Compounds having anti-mycobacterial activity

Abstract

The invention belongs to the field of medicines and food additives, and particularly relates to a group of compounds with anti-mycobacterium activity. The invention provides a compound represented by a formula I, a formula II, a formula III, a formula IV, R2-COOH or R3-OH, and an application of an isomer, a prodrug and a pharmaceutically acceptable salt thereof in preparation of drugs for treating and / or preventing diseases caused by mycobacterial infection. The invention also relates to application of the compounds shown in the formula I, the formula II, the formula III and the formula IV, R2-COOH or R3-OH, and the isomers, the prodrugs and the pharmaceutically acceptable salts of the compounds in the formula I, the formula II, the formula III and the formula IV in blocking mycobacterium transmission. The invention relates to an application of a compound represented by formula I, a compound represented by formula II, a compound represented by formula III, a compound represented by formula IV, or a compound represented by formula I, a compound represented by formula II, a compound represented by formula III, a compound represented by formula IV, R2-COOH or R3-OH, and an isomer, a prodrug and a pharmaceutically acceptable salt thereof in in-vitro inhibition of mycobacteria, and R1, R2, R3, Ra and Rc are defined in the specification.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals and food additives, specifically relating to a group of compounds with anti-mycobacterial activity, and the application of such compounds in the treatment and prevention of mycobacterial infection-related diseases, as well as in blocking the transmission of mycobacteria. Background Technology

[0002] Mycobacterium bacteria include three main categories: Mycobacterium leprae, Mycobacterium tuberculosis complex, and nontuberculous mycobacteria, which can cause diseases such as leprosy and tuberculosis.

[0003] In terms of treatment, mycobacterial diseases, represented by tuberculosis, face multiple key challenges: (1) Long treatment cycle and significant side effects: The standard course of tuberculosis treatment is at least 6 months. Anti-tuberculosis drugs generally have side effects such as hepatotoxicity and neurotoxicity, which seriously affect patients' treatment compliance and delay the recovery process; (2) Prominent drug resistance: Drug-resistant strains continue to grow. The proportion of multidrug-resistant strains and extensively drug-resistant strains in clinical practice is increasing year by year, and even all-drug-resistant strains have appeared, which greatly increases the risk of treatment failure; (3) Lagging drug development: In the past 50 years, only three new anti-tuberculosis drugs, bedaquiline, delamaniline, and premiumiline, have been approved globally, and all of them have quickly developed drug resistance, which greatly weakens their therapeutic efficacy; (4) Lack of treatment methods for non-tuberculous mycobacterial diseases: The development of drugs for non-tuberculous mycobacterial diseases is almost blank. Anti-tuberculosis drugs are basically used, which lacks specificity and leads to unsatisfactory treatment results.

[0004] Therefore, there is an urgent need in the field of mycobacterial infection treatment to develop novel drugs with new mechanisms of action, fewer toxic side effects, and strong anti-mycobacterial specificity.

[0005] Meanwhile, the prevention of tuberculosis and other mycobacterial diseases remains a significant challenge in public health: the large number of tuberculosis infections, the long recovery period for patients, and the high risk of disease transmission make blocking transmission between patients and their contacts crucial for prevention and control. Current protective measures mainly involve disinfection of key locations and wearing masks, but their effectiveness is limited—patients' families, medical staff, and other close contacts remain high-risk groups for mycobacterial infection, necessitating the development of more efficient methods and products to block mycobacterial transmission. Summary of the Invention

[0006] The purpose of this invention is to provide a group of compounds with anti-mycobacterial activity, to solve the technical problems of prominent drug resistance, large toxic side effects, and insufficient protection against mycobacterial transmission of existing mycobacterial treatment drugs, while meeting the clinical demand for anti-mycobacterial products with high specificity and high safety.

[0007] The first aspect of the present invention provides the use of compounds of formula I, II, III, IV, R2-COOH or R3-OH, isomers thereof, prodrugs and pharmaceutically acceptable salts in the preparation of medicaments for treating and / or preventing diseases caused by mycobacterial infections.

[0008] A second aspect of the present invention provides an animal extract comprising compounds of formulas I, II, III, and IV described in the first aspect of the present invention, R2-COOH, and R3-OH.

[0009] A third aspect of the present invention provides a method for preparing the animal extract described in the second aspect of the present invention, the method comprising the steps of preparing the animal extract using a first organic solvent and then extracting the extract using a second organic solvent.

[0010] The fourth aspect of the present invention provides a pharmaceutical composition, personal care product, functional food, or sterilization composition, wherein the pharmaceutical composition, personal care product, functional food, or sterilization composition comprises compounds of formula I, II, III, and IV as described in the first aspect of the present invention, R2-COOH, R3-OH, and / or animal extracts as described in the second aspect of the present invention.

[0011] Beneficial effects:

[0012] The compounds and related products with anti-mycobacterial activity provided by this invention have the following significant advantages:

[0013] 1. High specificity against mycobacteria with minimal impact on normal flora: The compounds of this invention exhibit specific inhibitory or bactericidal activity against mycobacteria (including various drug-resistant strains), while no significant inhibitory effect has been found on other bacteria that humans come into daily contact with. Therefore, during use, interference with the normal human flora structure can be minimized, reducing potential health risks caused by flora imbalance.

[0014] 2. High safety and wide applicability: Taking compound 1 (palmitoyl monoglyceride) as an example, it has been widely used in the food and cosmetic fields, with a well-established safety profile. It can be used in long-term contact with the human body (skin, oral mucosa) or orally. It can be flexibly added to pharmaceuticals, care products (such as skin sprays and oral care products), and functional foods, making it suitable for prevention in healthy individuals and auxiliary protection for infected individuals (such as reducing oral bacteria). The product described in this article can block the spread of mycobacteria by direct spraying onto human or environmental surfaces, or by being present in the patient's oral cavity in an appropriate form (such as oral spray or lozenge) to reduce the titer of mycobacteria in the oral cavity and the patient's infectivity.

[0015] 3. Balancing treatment and protection: It has the potential to develop novel anti-tuberculosis and non-tuberculosis mycobacterial drugs, breaking through existing drug resistance limitations; it can also block transmission through in vitro sterilization and reducing oral infectivity in patients, filling the gap in protection in close contact scenarios.

[0016] 4. Environmentally friendly and long-lasting: It is biodegradable, poses no risk of environmental residue, and is not easily volatilized, thus having long-lasting antibacterial activity and providing continuous protection. It is suitable for critical places such as homes and hospitals.

