CN113318107B - Application of nitrogen-containing compound in preparation of antifungal medicine - Google Patents
Application of nitrogen-containing compound in preparation of antifungal medicine Download PDFInfo
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- CN113318107B CN113318107B CN202110774019.1A CN202110774019A CN113318107B CN 113318107 B CN113318107 B CN 113318107B CN 202110774019 A CN202110774019 A CN 202110774019A CN 113318107 B CN113318107 B CN 113318107B
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- candida albicans
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a new application of a nitrogen-containing compound shown in a formula I. The new application is the preparation of the compound shown in the formula I or the pharmaceutically acceptable salt thereofApplication in products for resisting fungi, especially Candida albicans infection. According to the invention, the compound shown in the formula I is subjected to anti-Candida albicans activity determination by a microplate double dilution method, and the result shows that the compound shown in the formula I has better bacteriostatic activity on Candida albicans, and is expected to develop a new medicine for treating Candida albicans infection.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to an application of a nitrogen-containing compound in preparation of an antifungal medicine.
Background
Along with the spread of chronic diseases such as hypertension, hyperlipidemia, diabetes and the like, the increase of the number of patients suffering from cancer radiotherapy, chemotherapy and organ transplantation, the wide use of immunosuppressive agents, the decrease of the immunocompetence of human bodies caused by the global epidemic of AIDS and the like, and the incidence rate of fungal infection is obviously increased. Currently, clinically used antifungal drugs mainly include polyenes (polyenes), allylamines (allylamines), flucytosines (flucytosines), and the like, but the drug resistance of pathogenic fungi is increasingly serious, and the required dosage has to be gradually increased, so that the research and development of new drugs for treating fungal infection diseases are imperative.
Candida is the most common pathogenic bacterium of fungi, and is also called candida. It often parasitizes on skin, oral cavity, vagina and intestinal mucosa of human, and is liable to cause candida infectious diseases when the immune function of organism is low or the micro-ecological environment of normal parasitizing part is disordered. Clinically common Candida species include Candida albicans (Candida albicans), Candida glabrata, and Candida guilliermondii. Among them, candida albicans is a pathogenic fungus widely spread in human, often causing acute, subacute or chronic infection, and is one of the most important pathogens of hospital acquired infection at present. It has been found that candida albicans does not normally cause diseases on mucosal surfaces of healthy persons, such as oral cavity, intestinal tract, etc., but causes serious systemic infection in patients with compromised or suppressed immune systems, such as chemotherapy patients, organ transplant patients or aids patients, with a mortality rate of up to 40%.
Therefore, the development of a novel safe and effective anti-candida albicans infection drug has important practical significance.
Disclosure of Invention
An object of the present invention is to provide a novel use of a nitrogen-containing compound or a pharmaceutically acceptable salt thereof.
The CAS No.314284-92-9 of the benzene sulfonamide compound has a structural formula shown in a formula I:
the novel application of the nitrogen-containing compound shown in the formula I or the pharmaceutically acceptable salt thereof provided by the invention is at least one of the following 1) -7):
1) the application in preparing fungus bacteriostat;
2) the use in the preparation of a product for inhibiting fungal activity;
3) the application in preparing products for resisting fungal infection;
4) the application in preparing products for preventing and/or treating diseases caused by fungal infection;
5) use in inhibiting fungal activity;
6) use against fungal infections;
7) the application in preventing and/or treating diseases caused by fungal infection.
Another object of the present invention is to provide a fungal bacteriostatic agent.
The active ingredient of the fungus bacteriostatic agent provided by the invention is a nitrogen-containing compound shown in a formula I or a pharmaceutically acceptable salt thereof.
It is yet another object of the present invention to provide a product.
The active ingredient of the product provided by the invention is a nitrogen-containing compound shown in a formula I or a pharmaceutically acceptable salt thereof;
the product has at least one of the following effects:
a) inhibiting fungal activity;
b) resisting fungal infection;
c) preventing and/or treating diseases caused by fungi.
The product of the invention can be specifically a drug.
When necessary, one or more pharmaceutically acceptable carriers can be added into the medicine; the carrier includes diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc. which are conventional in the pharmaceutical field.
The above medicine can be made into various forms such as injection, tablet, powder, granule, capsule, oral liquid, paste, cream, etc.; the medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
The above medicine can be introduced into body such as muscle, intradermal, subcutaneous, intravenous, mucosa tissue by injection, spray, nose drop, eye drop, penetration, absorption, physical or chemical mediated method; or mixed or coated with other substances and introduced into body.
The invention also provides a method for inhibiting the activity of fungi.
The method for inhibiting the activity of the fungi comprises the following steps: a substance containing a nitrogen-containing compound represented by the formula I or a pharmaceutically acceptable salt thereof as an active ingredient is used for inhibiting fungal activity.
The minimum use concentration of the nitrogen-containing compound shown in the formula I or the pharmaceutically acceptable salt thereof as the substance of which the active ingredient is the nitrogen-containing compound shown in the formula I or the pharmaceutically acceptable salt thereof is not lower than the Minimum Inhibitory Concentration (MIC) of fungi inhibited by the nitrogen-containing compound shown in the formula I or the pharmaceutically acceptable salt thereof.
The method is a non-disease diagnostic treatment method. For example, as a positive control in screening for drugs sensitive to fungi (e.g., Candida albicans).
In the invention, the fungus is specifically candida albicans. The Candida albicans includes Candida albicans sensitive strains (e.g., Candida albicans SC5314), and Candida albicans resistant strains (e.g., C.albicans 17#, C.albicans g 5).
According to the invention, the activity of the nitrogen-containing compound shown in the formula I against Candida albicans is determined by a microplate double dilution method, and the result shows that the nitrogen-containing compound shown in the formula I has good bacteriostatic activity on Candida albicans, and is expected to develop a new medicine for treating Candida albicans infection.
