula is as follows:

[0058] Ceftozole was developed by Astellas Pharma Inc. and Uenoyama Pharmaceutical Co., Ltd. in Japan and patented in 2003. This drug is currently in clinical phase 2 / 3 research for the treatment of pyelonephritis, urinary tract infections, and abdominal infections and has not been approved for market yet.

[0059] Cefozopran (also known as SCE-2787), CAS No. 113359-04-9, molecular formula: C 19 H 17 N 9 O 5 S 2 , and the structural formula is as follows:

[0060] The commonly available form of cefozopran on the market is cefozopran hydrochloride with the same biological activity. It was developed by Takeda Pharmaceutical Company Limited in Japan and was first approved for market in Japan in August 1995 for the treatment of diseases such as cholangitis, cholecystitis, and cystitis.

[0061] The methylenetetrahydrofolate reductase activity is selected from the methylenetetrahydrofolate reductase of Mycobacterium.

[0062] Second, embodiments of the present invention provide an application of the compound shown in the above formula I, its pharmaceutically acceptable salt, hydrate of the salt or its hydrate in at least one of the following situations;

[0063] (1) Application in the preparation of an antibacterial agent for inhibiting the activity of Mycobacterium tuberculosis;

[0064] (2) Application in the preparation of a bactericidal agent for killing Mycobacterium tuberculosis;

[0065] (3) Application in the preparation of a product for inhibiting the activity of Mycobacterium tuberculosis;

[0066] (4) Application in the preparation of a product for preventing and treating Mycobacterium tuberculosis infection;

[0067] (5) Application in the preparation of a product for treating and / or preventing diseases caused by Mycobacterium tuberculosis;

[0068] (6) Application in the preparation of a drug for treating tuberculosis.

[0069] The compound shown in Formula I is the same as defined above. Compounds such as ceftobiprole and cefepime belong to cephalosporins. Most cephalosporins have little antibacterial activity against Mycobacterium tuberculosis. The biggest difference between compounds such as ceftobiprole and cefepime and other cephalosporins is that they all have the core structure shown in Formula I. It was found in the examples of the present invention that compounds with the core structure shown in Formula I, such as ceftobiprole and cefepime, have activity against Mycobacterium tuberculosis, have bacteriostatic and bactericidal effects on Mycobacterium tuberculosis, and then have therapeutic or preventive effects on Mycobacterium tuberculosis infection or diseases caused by it, such as pulmonary tuberculosis. At the same time, it can also inhibit the activity of methylenetetrahydrofolate reductase and can be used as a product for inhibiting the activity of methylenetetrahydrofolate reductase.

[0070] In a third aspect, the examples of the present invention provide a pharmaceutical composition, the active ingredients of which are composed of the compound shown in Formula I, its pharmaceutically acceptable salt, hydrate of the salt or its hydrate and para-aminosalicylic acid, or composed of the compound shown in Formula I, its pharmaceutically acceptable salt, hydrate of the salt or its hydrate and a β-lactamase inhibitor.

[0071] Among them, the mass ratio of the compound shown in Formula I to para-aminosalicylic acid is (0.01 - 100):(0.001 - 100), preferably (0.02 - 32):(0.0025 - 0.32);

[0072] The mass ratio of the compound shown in Formula I to the β-lactamase inhibitor is (0.02 - 20):(0.02 - 200), preferably (0.2 - 2):(0.2 - 32);

[0073] The β-lactamase inhibitor is selected from oxapenam β-lactamase inhibitors and / or penicillanic acid sulfone β-lactamase inhibitors.

[0074] Furthermore, one or more pharmaceutically acceptable carriers can be added to the above-mentioned pharmaceutical composition; the carriers include conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field.

[0075] The above-mentioned pharmaceutical composition can be prepared into various forms such as injection solutions, tablets, powders, granules, capsules, oral liquids, ointments, creams, etc.; the drugs in the above various dosage forms can all be prepared according to the conventional methods in the pharmaceutical field.

[0076] The above-mentioned pharmaceutical composition can be introduced into the body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, spraying, nasal dropping, eye dropping, penetration, absorption, physical or chemical mediated methods; or be introduced into the body after being mixed or wrapped with other substances.