[0017] In summary, the compounds and related products of this invention have significant application value in the treatment, prevention, and transmission blocking of mycobacterial infections, and can simultaneously meet the needs of clinical treatment and public health protection, thus showing promising application prospects. Attached Figure Description

[0018] Figure 1 This is a flowchart of the separation process for active components. Figure 2 This is the MS spectrum of compound 1. Figure 3 For compound 1 1 H-NMR nuclear magnetic resonance spectrum. Figure 4 For compound 1 13 C-NMR nuclear magnetic resonance spectrum. Figure 5 The image shows the DEPT NMR spectrum of compound 1. Figure 6 The image shows the HMBC NMR spectrum of compound 1. Figure 7 This is the MS spectrum of compound 2. Figure 8 For compound 2 1 H-NMR nuclear magnetic resonance spectrum. Figure 9 For compound 2 13 C-NMR nuclear magnetic resonance spectrum. Figure 10 This is the MS spectrum of compound 3. Figure 11 For compound 3 1 H-NMR nuclear magnetic resonance spectrum. Figure 12 For compound 3 13 C-NMR nuclear magnetic resonance spectrum. Figure 13 The MS spectrum of compound 3-2 is shown. Figure 14 For compound 3-2 1 H-NMR nuclear magnetic resonance spectrum. Figure 15 For compound 3-2 13 C-NMR nuclear magnetic resonance spectrum. Figure 16 LCMS plots for each fraction. Figure 17 LCMS plots for each fraction. Figure 18 LCMS plots for each fraction. Figure 19 LCMS plots for each fraction. Figure 20 LCMS plots for each fraction. Detailed Implementation

[0019] To enable those skilled in the art to understand the features and effects of the present invention, the terms and expressions used in the specification and claims are explained and defined in general below. Unless otherwise specified, all technical and scientific terms used herein have the ordinary meaning understood by those skilled in the art regarding the present invention, and in case of conflict, the definitions in this specification shall prevail.

[0020] The theories or mechanisms described and disclosed herein, whether right or wrong, should not in any way limit the scope of the invention, that is, the contents of the invention can be implemented without being limited by any particular theory or mechanism.

[0021] Unless otherwise specified, percentages refer to mass percentages and proportions refer to mass ratios in this article.

[0022] In this document, when describing embodiments or examples, it should be understood that it is not intended to limit the invention to those embodiments or examples. Rather, all alternatives, modifications, and equivalents of the methods and materials described herein are covered within the scope defined by the claims.

[0023] As used herein, “alkyl” refers to a straight-chain or branched monovalent saturated hydrocarbon group having a specified number of carbon atoms. Specifically, alkyl groups are those having 1 to 20 carbon atoms (“C1-C20 alkyl”), such as those having 6 to 20 carbon atoms (“C6-C20 alkyl”), and typically containing 8 to 18 carbon atoms (“C8-C18 alkyl”). Examples of alkyl groups include, but are not limited to, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, C11 alkyl, C12 alkyl, C13 alkyl, C14 alkyl, C15 alkyl, C16 alkyl, C17 alkyl, C18 alkyl, C19 alkyl, and C20 alkyl. As used herein, "alkoxy" refers to alkyl-O-, and preferably refers to C1-6 alkoxy, such as C1-4 alkoxy, which includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, etc.

[0024] As used herein, as part of a group or other group, the term "alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms and containing at least one double bond, which is linked by a single bond to the rest of the molecule. In some embodiments, the alkenyl group contains 6 to 20 carbon atoms ("C6-C20 alkenyl"), preferably 8 to 18 carbon atoms ("C8-C18 alkenyl"). Non-limiting examples of alkenyl groups include, but are not limited to, C6 alkenyl, C7 alkenyl, C8 alkenyl, C9 alkenyl, C10 alkenyl, C11 alkenyl, C12 alkenyl, C13 alkenyl, C14 alkenyl, C15 alkenyl, C16 alkenyl, C17 alkenyl, C18 alkenyl, C19 alkenyl, and C20 alkenyl. In some embodiments, the alkenyl group has 1, 2, 3, or 4 carbon-carbon double bonds.

[0025] As used herein, "halogenated" or "halogen" refers to elements in Group 17 with atomic numbers 9 to 85. "Halogen" or "halogen atom" refers to F, Cl, Br, and I. "Halogenated" means substituted by an atom selected from F, Cl, Br, and I.

[0026] As used herein, "amino" refers to -NH2. In this document, amino may be substituted with one or two alkyl groups.

[0027] In this article, the mycobacteria are selected from: Mycobacterium leprae, Mycobacterium tuberculosis complex, and nontuberculous mycobacteria.

[0028] In this article, the other antibacterial drugs mentioned are selected from one or more of the following: isoniazid (INH), rifampin (RIF), streptomycin (S), ethambutol (EMB), moxifloxacin (MXF), para-aminosalicylic acid (PAS), rifabutin (RFB), cycloserine (CYC), kanamycin (K), ofloxacin (OFL), pyrazinamide (PZA), ethionamide (ETH), and amikacin (AN).

[0029] In this document, the Mycobacterium tuberculosis complex is selected from: H37Rv strain and clinically isolated drug-resistant strains, wherein the clinically isolated drug-resistant strains are resistant to other antimicrobial agents. In some embodiments, the clinically isolated drug-resistant strain is 7R2 strain. In some embodiments, the clinically isolated drug-resistant strain is selected from one or more of SR, 7R, SZG, HMY, ZQY, HMF, and LXB. In some embodiments, SR is a strain resistant to S. In some embodiments, 7R is a strain resistant to one or more of INH, RIF, S, EMB, MXF, CYC, OFL, and PZA. In some embodiments, SZG is a strain resistant to one or more of INH, RIF, S, RFB, and CYC. In some embodiments, HMY is a strain resistant to one or more of INH, RIF, S, EMB, MXF, PAS, RFB, CYC, OFL, and PZA. In some embodiments, ZQY is a strain resistant to one or more of INH, RIF, S, EMB, MXF, RFB, K, OFL, AN, and PZA. In some embodiments, HMF is a strain resistant to one or more of INH, RIF, S, EMB, MXF, PAS, RFB, CYC, K, OFL, ETH, AN, and PZA. In some embodiments, LXB is a strain resistant to one or more of INH, RIF, S, EMB, MXF, PAS, RFB, CYC, K, OFL, ETH, AN, and PZA.

[0030] In this document, the nontuberculous mycobacteria include slow-growing and fast-growing nontuberculous mycobacteria. Preferably, the slow-growing nontuberculous mycobacteria are selected from one or more of Mycobacterium scrofula, Mycobacterium intracellularis, Mycobacterium Kansas, and Mycobacterium marineum. In some embodiments, the nontuberculous mycobacteria are selected from one or more of Mycobacterium scrofula and Mycobacterium intracellularis.

[0031] In this article, diseases caused by mycobacterial infection can be selected from tuberculosis (such as pulmonary tuberculosis), leprosy, nontuberculous mycobacterial diseases, etc.

