CN110063958A - Medical usage of the N- thiophene -2- hypoxanthine sulfenyl acetamide in Killing Mycobacterium Tuberculosis infection - Google Patents
Medical usage of the N- thiophene -2- hypoxanthine sulfenyl acetamide in Killing Mycobacterium Tuberculosis infection Download PDFInfo
- Publication number
- CN110063958A CN110063958A CN201910191636.1A CN201910191636A CN110063958A CN 110063958 A CN110063958 A CN 110063958A CN 201910191636 A CN201910191636 A CN 201910191636A CN 110063958 A CN110063958 A CN 110063958A
- Authority
- CN
- China
- Prior art keywords
- mycobacterium tuberculosis
- hypoxanthine
- thiophene
- drug
- tuberculosis infection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pulmonology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses N- thiophene -2- hypoxanthine sulfenyl acetamides (structural formula is as follows), it is inhibited to wild type and saltant type ribosomal protein S1 (RpsA), and then it is used to prepare Killing Mycobacterium Tuberculosis infection --- the especially purposes of the drug of the drug resistant mycobacterium tuberculosis infection of pyrazinamide.
Description
Technical field
The present invention relates to pharmaceutical fields, and in particular to N- thiophene substitution -2- hypoxanthine sulfenyl acetamide derivative is anti-
Medical usage in mycobacterium tuberculosis infection and the drug resistant mycobacterium tuberculosis infection of pyrazinamide.
Background technique
Related disease such as pulmonary tuberculosis, scrofula, intestinal tuberculosis caused by mycobacterium tuberculosis infects etc. is wide in Global prevalence
It is general.The first-line drug that pyrazinamide (PZA) is infected as Killing Mycobacterium Tuberculosis, with other first-line drugs such as ethambutol, benefit
Good fortune is flat, isoniazid combination when, can effectively shorten treatment cycle.But with the exacerbation of PZA resistance problems, people are for novel resistive connection
The pharmaceutical requirements of core mycobacterial infections are increasingly urgent.Science research achievement proposes that PZA is in vivo through pyrazine acyl within 2011
After amine enzyme (PZase) is hydrolyzed to pyrazine acid (POA), it is suppressed that the ribosomal protein S1 (RpsA) of mycobacterium tuberculosis, and then hinder
The trans- translation process for having stopped mycobacterium tuberculosis achievees the purpose that Killing Mycobacterium Tuberculosis infects.
In addition, RpsA can be used as Killing Mycobacterium Tuberculosis infection, especially anti-pyrazinamide Drug-Resistant Mycobacterium tuberculosis sense
The ideal targets of dye.On the one hand, according to clinical statistics as a result, in the drug resistant part M. tuberculosis strains of pyrazinamide,
No. 438 deletion of alanine mutation can occur for RpsA, and then POA can not inhibit RpsA and lose drug effect；On the other hand, tuberculosis branch
The RpsA of bacillus is very low with the albumen homology of people and other mammals, and inhibitor will have mycobacterium tuberculosis special
Property.
Fluorescence quenching titration is the common experimental for verifying protein ligand interaction.The spy that ligand and albumen occur
Different interaction, so that static quenching occurs for the amino acid for generating fluorescence in albumen.It is glimmering meanwhile under certain protein concentration
The degree of light static quenching depends on ligand concentration, and then according to Hill equation, the dissociation that can fit ligand and albumen is normal
Number.
Summary of the invention
The object of the present invention is to provide N- thiophene substitution -2- hypoxanthine sulfenyl acetamides in Killing Mycobacterium Tuberculosis
Medical usage in infection and the drug resistant mycobacterium tuberculosis infection of pyrazinamide.
Firstly, N- thiophene -2- hypoxanthine sulfenyl acetamide provided by the invention has the following structure:
Further, the N- thiophene substitution -2- hypoxanthine sulfenyl acetamide compound is in Killing Mycobacterium Tuberculosis sense
Novel medical use in dye is it by acting on wild type or saltant type RpsA, can be used for preparing Killing Mycobacterium Tuberculosis sense
Dye --- the especially drug of the drug resistant mycobacterium tuberculosis infection of pyrazinamide；
Further, Killing Mycobacterium Tuberculosis infection and the drug resistant mycobacterium tuberculosis infection of anti-pyrazinamide
Drug, before N- thiophene substitution -2- hypoxanthine sulfenyl acetamide compound or its pharmaceutically acceptable salt or its
The pharmaceutically acceptable salt and other pharmaceutically acceptable carriers of body drug or its pro-drug；
Further, Killing Mycobacterium Tuberculosis infection and the drug resistant mycobacterium tuberculosis infection of anti-pyrazinamide
Drug, dosage form are as follows: solid dosage forms, liquid dosage form, gas formulation and semisolid dosage form.