[0077] When using the pharmaceutical composition, the compounds (drugs) can be used simultaneously or successively, and the usage amounts are their respective effective doses, and each is used in a suitable administration method according to the standard administration method. It can also be used after mixing the respective effective doses to form a mixture.

[0078] The compound shown in Formula I is the same as the above definition. It was found in the examples of the present invention that the compound shown in Formula I has good antibacterial activity against Mycobacterium tuberculosis when used in combination with para-aminosalicylic acid or in combination with a β-lactamase inhibitor, and can be used for the treatment of tuberculosis. Therefore, the examples of the present invention provide the application of the above pharmaceutical composition in at least one of the following situations;

[0079] (1) Application in the preparation of an antibacterial agent for inhibiting the activity of Mycobacterium tuberculosis;

[0080] (2) Application in the preparation of a bactericide for killing Mycobacterium tuberculosis;

[0081] (3) Application in the preparation of a product for inhibiting the activity of Mycobacterium tuberculosis;

[0082] (4) Application in the preparation of a product for anti-Mycobacterium tuberculosis infection;

[0083] (5) Application in the preparation of a product for treating and / or preventing diseases caused by Mycobacterium tuberculosis;

[0084] (6) Preparation of an inhibitor for inhibiting the activity of methylenetetrahydrofolate reductase;

[0085] (7) Application in the preparation of a drug for treating tuberculosis.

[0086] The features and properties of the present invention will be further described in detail below in conjunction with examples.

[0087] Example 1 Molecular Docking

[0088] Based on the discovery of new drug design targets, molecular docking plays a key role in the drug discovery and development process. It is used to identify potential drug candidates and understand their binding interactions with target proteins. Virtual screening is one of the main applications of molecular docking in drug discovery, which involves rapidly screening large compound libraries to identify potential lead compounds that are likely to bind to specific target proteins. Docking algorithms can predict the binding affinity and binding mode of small molecules to target proteins, enabling the selection of promising candidate compounds for further experimental evaluation. At the same time, molecular docking can also be used for drug repurposing work, that is, screening existing drugs for new targets. Docking helps to identify potential therapeutic effects beyond the original indication by predicting their binding interactions with other target proteins, which can reduce the cost and time in the drug development process.

[0089] Therefore, in the embodiments of the present invention, molecular docking was used to study the inhibitory performance of the compounds shown in Formula I against methylenetetrahydrofolate reductase.

[0090] The methylenetetrahydrofolate reductase of Mycobacterium is a unique reductase that functions independently of FAD and only depends on NADH. The three-dimensional protein structures of the methylenetetrahydrofolate reductases Rv2172c of Mycobacterium tuberculosis, MSMEG_6649 of Mycobacterium smegmatis, and MHAS_04356 of Mycobacterium thermoresistibile are extremely similar, and the amino acid sequences of homologous methylenetetrahydrofolate reductase proteins are highly conserved in Mycobacterium (see Figure 1 ). Molecular docking was performed using the protein structure of Mycobacterium tuberculosis Rv2172c analyzed by the inventors to search for small molecule compounds that may inhibit the activity of methylenetetrahydrofolate reductase in Mycobacterium. Through molecular docking, we found that the compound structure shown in Formula I may bind to the active center of Rv2172c, and in the two docking poses with the highest scores, the compound structure shown in Formula I interacts with multiple key amino acid residues such as Val117, Met121, Arg153, and Arg159 that depend on the enzyme activity of Rv2172c (see Figure 2 ), which may prevent the enzyme from binding to the substrate or coenzyme NADH, thereby inhibiting enzyme activity. Searching for compounds with the structure shown in Formula I in all compound libraries available from MCE, the results are shown in Table 1, mainly including Ceftaroline, Ceftobiprole, Ceftolozane, Cefozopran, and their medicinal salts or hydrates.

[0091] Table 1 Compounds shown in Formula I

[0092]

[0093] Note: Ceftobiprole, Ceftobiprole; Ceftaroline, Ceftaroline; Ceftolozane; Ceftolozane; Cefozopran, Cefozopran.