[0032] In this document, "compounds with antimycobacterial activity" and "active ingredients" refer to compounds of formula I, II, III, IV, R2-COOH and / or R3-OH compounds, especially compound 1 (monoglycerate palmitate), compound 2 (7-ketocholesterol), and compound 3 (7β-hydroxycholesterol), with compound 1 being preferred.

[0033] In this article, "compounds with anti-mycobacterial activity" and / or "animal extracts" have specific antibacterial activity against Mycobacterium tuberculosis, meaning that while inhibiting mycobacteria, they have little effect on other related human flora (especially normal flora). Exemplary other related human flora may be selected from Bacillus subtilis, Staphylococcus aureus, Enterococcus faecalis, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, and Salmonella.

[0034] In vitro experiments show that the compounds of this invention have good antibacterial activity against mycobacteria and have development value in pharmaceutical and other related products. This invention attempts to isolate and obtain novel anti-tuberculosis active substances from geckos. This invention provides the use of compounds of formulas I, II, III, and IV, R2-COOH and R3-OH, their isomers, prodrugs, and pharmaceutically acceptable salts in the preparation of products (such as drugs) for the prevention and / or treatment of diseases caused by mycobacterial infections; or, the use of compounds of formulas I, II, III, and IV, R2-COOH or R3-OH, their isomers, prodrugs, and pharmaceutically acceptable salts in blocking the spread of mycobacteria; or, the use of compounds of formulas I, II, III, and IV, R2-COOH or R3-OH, their isomers, prodrugs, and pharmaceutically acceptable salts in in vitro inhibition (preferably selective inhibition) of mycobacteria:

[0035]

[0036] R1, R2 and R3 are each independently selected from substituted or unsubstituted C6-C20 alkyl, substituted or unsubstituted C6-C20 alkenyl and substituted or unsubstituted C6-C20 alkynyl groups;

[0037] R a and R c Each is independently selected from substituted or unsubstituted C1-C20 alkyl groups;

[0038] Unless otherwise specified, “substitution” means that one or more hydrogen atoms on a group are replaced by a substituent selected from the group consisting of halogens, amino groups, hydroxyl groups, and C1-C6 alkoxy groups.

[0039] In some embodiments, R1, R2, and R3 are each independently selected from substituted or unsubstituted C6-C20 alkyl and substituted or unsubstituted C6-C20 alkenyl groups; preferably, R1, R2, and R3 are each independently selected from substituted or unsubstituted C8-C18 alkyl and substituted or unsubstituted C8-C18 alkenyl groups. Preferably, R1, R2, and R3 are each independently selected from C8-C18 alkyl and C8-C18 alkenyl groups. Preferably, R1, R2, and R3 are each independently substituted with 0, 1, or 2 hydroxyl groups.

[0040] In some embodiments, the compound of formula III has the structure shown in formula IIIa: R b The C1-C20 alkyl group is substituted or unsubstituted. Unless otherwise specified, “substituted” means that one or more hydrogen atoms on the group are substituted by a substituent selected from the group consisting of halogens, amino groups, hydroxyl groups, and C1-C6 alkoxy groups.

[0041] In some embodiments, the compound of formula IV has the structure shown in formula IVa: R d The C1-C20 alkyl group is substituted or unsubstituted. Unless otherwise specified, “substituted” means that one or more hydrogen atoms on the group are substituted by a substituent selected from the group consisting of halogens, amino groups, hydroxyl groups, and C1-C6 alkoxy groups.

[0042] In some embodiments, compounds of formula I and formula II are selected from glyceryl monocaprylate, glyceryl monocaprylate, glyceryl monolaurate, glyceryl monomyristate, glyceryl monopalmitate (glyceryl α-monopalmitate), glyceryl β-monopalmitate, glyceryl monostearate, and glyceryl α-monotrans oleate. In some embodiments, compounds of formula I and formula II are selected from glyceryl monocaprylate, glyceryl monolaurate, glyceryl monomyristate, glyceryl monopalmitate, glyceryl β-monopalmitate, and glyceryl α-monotrans oleate. In some embodiments, compounds of formula I and formula II are selected from glyceryl monomyristate, glyceryl monocaprylate, glyceryl monolaurate, glyceryl monomyristate, and glyceryl α-monotrans oleate. Preferably, compounds of formula I and formula II are selected from glyceryl monomyristate, glyceryl monopalmitate, glyceryl β-monopalmitate, and glyceryl α-monotrans oleate. In some embodiments, compound I is glyceryl monopalmitate.

[0043] In some embodiments, the compounds of formula I, II, III and IV are selected from:

[0044]

[0045] Experiments have shown that compounds 1 (monoglycerate palmitate), 2 (7-ketocholesterol), and 3 (7β-hydroxycholesterol) have excellent anti-mycobacterial activity. Therefore, this invention provides the use of compounds 1, 2, and 3 in the preparation of medicaments for the prevention and / or treatment of diseases caused by mycobacterial infections.

[0046] In some embodiments, the R2-COOH is selected from nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid (lauric acid), tridecanoic acid, tetradecanoic acid (myristic acid), pentadecanoic acid, hexadecanoic acid (palmitic acid), heptadecanoic acid, 2-hexadecenoic acid, cis-9-hexadecenoic acid, 16-hydroxypalmitic acid, 2-hydroxypalmitic acid, and 3-hydroxypalmitic acid; preferably palmitic acid.

[0047] In some embodiments, R3-OH is palmitol.

[0048] The present invention also provides an animal extract comprising the compounds of the present invention having antimycobacterial activity. Preferably, the animal extract comprises one or more of compound 1, compound 2, and compound 3. In some embodiments, the animal is a gecko. Preferably, the gecko is (1) a fresh individual of a gecko; or (2) a medicinal gecko or a medicinal gnat. Preferably, the gecko is selected from one or more of the genera *Hemidactylus*, *Gehyra*, and *Gekko*. More preferably, the gecko is selected from one or more of the genera *Gekko swinhonis*, *Gekko japonicus*, *Hemidactylus aquilonius*, *Hemidactylus frenatus*, *Gehyra mutilata*, and *Gekko gecko*.

[0049] The present invention also provides a method for preparing the animal extract of the present invention, the method comprising the steps of preparing an extract from the animal using a first organic solvent and then extracting the extract using a second organic solvent. In some embodiments, the first organic solvent is ethanol. In some embodiments, the second organic solvent is selected from one or both of petroleum ether and ethyl acetate.

[0050] The present invention also provides the use of the animal extract in the preparation of products (such as pharmaceuticals) for the prevention and / or treatment of diseases caused by mycobacterial infections.

[0051] The antimycobacterial active compounds and animal extracts disclosed in this invention exhibit excellent antibacterial activity against mycobacteria. Some components of these antimycobacterial active compounds and animal extracts are derived from food-grade medicinal materials and include mono- and diglyceride fatty acid esters (such as palmitic acid monoglyceride) that are generally recognized as safe in food standards of various countries. These components demonstrate good biocompatibility and are suitable for human application, including oral administration.