Further, Killing Mycobacterium Tuberculosis infection and the drug resistant mycobacterium tuberculosis infection of anti-pyrazinamide
Drug, the other pharmaceutically acceptable carriers contained refer to: diluent, excipient, adhesive, wetting agent, collapses filler
Solve agent, surfactant, sorbefacient, lubricant or absorption carrier.
Specific embodiment
Following non-limiting embodiments can make this field related personnel that the present invention be more fully understood, but not with any side
The formula limitation present invention.
Embodiment: by fluorescence quenching titration experimental fit compound and wild type RpsA [MtRpsA (285-476)] and
The dissociation constant of saltant type RpsA [MtRpsA (285-476) d438A], and further verified mutually by nuclear-magnetism titration experiments
Effect.
Main agents: MtRpsA (285-476), MtRpsA (285-476) d438A,15The MtRpsA (285-438) of N label
6.0 solution of PBS, DMSO, the 100%DMSO liquid storage of drug, POA 100% liquid storage.
Key instrument: F-7000 sepectrophotofluorometer (Hitachi, Japan), AVANCE III 850MHz nuclear magnetic resonance
Spectrometer (Bruker).
The quenching type decision of compound and albumen and dissociation constant (Kd) are measured
Experimentation: solution system is tested using 200 μ l, for 6.0 solution of PBS containing 20 μM of albumen, 17%DMSO.
The concentration gradient that PXYC8, POA are used is 0 μM, 5 μM, 10 μM, 20 μM, 40 μM, 80 μM, 160 μM, 250 μM, 350 μM, 500 μM.
Scan the fluorescence emission spectrum of each concentration gradient of each compound respectively, parallel sweep three times, acquisition parameter are as follows: EX WL:
279.0nm, EM Start WL:290.0nm, EM End WL:450.0nm, Scan speed:1200nm/min, Delay:
0.0s, EX Slit:5.0nm, EM Slit:5.0nm, PMT Voltage:700V, Response:0.002s.Then in 330nm
Fluorescence intensity level is obtained, fitting of the average value being measured in parallel three times for subsequent equation is taken.
Quenching type decision: obtaining quenching constant first with the fitting (as follows) of Stern-Volmer equation,
F0/F=1+Kq τ 0 [Q]
Wherein, F0 and F is indicated not add quencher and is added the fluorescence intensity of quencher, and [Q] is molar concentration of quencher, Kq
For static quenching constant, τ 0 is fluorescence lifetime, and protein molecular is generally 10-8s.If Kq > 2.0 × 1010(mol·L-1)-1·s-1, then show that fluorescent quenching is static quenching.
Kd measurement: with Hill equation fitting Kd (as follows),
Lg [(F0-F)/F]=lg (1/Kd)+nlg [Q]
Wherein, F0 and F is indicated not add quencher and is added the fluorescence intensity of quencher, and [Q] is molar concentration of quencher, Kd
For dissociation constant, n is binding site number.
As a result: the Kq of 13 PXYC series compounds and two albumen is all larger than 2.0 × 1010(mol·L-1)-1·s-1, table
Bright fluorescent quenching is static quenching.POA and 13 PXYC series compound and MtRpsA (285-476), MtRpsA (285-476)
The Kd of d438A compound such as following table,
The interaction of PXYC8 compound and wild type RpsA [MtRpsA (285-476)] are suitable with POA even stronger,
More importantly PXYC8 compound also has stronger phase interaction with saltant type RpsA [MtRpsA (285-476) d438A]
With.
Claims (4)
1.N- thiophene -2- hypoxanthine sulfenyl acetamide derivative is infected in Killing Mycobacterium Tuberculosis, especially resists the acyl of resistance to pyrazine
Medical usage in the infection of amine mycobacterium tuberculosis, feature meet following structural formula.
2. Killing Mycobacterium Tuberculosis drug acts on wild type or saltant type mycobacterium tuberculosis ribosomal protein S1 (RpsA),
It is characterized in that-the 2- of N- thiophene described in claim 1 hypoxanthine sulfenyl acetamide compound and one or more pharmacy
Upper acceptable carrier.
3. antibacterials as described in claim 2, it is characterised in that the pharmaceutically acceptable carrier refers to: dilution
Agent, filler, excipient, adhesive, wetting agent, disintegrating agent, surfactant, sorbefacient, lubricant or absorption carrier.