[0094] Through molecular docking, it was found that compounds with the structure shown in Formula I such as Ceftaroline or Ceftobiprole may bind to the active center of Rv2172c, and in the two docking poses with the highest scores for each, the compounds interact with multiple key amino acid residues such as Glu9, Thr86, Pro118, Arg119, Met121, Arg153, and Arg159 that depend on the enzyme activity of Rv2172c (see Figure 3 , Figure 4 ,Figure 5 and Figure 6 )。

[0095] For further enzyme kinetics experiments, the operations of the enzyme kinetics experiments are as follows: Under the conditions of 100 mM phosphate buffer (pH 8.0) and a substrate concentration of 100 μM, the inhibition of ceftobiprole and cefepime on the methylenetetrahydrofolate reductase activity of Rv2172c was detected at room temperature. The concentration range of ceftobiprole was 0.1 - 50 μM, and the concentration range of cefepime was 0.01 - 3 μM. Ceftobiprole and cefepime were incubated with 1 μM Rv2172c protein at room temperature for 20 min, and then the substrate was added to start the reaction. Subsequently, the absorbance of NADH was detected at 340 nm and 25 °C.

[0096] For the results of the enzyme kinetics experiments, see Figure 7 , according to the results shown, both ceftobiprole and cefepime can inhibit the methylenetetrahydrofolate reductase activity of Rv2172c, and the half-inhibitory concentration IC 50 were 1.75 μM and 0.37 μM respectively, proving that the compound with the structure shown in formula I can inhibit the enzymatic catalytic activity of the methylenetetrahydrofolate reductase unique to mycobacteria.

[0097] Example 2 Detection of the antibacterial activity of the compound shown in formula I against Mycobacterium tuberculosis

[0098] Mycobacterium tuberculosis H37Ra and H37Rv were cultured in 7H9 + OADC liquid medium until the logarithmic growth phase, and the drug-containing bacterial suspension was diluted to 1×10 5 CFU / mL by the microplate two-fold dilution method to determine the minimum inhibitory concentration (MIC) of ceftobiprole and cefepime against Mycobacterium tuberculosis. At the same time, the MIC of different cephalosporins against Mycobacterium tuberculosis was detected as a control. The detailed information of all detected cephalosporins is shown in Table 2.

[0099] Table 2 Types of cephalosporins

[0100]

[0101] For the detection results, see Table 3.

[0102] Table 3 MIC of different cephalosporins against Mycobacterium tuberculosis

[0103]

[0104] Note: Cephalexin, Cefazolin, Cefoxitin, Cefaclor, Ceftazidime, Cefoperazone, Cefixime, Ceftriaxone, Ceftobiprole, Ceftaroline.

[0105] As can be seen from Table 3, Ceftaroline or Ceftobiprole has good antibacterial effects on Mycobacterium tuberculosis at low concentrations (1 - 2 μg / mL). However, the other cephalosporins tested have no good antibacterial activity against Mycobacterium tuberculosis (MIC > 16 μg / mL). It can be seen that only the compounds with the core structure shown in Formula I can inhibit the activity of Mycobacterium tuberculosis.

[0106] Since the antibacterial activities of Ceftaroline and Ceftobiprole in Mycobacterium tuberculosis are exactly the same, the embodiments of the present invention select Ceftaroline to representatively conduct subsequent embodiments to further study the bactericidal effects of the compounds with the core structure shown in Formula I on Mycobacterium tuberculosis.

[0107] Example 3 Detection of the bactericidal effect of Ceftaroline on Mycobacterium tuberculosis

[0108] Culture Mycobacterium tuberculosis H37Ra in 7H9 + OADC liquid medium until the logarithmic growth phase, and then dilute the bacterial suspension to 1×10 6 CFU / mL, and add Ceftaroline at 1-fold, 2-fold, and 5-fold MIC concentrations (1, 2, 5 μg / mL). Incubate the bacterial solution after adding the drug at 37°C, and take the bacterial solution at regular intervals to dilute and plate to count the viable bacteria. Each group of experiments has three biological replicates and is technically repeated twice.

[0109] The results are shown in Figure 8 According to Figure 8 It can be seen that Ceftaroline has a very strong bactericidal effect on Mycobacterium tuberculosis at a concentration of 1 μg / mL, and 1-fold MIC is the minimum bactericidal concentration (MBC).

[0110] Example 4 Detection of the anti-tuberculosis activity of Ceftaroline in mice

[0111] Inject Balb / c mice with a safe dose of 50 mg / kg of Ceftaroline ester for pharmacokinetic detection.