[0052] Based on this, the present invention provides a pharmaceutical composition, an in vitro antibacterial agent, and / or a functional food containing the antimycobacterial active compound and / or animal extract of the present invention as active ingredients (the antimycobacterial active compound and animal extract are as defined in any embodiment herein). In some embodiments, the active ingredient is gecko powder, aqueous extract, and / or ethanol extract.

[0053] In some embodiments, the pharmaceutical composition, in vitro antibacterial agent, and / or functional food further comprises pharmaceutically acceptable excipients or auxiliary ingredients. These auxiliary ingredients possess certain physiological activity, but their addition does not alter the dominant role of the compound or derivative of the present invention in disease treatment; they merely exert their conventional auxiliary efficacy based on known activity. Such adjunctive uses of auxiliary ingredients in conjunction with the compound of the present invention remain within the scope of protection of this invention. In some embodiments, the pharmaceutical composition further comprises other antibacterial agents.

[0054] The pharmaceutical compositions, in vitro antibacterial agents, and / or functional foods of the present invention can be used to kill or inhibit the activity of mycobacteria as defined in any embodiment herein.

[0055] This invention provides a personal care product that specifically inhibits mycobacteria while having little or no inhibitory activity on other flora in animals (especially normal flora). The product comprises the anti-mycobacterial active compound of this invention and / or animal extracts (as defined in any embodiment herein), selected in some embodiments from chewing gum, toothpaste, skin care products, and mouthwash.

[0056] Based on the good antibacterial activity and biosafety of the antimycobacterial active compounds and animal extracts, the present invention provides a bactericidal composition comprising the aforementioned antimycobacterial active compounds and / or animal extracts (as defined in any embodiment herein). The bactericidal composition can be used as a long-lasting disinfectant for body surfaces and special locations, such as spraying onto the human body surface, the surface of objects in tuberculosis wards or patient residences. Compared to alcohol, it is less volatile and can exert its antibacterial effect for a longer period.

[0057] In some embodiments, the bactericidal composition is an anti-tuberculosis food additive or an anti-tuberculosis food additive, which can be used to prepare functional foods. Tuberculosis is a disease caused by Mycobacterium tuberculosis, such as pulmonary tuberculosis.

[0058] In some embodiments, the bactericidal composition of the present invention further includes adjuvants commonly used in bactericides.

[0059] In some embodiments, the bactericidal composition of the present invention further includes other antibacterial agents.

[0060] The bactericidal composition of the present invention is used to kill or inhibit the activity of mycobacteria, said mycobacteria as defined in any embodiment herein.

[0061] This invention provides the use of compounds of formula I, II, III, IV, R2-COOH, R3-OH and / or animal extracts in the preparation of pharmaceutical compositions, functional foods, personal care products and antibacterial compositions of this invention.

[0062] The pharmaceutical compositions, personal care products, functional foods, or bactericidal compositions of the present invention can be used to treat and / or prevent diseases caused by mycobacterial infections.

[0063] This invention provides a method for killing or inhibiting the activity of mycobacteria, the method comprising:

[0064] (1) Co-culturing mycobacteria with compounds of formula I, II, III, IV, R2-COOH, R3-OH, and / or animal extracts; or

[0065] (2) Applying compounds of formula I, II, III, IV, R2-COOH, R3-OH and / or animal extracts of the present invention to the body surface, oral cavity and external environment where mycobacterial inhibition is required.

[0066] (3) Apply an effective amount of compound of formula I, formula II, formula III, formula IV, R2-COOH, R3-OH and / or animal extract to the subject in need.

[0067] The present invention also provides a method for reducing the infectivity of mycobacteria and / or blocking the spread of mycobacteria, the method comprising the steps of:

[0068] Compounds of Formula I, II, III, IV, R2-COOH, R3-OH and / or animal extracts are applied to the human body surface and / or environment;

[0069] Alternatively, compounds of formula I, II, III, IV, R2-COOH, R3-OH, and / or animal extracts may be applied to the patient's oral cavity;

[0070] Alternatively, the personal care products described herein may be applied to the human body surface; or the patient may ingest the functional foods described herein (e.g., oral sprays, lozenges);

[0071] Alternatively, the bactericidal composition described herein may be applied to the surface of a human body (e.g., a patient) and / or the environment; the patient has a disease caused by mycobacterial infection.

[0072] Compounds of Formula I, II, III, IV, R2-COOH, R3-OH, and animal extracts are defined as described in any embodiment herein.

[0073] In some implementations, in method (2), the application is by spraying.

[0074] In some implementations, the application in method (3) can be by swallowing, holding in the mouth, chewing, applying, etc.

[0075] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0076] Example 1

[0077] This embodiment provides a method for extracting anti-mycobacterial active components from geckos. It should be noted that this embodiment is merely an example, and similar methods can be used to obtain the active components described in this invention. Details are as follows (see...). Figure 1 ):

[0078] 1. Extract

[0079] One kilogram of commercially available dried gecko individuals was ground into powder and extracted twice with 95 wt% ethanol under reflux at a material-to-liquid ratio of 1:10 (w / v), for 2 hours each time. The extract was filtered, and the filtrate was concentrated under reduced pressure at 40°C until no alcohol odor was detected, yielding a crude extract (256 g, named SH).

[0080] 2. Extraction

[0081] The crude extract (SH) was suspended in water and extracted three times sequentially with equal volumes of petroleum ether, ethyl acetate, and n-butanol. The extracts and the remaining aqueous phase were concentrated under reduced pressure at 40°C to obtain a petroleum ether layer (SH-PE 169.6 g), an ethyl acetate layer (SH-EA 42.3 g), a n-butanol layer (20.6 g), and an aqueous layer (29.9 g). Antibacterial activity against Mycobacterium tuberculosis was tested (referring to the method in Example 3), showing that the SH-PE and SH-EA layers exhibited better antibacterial activity.

[0082] 3. Separation and purification

[0083] The SH-PE and SH-EA layers were combined and named SH-PA (211.9 g). Separation was performed by normal-phase flash chromatography using a gradient elution system of petroleum ether-ethyl acetate (100:0–0:100). Fractions were collected in 500 mL bottles. Based on LCMS analysis results, similar fractions were combined, ultimately yielding seven fractions (SH-PE-1, SH-PE-3, SH-PE-8, SH-PE-12, SH-PE-14, SH-PE-15, and SH-PE-17). The LCMS chromatograms of each fraction are shown below. Figure 16 As shown in the figure. Antibacterial assays for Mycobacterium tuberculosis showed that SH-PE-8, SH-PE-12, SH-PE-14, and SH-PE-15 exhibited good activity.