4. antibacterials as described in claim 2, it is characterised in that the dosage form of the drug are as follows: tablet, capsule, hangs pill
Floating agent, emulsion, injection or dry powder doses.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910191636.1A CN110063958A (en) | 2019-03-12 | 2019-03-12 | Medical usage of the N- thiophene -2- hypoxanthine sulfenyl acetamide in Killing Mycobacterium Tuberculosis infection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910191636.1A CN110063958A (en) | 2019-03-12 | 2019-03-12 | Medical usage of the N- thiophene -2- hypoxanthine sulfenyl acetamide in Killing Mycobacterium Tuberculosis infection |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110063958A true CN110063958A (en) | 2019-07-30 |
Family
ID=67365256
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910191636.1A Pending CN110063958A (en) | 2019-03-12 | 2019-03-12 | Medical usage of the N- thiophene -2- hypoxanthine sulfenyl acetamide in Killing Mycobacterium Tuberculosis infection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110063958A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1684966A (en) * | 2002-09-27 | 2005-10-19 | 住友制药株式会社 | Novel adenine compound and use thereof |
| CN101072787A (en) * | 2004-10-15 | 2007-11-14 | 阿斯利康(瑞典)有限公司 | Substituted adenines and the use thereof |
-
2019
- 2019-03-12 CN CN201910191636.1A patent/CN110063958A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1684966A (en) * | 2002-09-27 | 2005-10-19 | 住友制药株式会社 | Novel adenine compound and use thereof |
| CN101072787A (en) * | 2004-10-15 | 2007-11-14 | 阿斯利康(瑞典)有限公司 | Substituted adenines and the use thereof |
Non-Patent Citations (3)
| Title |
|---|
| DEBMALYA BARH等: "A Novel Comparative Genomics Analysis for Common Drug and Vaccine Targets in Corynebacterium pseudotuberculosis and other CMN Group of Human Pathogens", 《CHEM BIOL DRUG DES》 * |
| JOHNS, CARL O.等: "RESEARCHES ON PURINES:On 2-Thio-6,8-dioxypurine and 2,8-Dithio-6-oxypurine. The. Desulfurization of Thiopurines. A New Method of Preparing Xanthine", 《J. BIOL. CHEM.》 * |
| YI FAN等: "Structural basis for ribosome protein S1 interaction with RNA in transtranslation of Mycobacterium tuberculosis", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102399483B1 (en) | HIV capsid inhibitor in solid form | |
| KR102389850B1 (en) | HIV capsid inhibitor in choline salt form | |
| ES2197201T3 (en) | TREATMENT OF OPTICAL NEURITIS. | |
| JP2023011754A (en) | Therapeutic compound useful in preventive or therapeutic treatment of hiv virus infection | |
| Motzer et al. | Phase I/II trial of dexverapamil plus vinblastine for patients with advanced renal cell carcinoma. | |
| WO2013188848A2 (en) | Antiviral compounds and methods of use | |
| US11154587B2 (en) | Use of peptides to stimulate the immune system | |
| US7118730B2 (en) | Quinoline derivative as diagnostic probe for disease with tau protein accumulation | |
| Figarella-Branger et al. | Pathological findings in 165 patients explored for malignant hyperthermia susceptibility | |
| AU2018234056B2 (en) | Subcutaneous administration of a P2Y12 receptor antagonist | |
| CN110063958A (en) | Medical usage of the N- thiophene -2- hypoxanthine sulfenyl acetamide in Killing Mycobacterium Tuberculosis infection | |
| CN109758469A (en) | Medical usage of the N- substitution -2- hypoxanthine sulfenyl acetamide derivative in Killing Mycobacterium Tuberculosis infection | |
| CN109908150A (en) | Medical usage of the N- benzyl -2- hypoxanthine sulfenyl acetamide derivative in Killing Mycobacterium Tuberculosis infection | |
| CN109758468A (en) | Medical usage of the N- benzene substitution -2- hypoxanthine sulfenyl acetamide derivative in Killing Mycobacterium Tuberculosis infection | |
| CN109908149A (en) | Medical usage of the 2- hypoxanthine ethyl thioglycollic acid derivative in Killing Mycobacterium Tuberculosis infection | |
| Rolla et al. | Maintaining safety with SARS-CoV-2 vaccines | |
| CN110464719A (en) | 5- Sunkatol No. 1 replaces medical usage of the N- chlorphenyl-acetamide in Killing Mycobacterium Tuberculosis infection | |
| Leporati et al. | Antiretroviral hydrophobic core graft-copolymer nanoparticles: the effectiveness against mutant HIV-1 strains and in vivo distribution after topical application | |
| Coltart et al. | Investigation of the safe withdrawal period for propranolol in patients scheduled for open heart surgery. | |
| CN110403930A (en) | Medical usage of 5- Sunkatol No. 1 substitution-N-3 ' the methylbenzyl acetamide in Killing Mycobacterium Tuberculosis infection | |
| US20210188880A1 (en) | One-step, fast, 18f-19f isotopic exchange radiolabeling of difluoro-dioxaborinins and use of such compounds in treatment | |
| Barbaud et al. | Occupational contact dermatitis to propacetamol: Allergological and chemical investigations in two new cases | |
| KR20210011961A (en) | Dantrolene formulation and method of use thereof | |
| Richards et al. | Malaria studies in vitro: III: The protein synthesising activity of Plasmodium falciparum in vitro after drug treatment in vivo | |
| JP2024517506A (en) | Pharmaceutical Hydronidone Formulations for Diseases |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190730 |