[0112] The results are as shown in Figure 9As shown, the blood drug concentration of ceftobiprole can reach 40 μg / mL at 0.5 hour after injection, but it is rapidly metabolized to below 1 μg / mL within 2 hours after injection.

[0113] The antituberculosis activity of ceftobiprole in mice was detected using a drug activity evaluation model of Mycobacterium tuberculosis H37Ra (UA1Ra) that emits light autonomously without selection. The specific operations are as follows: UA1Ra was transferred to fresh 7H9 medium containing OADC and cultured until the logarithmic phase (OD600 ≈ 0.5 - 1.0). And the relative light unit (RLU) value ≥ 2 million / 200 μl of bacterial suspension was used to infect mice. 200 μl of the UAlRa bacterial suspension was injected into 4 - 6-week-old female BALB / c mice through the tail vein. On the 2nd day after infection (i.e., the 0th day of treatment), the RLU value of the mice was detected. First, the mice were anesthetized with isoflurane, and then the mice were placed in a luminescence detector with their chests closely attached to the photometric detection hole, and the light production was measured continuously twice for 3 seconds, and the RLU value was recorded. Mice with too low RLU values were eliminated, and then the mice with qualified RLU values were randomly grouped, with 5 mice in each group, and each was marked. PBS was given as a negative control, and rifampicin (RIF, 10 mg / kg) was given as a positive control. The dosing doses of the ceftobiprole treatment group were 20 mg / kg and 50 mg / kg. Except for the positive control given by gavage, the treatment group and the negative control group were both given by subcutaneous injection once a day for 4 consecutive days. The RLU values were detected on the 2nd, 4th, and 5th days of treatment respectively. The mice were euthanized on the second day after the end of dosing (i.e., the 5th day of treatment), the lung tissues were taken out, placed in 2 mL of sterile PBS solution, ground and homogenized with a tissue grinder, and then the RLU values of the mouse lung homogenates were detected respectively by a luminescence detector. The antibacterial activity of the compound was evaluated by detecting the RLU value to measure the number of viable bacteria in the system.

[0114] The results are shown in Figure 10 , according to Figure 10 it can be seen that ceftobiprole has antituberculosis activity in mice, and the 50 mg / kg dose injection shows the most obvious effect, but it is slightly inferior to the first-line antituberculosis drug rifampicin. However, combined with the pharmacokinetic data, such an effect can be achieved when the effective bactericidal concentration of 1 μg / mL of this compound at a 50 mg / kg injection dose in mice is maintained for less than 2 hours per day. And ceftobiprole ester at 600 mg (for a patient of 60 kg, i.e., a dose of 10 mg / kg) can maintain a serum drug concentration above 1 μg / mL in humans for about 8 hours.

[0115] It can be seen that the development and application of the compound with formula I as an antituberculosis drug have broad prospects.

[0116] Example 5 Detection of Enhancement of the Antibacterial Activity of Ceftobiprole against Mycobacterium tuberculosis by β-Lactamase Inhibitor

[0117] It is generally believed that β-lactamase inhibitors do not have antibacterial activity against Mycobacterium tuberculosis. The inventors did indeed detect that the MIC of β-lactamase inhibitors, such as Avibactam or Relebactam, against Mycobacterium tuberculosis is greater than 64 μg / mL.

[0118] In order to detect whether β-lactamase inhibitors enhance the antibacterial activity of the compound with formula I against Mycobacterium tuberculosis, all available β-lactamase inhibitors were purchased, and the details are shown in Table 4.

[0119] Table 4 β-Lactamase Inhibitors Tested

[0120]

[0121] Mycobacterium tuberculosis H37Ra was cultured in 7H9 + OADC liquid medium until the logarithmic growth phase. The drug-containing bacterial suspension was diluted to 1×10 5 CFU / mL by the microplate two-fold dilution method, and the MIC of ceftobiprole against Mycobacterium tuberculosis was determined in the presence of 0.5 μg / mL of different β-lactamase inhibitors. The experiment was repeated three times, and the results are shown in Table 5.

[0122] According to Table 5, it can be seen that a variety of β-lactamase inhibitors can increase the antibacterial activity of ceftobiprole against Mycobacterium tuberculosis, such as Avibactam, Relebactam, Taniborbactam, Clavulanate, etc. Avibactam and Relebactam were selected as representatives of β-lactamase inhibitors to continue the subsequent research.