[0084] Samples SH-PE-8 and SH-PE-12 were combined and named SH-PE-8 (64.9 g). They were separated by reversed-phase Flash chromatography using a gradient elution system of water and acetonitrile. Fractions were collected, and similar fractions were combined based on LCMS analysis results to obtain five fractions (SH-PE-8F6, SH-PE-8F9, SH-PE-8F11, SH-PE-8F14, and SH-PE-8F22). The LCMS chromatograms of each fraction are shown below. Figure 17 As shown. Sample SH-PE-14 (689.9 mg) was separated by reversed-phase Pre-HPLC using a gradient elution system of water-acetonitrile. Fractions were collected, and similar fractions were combined based on LCMS analysis results to obtain two fractions (SH-PE-14P5 and SH-PE-14P7). The LCMS chromatograms are shown below. Figure 18 As shown. Sample SH-PE-15 (2.17 g) was separated by reversed-phase Pre-HPLC using a gradient elution system of water-acetonitrile. Fractions were collected, and similar fractions were combined based on LCMS analysis results to obtain four fractions (SH-PE-15P2, SH-PE-15P4, SH-PE-15P6, and SH-PE-15P7). The LCMS chromatograms of each fraction are shown below. Figure 20 As shown in the figure. Antibacterial assays showed that SH-PE-15P6 and SH-PE-15P7 exhibited good activity.

[0085] Sample SH-PE-15P6 (980 mg) was separated by Semi-Pre-HPLC (C18 column) to obtain fractions SH-PE-15P6P2 (488 mg) and SH-PE-15P6P3 (320 mg); the two fractions were further purified by Semi-Pre-HPLC (5-fluorophenyl column) to obtain compounds SH-PE-15P6P2P1 (228 mg, purity: 99.20%) and SH-PE-15P6P3P3 (28 mg, purity: 94.04%), respectively. LCMS chromatograms are shown below. Figure 19As shown. The fraction SH-PE-15P7 (180 mg) was separated by Pre-HPLC to obtain compound SH-PE-15P7P16 (40 mg, purity: 100%) and fraction SH-PE-15P7H. The LCMS chromatograms are shown below. Figure 19 As shown. Fraction SH-PE-15P7H (68 mg) was separated by Pre-HPLC to obtain fractions SH-PE-15P7HP12 (4.5 mg) and SH-PE-15P7H-H (25.8 mg). Antibacterial assays showed that SH-PE-15P6P3P3 and SH-PE-15P7HP12 exhibited good antibacterial activity.

[0086] Example 2, Structural Analysis

[0087] (1) Compound 1

[0088] Compound 1 (SH-PE-15P6P3P3) is a white powder. ESI-MS (m / z) shows [M+Na]. + :353 and [M+H] + 331, meaning the molecular weight of this compound is 330. See also: Figure 2 .

[0089] See Figure 3-4 , 1 The 1H NMR (CDCl3, 400 Hz) spectrum shows five proton signals at δH 4.20 (2H), 3.95 (1H), and 3.65 (2H). 13 The CNMR (CDCl3, 400 Hz) spectrum showed three carbon-2 hydroxyl signals: δC 70.26, δC 65.13 and δC 63.30, indicating that the compound contains a glycerol structural fragment; δH 0.89 (3H) and 1.26 (24H), indicating that the compound contains an aliphatic chain fragment.

[0090] DEPT spectrum Figure 5 The HMBC spectrum shows one CH3 carbon signal, one CH carbon signal, and multiple CH2 carbon signals, indicating that the compound contains an aliphatic chain fragment. Figure 6 In the figure, the correlation between δH4.20(2H) and δC174.36 suggests that the hydroxyl group at the 1-position of glycerol is linked to a fatty acid to form a glycerol ester.

[0091] Figure 1-6The NMR data of compound 1 shown are basically consistent with those reported in the literature (Journal of Agricultural and Food Chemistry, 2020, 68(38):10361-10373.), therefore, this compound is identified as palmitic acid monoglyceride (abbreviated as 1-MP, CAS: 542-44-9). Compared with commercially available palmitic acid monoglyceride compounds, the LCMS, 1 HNMR and 13 The CNMR spectra were consistent, and antibacterial experiments confirmed that the purchased palmitic acid monoglyceride compound also had similar antibacterial activity and concentration against Mycobacterium tuberculosis.

[0092] (2) Analysis of compound 2,3,3-2

[0093] The fraction SH-PE-15P7HP12 is a pale yellow solid, and its LCMS and 1 HNMR results showed that it was a mixture of multiple compounds, according to LCMS, 1 H-NMR and 13 Based on C-NMR data and literature, three compounds were identified.

[0094] Compound 2

[0095] Compound 2 was observed as [M+H] in ESI-MS (m / z). + :401, meaning the molecular weight of this compound is 400, see Figure 7 .

[0096] 1 In the HNMR (CDCl3, 400 Hz) spectrum, δ H 5.70 (1H, m) is the olefin proton signal, δ H 3.68 (1H, m) is the signal of the hydrogen ion bond proton, δ H [1.21(3H, s), 0.92(3H, d, J = 6.4 Hz), 0.87(3H, d, J = 6.8 Hz), 0.86(3H, d, J = 6.8 Hz), 0.67(3H, s)] represents the signal of five angular methyl protons, suggesting the compound is a steroid. See [link to article]. Figure 8 .

[0097] 13 In the CNMR (CDCl3, 400 Hz) spectrum, δ C 202.3 is the signal of the ketone carbonyl carbon, δ C [165.0, 126.1] is the olefin signal, δ C 70.4 is the carbon sulfide signal, δ C[22.8, 22.7, 19.2, 17.3, 12.0] represents the signals of five angular methyl carbons, δ C [54.8,49.9,45.4,43.1,41.8,39.5,38.7,36.4,36.3,35.7,31.2,29.7(2),28.5,28.0,26.4,23.8,21.2] are carbon signals at other locations; see [link to relevant documentation]. Figure 9 .

[0098] The above NMR data are basically consistent with those reported in the literature [Chemistry-An Asian Journal, 2018, 13(17): 2369-2372.], therefore the compound was identified as 7-Oxocholesterol (OCS, CAS: 566-28-9). Compared with commercially available 7-ketocholesterol compounds, the LCMS and NMR data showed good correlation. 1 HNMR and 13 The CNMR spectra were consistent, and antibacterial experiments confirmed that the purchased 7-ketocholesterol compound had similar antibacterial activity and concentration.

[0099] Compound 3

[0100] Compound 3 was observed as [M+Na] in ESI-MS (m / z). + 425, [M+H-H2O] + : 385 and [M+H-2H2O] + 367, meaning the molecular weight of this compound is 402. See [link / reference]. Figure 10 .