Detailed Description
The present invention will be further illustrated with reference to the following examples, but the present invention is not limited to the following examples. The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified. The quantitative tests in the following examples, all set up three replicates and the results averaged.
The benzenesulfonamides of formula I (CAS: 314284-92-9) used in the following examples: purchased from shanghai pottery biotechnology limited, cat #: f0007-1076.
Or prepared according to the method of the #1 compound in the patent US 2006/0025415A 1.
EXAMPLE 1 Activity of Compounds of formula I against Candida albicans
RPMI Media 1640: gibco, USA. Fluconazole, itraconazole and amphotericin B Sigma-Aldrich, USA.
1) Preparation of bacterial liquid
Sensitive strains of Candida albicans (Candida albicans SC5314), resistant strains of Candida albicans (C.albicans 17#, C.albicans g5) (Gong Jianao, Wu Ju, Ikeh Melanie, Tao Li, Zhang Yuleng, Bing Jian, Nobil Clarisa J., Huangg Guanghua. Antifungal 1 Activity of Mammali Serumal analog A1 against Candida albicans and Chemotherapy.64(1): e 75-19) were prepared by counting on a hemacytometer plate into (2-5) 10X 019195cell/mL of culture broth.
2) Preparation of test Compounds solutions of formula I
Compound I is prepared into 4mg/mL mother solution by using sterile DMSO as a solvent, and then diluted by the sterile DMSO sequentially to obtain diluted solutions with the concentrations of 2mg/mL, 1mg/mL, 500. mu.g/mL, 250. mu.g/mL, 125. mu.g/mL, 62.5. mu.g/mL, 31.25. mu.g/mL, 15.625. mu.g/mL, 7.81. mu.g/mL, 3.91. mu.g/mL, 1.95. mu.g/mL and 0.98. mu.g/mL.
The positive control drugs (fluconazole, itraconazole and amphotericin B) are sequentially prepared into mother liquor of 320 mu g/mL by taking sterile DMSO as a solvent, and then the mother liquor is sequentially diluted by the sterile DMSO to obtain diluents with the concentrations of 160 mu g/mL, 80 mu g/mL, 40 mu g/mL, 20 mu g/mL, 10 mu g/mL, 5 mu g/mL and 2.5 mu g/mL, and the diluents are used as the positive control drugs when the Candida albicans is detected.
3) Determining the minimum inhibitory concentration of the compound of formula I for inhibiting Candida albicans
a. A96-well cell culture plate was prepared and 40. mu.L of RPMI Media 1640 medium was added to each well.
b. Taking a 96-well cell culture plate which completes the step a, grouping and processing the 96-well cell culture plate as follows:
positive control group (7 wells): respectively adding 2 mu L of the 7-dilution positive control drug diluent prepared in the step 2);
experimental groups (7 wells per compound): adding 2 mu L of the compound diluent prepared in the step 2) respectively;
negative control group (7 wells): add 2. mu.L of sterile DMSO each.
c. Taking a 96-well cell culture plate which finishes the step b, adding 78 mu L of the bacterial liquid obtained in the step 1) into each well, culturing at 35 ℃ for 24 hours, and observing the growth condition of candida albicans in each well: if the wells are turbid, the corresponding concentrations of the compound are indicated to have no anti-Candida albicans activity; if the wells are clear, the corresponding concentrations of the compounds are indicated to have anti-Candida albicans activity. For each compound, the final concentration of the compound (compound solution concentration in the added diluent/40) corresponding to the well in which the growth of candida albicans is completely inhibited is the minimum inhibitory concentration, MIC value, of the compound against candida albicans. The results are shown in Table 1
TABLE 1 results of antifungal Activity assay of Compounds of formula I (MIC values, μ g/ml)
As can be seen from Table 1, the compounds represented by formula I provided by the invention have smaller MIC values, and show more excellent antifungal effects.
Claims (2)
1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof in at least one of:
1) the application in preparing fungus bacteriostat;
2) the use in the preparation of a product for inhibiting fungal activity;
3) the application in preparing products for resisting fungal infection;
4) the application in preparing products for preventing and/or treating diseases caused by fungal infection;
the fungus is candida albicans;
the product is a medicine.
2. A method of inhibiting fungal activity comprising the steps of: inhibiting a fungal activity using a substance containing a compound represented by the formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient;
the fungus is candida albicans;
the method is a non-disease diagnostic and therapeutic method.
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| CN202110774019.1A CN113318107B (en) | 2021-07-08 | 2021-07-08 | Application of nitrogen-containing compound in preparation of antifungal medicine |
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| CN202110774019.1A CN113318107B (en) | 2021-07-08 | 2021-07-08 | Application of nitrogen-containing compound in preparation of antifungal medicine |
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| CN113318107B true CN113318107B (en) | 2022-07-12 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US9211259B2 (en) * | 2002-11-29 | 2015-12-15 | Foamix Pharmaceuticals Ltd. | Antibiotic kit and composition and uses thereof |
| CN101643458A (en) * | 2003-08-08 | 2010-02-10 | 沃泰克斯药物股份有限公司 | Heteroarylaminosulfonylphenyl derivatives for use as sodium or calcium channel blockers in the treatment of pain |
| US20070203236A1 (en) * | 2006-01-11 | 2007-08-30 | Smith Jeffrey W | Novel antagonists of the human fatty acid synthase thioesterase |
| GB0815947D0 (en) * | 2008-09-02 | 2008-10-08 | Univ Dundee | Compounds |
| MX359921B (en) * | 2013-02-08 | 2018-10-16 | Luoda Pharma Pty Ltd | Methods of treating topical microbial infections. |
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