[0123] Table 5 MIC of Ceftobiprole against Mycobacterium tuberculosis when Combined with Different β-Lactamase Inhibitors

[0124]

[0125] Note: Ceftaroline, ceftobiprole

[0126] Mycobacterium tuberculosis H37Rv was cultured in 7H9 + OADC liquid medium until the logarithmic growth phase. The drug-containing bacterial suspension was diluted to 1×10 5 CFU / mL by the microplate two-fold dilution method, and the MIC of ceftobiprole against Mycobacterium tuberculosis was determined in the presence of different concentrations of the β-lactamase inhibitor Avibactam or Relebactam. The experiment was repeated three times, and the results are shown in Table 6.

[0127] Table 6 MIC of Ceftobiprole against Mycobacterium tuberculosis when Different Concentrations of β-Lactamase Inhibitors are Added

[0128]

[0129] Note: Avibactam, Ceftaroline, Relebactam

[0130] As can be seen from Table 6, Avibactam or Relebactam can increase the anti-tuberculosis activity of Ceftaroline, and the effect of Avibactam is slightly better than that of Relebactam. That is to say, β-lactamase inhibitors can cooperate with the compound shown in Formula I to have antibacterial activity against Mycobacterium tuberculosis.

[0131] Example 6 Detection of the Synergistic Anti-tuberculosis Effect of Ceftaroline or Ceftobiprole and Para-aminosalicylic Acid

[0132] Para-aminosalicylic acid (PAS), as an anti-tuberculosis drug used clinically, inhibits Mycobacterium tuberculosis by inhibiting dihydrofolate reductase. PAS is mainly used for the treatment of drug-resistant tuberculosis and has good anti-tuberculosis activity itself (MIC is 0.02 - 0.04 μg / mL).

[0133] To detect its synergistic anti-tuberculosis activity with the compound shown in Formula I, Mycobacterium tuberculosis H37Rv was cultured to the logarithmic phase and then serially diluted to 10 5 CFU / mL. Each 500 μl was aliquoted into a 48-well plate and added with increasing concentrations of Ceftaroline or Ceftobiprole and PAS, and the fractional inhibitory concentration index (FICI) of the combined drug use was calculated (FICI = MIC of A when used in combination / MIC of A when used alone + MIC of B when used in combination / MIC of B when used alone). FICI ≤ 0.5 indicates a synergistic effect, 0.5 < FICI ≤ 4 indicates no interaction, and FICI > 4 indicates an antagonistic effect.

[0134] The results are as Figure 11 and Figure 12 shown. According to Figure 11 and Figure 12 it can be seen that Ceftaroline or Ceftobiprole and the clinical anti-tuberculosis drug PAS have good synergistic anti-tuberculosis effects, that is, adding a very small amount of PAS can significantly reduce the MIC of Ceftaroline or Ceftobiprole against Mycobacterium tuberculosis, and adding a very small amount of Ceftaroline or Ceftobiprole can also significantly reduce the MIC of PAS against Mycobacterium tuberculosis. It shows that the compound shown in Formula I can produce a synergistic effect with PAS, has antibacterial effects against Mycobacterium tuberculosis, and has a therapeutic effect on diseases caused by Mycobacterium tuberculosis.

[0135] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. Use of a compound represented by formula I, its pharmaceutically acceptable salt, hydrate of the salt or hydrate thereof in the preparation of an inhibitor for inhibiting the activity of methylenetetrahydrofolate reductase, characterized in that, Among them, R 1 represents any one of H, a carboxylic acid, and an alkyl group, and R 2 represents any one of a heteroaryl-substituted alkenyl group containing a heteroatom, a heteroaryl-substituted thioether group containing a heteroatom, a heteroaryl-substituted alkyl group containing a heteroatom, and a fused heteroaryl group containing a heteroatom, and the heteroatom includes at least one of sulfur, oxygen, and nitrogen.