[0101] 1 In the HNMR (CDCl3, 400 Hz) spectrum, δ H 5.30 (1H, br.s) is the olefin proton signal, δ H [3.87(1H,br.s),3.51(1H,m)] represents the signals of two protons bonded to oxygen atoms, δ H [1.06(3H,s), 0.92(3H,d,J=6.4Hz), 0.87(3H,d,J=6.8Hz), 0.86(3H,d,J=6.8Hz), 0.69(3H,s)] represents the signal of five angular methyl protons, suggesting the compound is a steroid. See [link to article]. Figure 11 .

[0102] 13 In the CNMR (CDCl3, 400 Hz) spectrum, δ C [143.4, 125.4] is the olefin signal, δ C [73.3, 71.4] are two oxygen-carbon signals, δC [22.8, 22.5, 19.2, 18.8, 11.8] represents the signals of five angular methyl carbons, δ C [55.9,55.5,48.3,42.9,41.7,41.0,39.6,39.5,36.9,36.4,36.2,35.7,31.6,28.5,28.0,26.3,23.8,21.1] represents carbon signals at other locations; see [link to relevant documentation]. Figure 12 .

[0103] The above NMR data are basically consistent with those reported in the literature [Letters in Organic Chemistry, 2015, 12(10):708-712.], therefore the compound was identified as 7β-hydroxycholesterol (Cholest-5-en-3β,7β-diol, abbreviated as BCS, CAS: 566-27-8). Compared with commercially available 7β-hydroxycholesterol compounds, the LCMS and NMR data showed good correlation. 1 HNMR and 13 The CNMR spectra were consistent, and antibacterial experiments confirmed that the purchased 7β-hydroxycholesterol compound had similar antibacterial activity and concentration.

[0104] Compound 3-2

[0105] Compound 3-2 was observed as [M+Na] in ESI-MS (m / z). + 425, [M+H-H2O] + : 385 and [M+H-2H2O] + 367, meaning the molecular weight of this compound is 402. See [link / reference]. Figure 13 .

[0106] 1 In the HNMR (CDCl3, 400 Hz) spectrum, δ H 5.61 (1H, dd, J = 2.0, 5.2 Hz) is the olefin proton signal, δH [3.87 (1H, br.s), 3.57 (1H, m)] is the signal of two oxygen-bonded protons, δ H [1.00(3H,s), 0.92(3H,d,J=6.4Hz), 0.87(3H,d,J=6.8Hz), 0.86(3H,d,J=6.8Hz), 0.70(3H,s)] represents the signal of five angular methyl protons, suggesting the compound is a steroid. See [link to article]. Figure 14 .

[0107] 13 In the CNMR (CDCl3, 400 Hz) spectrum, δ C [146.2, 123.9] is the olefin signal, δ C[71.3, 65.4] represents two oxygen-carbon signals, δ C [22.8, 22.7, 18.7, 18.2, 11.6] represents the signals of five angular methyl carbons, δ C [55.8,49.4,42.2,42.1,42.0,39.6,39.2,37.5,37.4,37.1,36.2,35.8,31.4,28.3,27.9,24.3,23.7,21.0] represents carbon signals at other locations; see [link to relevant documentation]. Figure 15 .

[0108] The above NMR data are basically consistent with those reported in the literature [European Journal of Medicinal Chemistry, 2013, 70: 558-567.], therefore, this compound was identified as 7α-hydroxycholesterol (ACS, CAS: 566-26-7), which is a diastereomer of the aforementioned compound 3 (7β-hydroxycholesterol). Compared with commercially available 7α-hydroxycholesterol compounds, the LCMS and... 1 HNMR and 13 The CNMR spectra were consistent, and the antibacterial experiment showed that neither the purchased 7α-hydroxycholesterol nor compound 3-2 had antibacterial activity against Mycobacterium tuberculosis.

[0109] Example 3: Determination of the anti-tuberculosis activity of extracts and compounds

[0110] All compounds were dissolved in DMSOE (DMSO:ethanol, 10:1) to prepare the test solution.

[0111] A Mycobacterium tuberculosis H37Rv bacterial suspension with a McFarland concentration of 1 was prepared by diluting with physiological saline. This suspension was then diluted 50-fold with 7H10 (containing OADC) liquid medium, and 200 μL was added to 7 mL of culture medium as a 2× test suspension. When using the suspension, 100 μL was added to an equal volume of culture medium.

[0112] The resalicylate microplate assay (REMA) was used to determine the minimum inhibitory concentration (MIC) of various extracts and isolated components against Mycobacterium tuberculosis H37Rv. The culture medium was 7H9 liquid medium supplemented with OADC. After the extracts and compounds were added to the first column of wells in a 96-well plate, subsequent wells were serially diluted two-fold. Negative control wells containing only culture medium and positive control wells (indicator wells) containing only bacterial culture (without extract) were included. After 2 weeks of incubation, 32.5 μL of resalicylate indicator (20 μL of 0.015 wt% resalicylate and 12.5 μL of 20% Tween 80) was added to one indicator well. If the indicator did not turn pink within 3 days, the indicator was added to another well until it changed from blue to pink. This process was repeated for all wells, and results were recorded within 3 days. All samples were tested in triplicate. The minimum inhibitory concentration (MIC) was defined as the lowest concentration that prevented resalicylate from turning from blue to pink. For the sake of rigor, experiments have verified that the solvent DMSOE has no antibacterial activity against mycobacteria and does not affect the antibacterial test. The experimental results are shown in Table 1.

[0113] Table 1: Anti-tuberculosis (H37Rv) activity of various compounds

[0114]

[0115]

[0116] The experimental results show that, among the four isolated compounds, three compounds other than ACS—1-MP, OCS, and BCS—all exhibited good antibacterial activity.

[0117] To further identify the antibacterial activities of ACS, 1-MP, OCS, and BCS against drug-resistant strains, a clinical isolate, 7R2, which exhibited resistance to twelve commonly used anti-tuberculosis drugs, including isoniazid (0.2 μg / mL), rifampin (1 μg / mL), streptomycin (2 μg / mL), ethambutol (5 μg / mL), moxifloxacin (0.5 μg / mL), para-aminosalicylic acid (2 μg / mL), rifabutin (0.5 μg / mL), cycloserine (25 μg / mL), kanamycin (5 μg / mL), ofloxacin (2 μg / mL), ethionamide (5 μg / mL), and amikacin (4 μg / mL), was selected. The antibacterial effects of the four isolated compounds on strain 7R2 were determined, and the results are shown in Table 2.

[0118] Table 2: Antibacterial activity of compounds against extensively drug-resistant strain 7R2

[0119] NO. Compound MIC μg / mL 1 1-MP 31 2 OCS 63 3 BCS 16 4 ACS >250

[0120] 1-MP, OCS, and BCS all exhibit good antibacterial activity against the widely drug-resistant strain 7R2, and have the potential value as drug precursors for further development into new anti-tuberculosis drugs.

[0121] Example 4: Antibacterial activity of 1-MP against different drug-resistant strains in clinical practice

[0122] This invention determined the antibacterial activity of palmitic acid monoglyceride against various clinically resistant strains of Mycobacterium tuberculosis. The resistance of each strain is shown in Table 3. The antibacterial activity was tested according to the method described in Example 3, and the results are shown in Table 3.

[0123] Table 3: Antibacterial activity of palmitic acid monoglyceride against various clinically resistant bacterial strains

[0124]

[0125] In Table 3, INH isoniazid, RIF rifampin, S streptomycin, EMB ethambutol, MXF moxifloxacin, PAS para-aminosalicylic acid, RFB rifabutin, CYC cyclic serine, K kanamycin, OFL ofloxacin, ETH ethionamide, AN amikacin, and PZA pyrazinamide are listed. Seq indicates that the pyrazinamide resistance activity was verified by sequencing (pncA and rpsA genes). R indicates resistance, * indicates multidrug-resistant strains, and ** indicates extensively drug-resistant strains.

[0126] Glyceryl palmitate showed good antibacterial activity against all tested clinically resistant strains, including single-drug resistant, multi-drug resistant, and extensively drug-resistant strains. Two of the clinically resistant strains were antagonistic to 13 commonly used antibiotics, but both were inhibited by glyceryl palmitate.

[0127] Example 5: Antibacterial activity against nontuberculous mycobacteria

[0128] Palmitate monoglyceride was dissolved in DMSOE (DMSO:ethanol, 10:1) to prepare the test solution.

[0129] Prepare McFarland concentration (1) bacterial suspensions of various nontuberculous mycobacteria using physiological saline. Dilute each suspension 50-fold with the corresponding culture medium for each strain (see Table 4). Take 200 μL of each suspension and add it to 7 mL of the corresponding culture medium to prepare a 2× test suspension. When using the suspension, take 100 μL and add it to an equal volume of culture medium.

[0130] Following the method described in Example 3, the minimum inhibitory concentration (MIC) of palmitic acid monoglyceride against each bacterial strain was determined. Based on the growth rate of the strains, after a certain period of culture, color development was performed and recorded according to the method described in Example 3. The results are shown in Table 4.

[0131] Table 4: Antibacterial activity of palmitic acid monoglyceride against nontuberculous mycobacteria

[0132] Test bacteria Number or source Classification culture medium MIC (μg / mL) Mycobacterium scrofula ATCC 19981 slow growing type CAMHB+5% OADC 7.8 Intracellular mycobacteria ATCC 13950 slow growing type CAMHB+5% OADC 2 Mycobacterium Kansas ATCC 12478 slow growing type CAMHB+5% OADC 125 Mycobacterium marineum ATCC 927 slow growing type CAMHB+5% OADC 250 Mycobacterium smegmatis ATCC 19420 fast-growing type CAMHB >500 Mycobacterium tectorum ATCC 14472 fast-growing type CAMHB >500 Mycobacterium abscessus Clinical separation fast-growing type CAMHB >500 Occasional Mycobacteria ATCC 6841 fast-growing type CAMHB >500 Foreign mycobacteria ATCC 700686 fast-growing type CAMHB >500

[0133] Experiments showed that, within the tested concentration range (500 μg / mL), palmitic acid monoglyceride had no antibacterial activity against fast-growing mycobacteria such as smegma, balanitis, abscesses, sporadic mycobacteria, and exogenous mycobacteria. However, it exhibited some antibacterial activity against slow-growing mycobacteria, with better antibacterial activity against scrofula and intracellular mycobacteria, even superior to that against Mycobacterium tuberculosis.

[0134] Example 6: Antibacterial activity against other bacteria

[0135] Palmitate monoglyceride was dissolved in DMSOE (DMSO:ethanol, 10:1) to prepare the test solution.

[0136] Prepare McFarland concentration 1 bacterial suspensions by diluting with physiological saline. Dilute 50-fold with CAMBH medium, and take 200 μL to add to 7 mL of the corresponding culture medium as 2× test bacterial suspension for later use. When using, take 100 μL and add to an equal volume of culture medium.

[0137] Following the method described in Example 3, the minimum inhibitory concentration (MIC) of palmitic acid monoglyceride against each bacterial strain was determined. These bacteria grow rapidly, and 32.5 μL of resazurin indicator was added to one of the indicator wells during culturing. The color was then developed and recorded according to the method described in Example 3. The experimental results are shown in Table 5.

[0138] Table 5: Antibacterial activity of palmitic acid monoglyceride against other bacteria

[0139]

[0140]

[0141] Test results showed that glyceryl palmitate exhibited significant specificity in its antibacterial activity against each tested strain, as detailed below:

[0142] Against Staphylococcus epidermidis, glycerol palmitate showed only a weak inhibitory effect, with a minimum inhibitory concentration (MIC) of 500 μg / ml, which is about 10 times that against Mycobacterium tuberculosis. For the other tested strains, regardless of whether they were Gram-positive or Gram-negative, glycerol palmitate did not show any inhibitory activity, which fully demonstrates its specificity against mycobacteria.

[0143] The strains selected for this test are all common bacteria that humans are easily exposed to in daily life, covering two major categories: Gram-positive bacteria and Gram-negative bacteria. They also include many strains that are closely related to human health: (1) normal human intestinal flora, including Escherichia coli and Enterococcus faecalis; (2) normal human skin flora, including Staphylococcus aureus and Staphylococcus epidermidis; (3) Bacillus subtilis, which is widely distributed in soil and on the surface of plants and may temporarily colonize the human intestine; (4) Salmonella, a pathogenic bacterium that can cause diarrhea symptoms in humans; and (5) Pseudomonas aeruginosa, a typical opportunistic pathogen.

[0144] In summary, the test results above indicate that during the application of palmitic acid monoglyceride to inhibit mycobacteria, its impact on other flora (including normal flora, opportunistic pathogens, and specific pathogens) that humans come into daily contact with is minimal. It can effectively reduce the health risks that may be caused by changes in flora structure, providing safety support for its subsequent application.

[0145] Example 7: Antibacterial activity of palmitic acid monoglyceride analogs and isomers

[0146] Referring to the detection method in Example 3, this application tested the anti-tuberculosis (H37Rv) activity of palmitate monoglyceride analogs. Each compound was prepared into a working solution concentration using a suitable solvent, and the test results are shown in Table 6.