2. The use according to claim 1, characterized in that, Said R 1 represents any one of H, C1-C7 carboxylic acids and C1-C8 alkyl groups, preferably any one of H, C1-C5 carboxylic acids and C1-C5 alkyl groups, more preferably any one of H, C3-C5 carboxylic acids and C1-C3 alkyl groups, still more preferably any one of hydrogen, n-butyric acid, isobutyric acid, methyl and ethyl; Preferably, R 2 represents any one of an oxygen- and nitrogen-containing C3-C10 heteroaryl-substituted C2-C5 alkenyl, a sulfur- and nitrogen-containing C3-C10 heteroaryl-substituted thioether group, a C1-C3 alkyl group of a heteroaryl substituted with a nitrogen atom, and a C4-C8 fused heteroaryl containing a single atom; Preferably, R 2 represents any one of; Preferably, the compound represented by formula I is selected from any one of ceftobiprole, ceftobiprole medocaril, ceftobiprole pivoxil, ceftobiprole pivoxil hydrochloride, ceftobiprole pivoxil mesylate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil phthalate, ceftobiprole pivoxil terephthalate, ceftobiprole pivoxil adipate, ceftobiprole pivoxil sebacate, ceftobiprole pivoxil glutarate, ceftobiprole pivoxil malate, ceftobiprole pivoxil tartrate, ceftobiprole pivoxil citrate, ceftobiprole pivoxil fumarate, ceftobiprole pivoxil succinate, ceftobiprole pivoxil maleate, ceftobiprole pivoxil benzoate, ceftobiprole pivoxil nicotinate, ceftobiprole pivoxil isonicotinate, ceftobiprole pivoxil salicylate, ceftobiprole pivoxil ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Among them, R 1 represents any one of H, a carboxylic acid, and an alkyl group, and R 2 represents any one of a heteroaryl-substituted alkenyl group containing a heteroatom, a heteroaryl-substituted thioether group containing a heteroatom, a heteroaryl-substituted alkyl group containing a heteroatom, and a fused heteroaryl group containing a heteroatom, and the heteroatom includes at least one of sulfur, oxygen, and nitrogen. ​ ​ Said R 1 represents any one of H, C1-C7 carboxylic acids and C1-C8 alkyl groups, preferably any one of H, C1-C5 carboxylic acids and C1-C5 alkyl groups, more preferably any one of H, C3-C5 carboxylic acids and C1-C3 alkyl groups, still more preferably any one of hydrogen, n-butyric acid, isobutyric acid, methyl and ethyl; Preferably, R 2 represents any one of an oxygen- and nitrogen-containing C3-C10 heteroaryl-substituted C2-C5 alkenyl, a sulfur- and nitrogen-containing C3-C10 heteroaryl-substituted thioether group, a C1-C3 alkyl group of a nitrogen atom-substituted heteroaryl, and a C4-C8 fused heteroaryl containing a single atom; Preferably, R 2 represents any one of; ​ ​ ​ ​ Among them, R 1 represents any one of H, carboxylic acid, and alkyl, and R 2 represents any one of a heteroaryl-substituted alkenyl containing a heteroatom, a heteroaryl-substituted thioether group containing a heteroatom, a heteroaryl-substituted alkyl containing a heteroatom, and a fused heteroaryl containing a heteroatom, and the heteroatom includes at least one of sulfur, oxygen, and nitrogen. ​ ​ Said R 1 represents any one of H, C1-C7 carboxylic acids, and C1-C8 alkyl groups, preferably any one of H, C1-C5 carboxylic acids, and C1-C5 alkyl groups, more preferably any one of H, C3-C5 carboxylic acids, and C1-C3 alkyl groups, and even more preferably any one of hydrogen, n-butyric acid, isobutyric acid, methyl, and ethyl; Preferably, R 2 represents any one of an oxygen- and nitrogen-containing C3-C10 heteroaryl-substituted C2-C5 alkenyl, a sulfur- and nitrogen-containing C3-C10 heteroaryl-substituted thioether group, a C1-C3 alkyl group of a heteroaryl substituted with a nitrogen atom, and a C4-C8 fused heteroaryl containing a single atom; Preferably, R 2 represents any one of; ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ (5) Use in the preparation of a product for treating and / or preventing diseases caused by Mycobacterium tuberculosis; (6) Preparation of an inhibitor for inhibiting the activity of methylenetetrahydrofolate reductase; (7) Use in the preparation of a medicament for treating tuberculosis.

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