[0147] Tests showed that glycerides with fatty acid carbon chain lengths ranging from 8 to 18 all exhibited certain anti-tuberculosis activity. The MIC values ​​of glyceryl monodecanoate (compound 4, hereinafter the same), glyceryl monolaurate (compound 5), glyceryl monomyristate (compound 6), and α-monotransoleic glyceryl (compound 7) were no greater than 125 μg / mL, while glyceryl trimalatate and glycerol showed no antibacterial activity. Glyceryl palmitate exhibited the best antibacterial activity, with a MIC value of 31 μg / mL. Its isomer, β-monopalmitate glycerol, also possessed antibacterial activity (MIC 62.5 μg / mL).

[0148] Table 6: Antibacterial activity of palmitate monoglyceride analogs and isomers against H37Rv

[0149]

[0150]

[0151] The antibacterial activity of palmitic acid structural analogs and their derivatives against Mycobacterium tuberculosis was further tested (see Table 7, all solvents were DMSOE, and the detection method was the same as in Example 3). Fatty acids with carbon chain lengths of 9-17 showed certain antibacterial activity (MIC < 500 μg / mL), and most palmitic acid-related fatty acids and palmitol showed good antibacterial activity (MIC = 125 μg / mL). Non-fatty acid derivatives showed poor antibacterial effect (MIC > 500 μg / mL).

[0152] Table 7: Antibacterial activity of palmitic acid structural analogs and derivatives against H37Rv

[0153] reagents CAS Fatty acid carbon chain length and unsaturated bonds MIC Sour 124-07-2 C8:0 500 nonanoic acid 112-05-0 C9:0 250 Decanoic acid 334-48-5 C10:0 250 Undecanoic acid 112-37-8 C11:0 125 Lauryl acid (lauric acid) 143-07-7 C12:0 125 Tridecanoic acid 638-53-9 C13:0 250 Myristic acid (Tetradecanoic acid) 544-63-8 C14:0 125 Five-fifteen acid 1002-84-2 C15:0 125 Palmitic acid (hexadecanoic acid) 57-10-3 C16:0 125 heptadecanoic acid 506-12-7 C17:0 250 Stearic acid (octadecanoic acid) 57-11-4 C18:0 1000 Nineteen acid 646-30-0 C19:0 1000 Arachia acid (arachidic acid) 506-30-9 C20:0 1000 Twenty-one acid 2363-71-5 C21:0 >1000 2-Hexadecenoic acid 629-56-1 C16:1 125 cis-9-hexadecenoic acid 373-49-9 C16:1 125 16-Hydroxypalmitic acid 506-13-8 C16:0 125 2-Hydroxypalmitic acid 764-67-0 C16:0 250 3-Hydroxypalmitic acid 2398-34-7 C16:0 125 9,10,16-Trihydroxypalmitic acid 533-87-9 C16:0 >500 Palmitoyl aniline 6832-98-0 C16:0 >1000 Palmitoylethanolamine 544-31-0 C16:0 500 Palmitamide 629-54-9 C16:0 >1000 Methyl palmitate 112-39-0 C16:0 >1000 palmitic acid hexadecyl 540-10-3 C16:0 >1000 Cholesterol palmitate 601-34-3 C16:0 >1000 Palmitol 36653-82-4 C16:0 125 hexadecaldehyde 629-80-1 C16:0 >1000

Claims

1. The use of compounds of formula I, II, III, IV, R2-COOH or R3-OH, their isomers, prodrugs and pharmaceutically acceptable salts in the preparation of medicaments for the treatment and / or prevention of diseases caused by mycobacterial infections; Alternatively, the use of compounds of formula I, II, III, IV, R2-COOH or R3-OH, their isomers, prodrugs and pharmaceutically acceptable salts in blocking the spread of mycobacteria; Alternatively, the use of compounds of formula I, II, III, and IV, R2-COOH or R3-OH, their isomers, prodrugs, and pharmaceutically acceptable salts in the in vitro inhibition of mycobacteria: R1, R2 and R3 are each independently selected from substituted or unsubstituted C6-C20 alkyl, substituted or unsubstituted C6-C20 alkenyl and substituted or unsubstituted C6-C20 alkynyl groups; R a and R c Each is independently selected from substituted or unsubstituted C1-C20 alkyl groups; Unless otherwise specified, "substitution" means that one or more hydrogen atoms on a group are replaced by a substituent selected from the group consisting of halogens, amino groups, hydroxyl groups, and C1-C6 alkoxy groups.

2. The application as described in claim 1, characterized in that, R1, R2 and R3 are each independently selected from substituted or unsubstituted C6-C20 alkyl and substituted or unsubstituted C6-C20 alkenyl groups.

3. The application as described in claim 1, characterized in that, The compound of formula III has the structure shown in formula IIIa: R b The compounds are substituted or unsubstituted C1-C20 alkyl groups; and / or, the compounds of formula IV have the structure shown in formula IVa: R d The substituted or unsubstituted C1-C20 alkyl group; unless otherwise specified, "substituted" means that one or more hydrogen atoms on the group are substituted by a substituent selected from the group consisting of halogens, amino groups, hydroxyl groups and C1-C6 alkoxy groups.

4. The application as described in claim 1, characterized in that, Compounds of Formula I and Formula II are selected from: glyceryl monocaprylate, glyceryl monodecanoate, glyceryl monolaurate, glyceryl monomyristate, glyceryl monopalmitate, glyceryl monostearate, and glyceryl monotransoleate.

5. The application as described in claim 1, characterized in that: The compounds of formulas I, II, III and IV are selected from: The R2-COOH is palmitic acid; The R3-OH is palmitol.

6. The application as described in any one of claims 1, characterized in that, The mycobacteria are selected from: Mycobacterium leprae, Mycobacterium tuberculosis complex, and non-tuberculous mycobacteria; preferably, the Mycobacterium tuberculosis complex is selected from: H37Rv strain and clinically isolated drug-resistant strain; preferably, the non-tuberculous mycobacteria are selected from Mycobacterium scrofula, intracellular mycobacteria, Mycobacterium kansas, and Mycobacterium marinum.

7. An animal extract comprising any one of the formulas I, II, III, and IV, R2-COOH, and R3-OH as claimed in any one of claims 1-6.

8. The animal extract as described in claim 7, characterized in that, The animal is a gecko; and / or, the animal extract is used to prepare a medicine for treating and / or preventing diseases caused by mycobacterial infection.

9. The method for preparing the animal extract according to claim 7 or 8, characterized in that, The method includes the steps of preparing an extract from the animal using a first organic solvent and then extracting the extract using a second organic solvent.

10. A pharmaceutical composition, personal care product, functional food, or sterilization composition, characterized in that, The pharmaceutical compositions, personal care products, functional foods, and antibacterial compositions comprise compounds of formula I, II, III, IV, R2-COOH, R3-OH, and / or the animal extracts of claim 7 or 8, as described in any one of claims 1-6; and / or, the pharmaceutical compositions, personal care products, functional foods, or antibacterial compositions are used to treat and / or prevent diseases caused by mycobacterial infections.

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