CN110464719A - 5- Sunkatol No. 1 replaces medical usage of the N- chlorphenyl-acetamide in Killing Mycobacterium Tuberculosis infection - Google Patents
5- Sunkatol No. 1 replaces medical usage of the N- chlorphenyl-acetamide in Killing Mycobacterium Tuberculosis infection Download PDFInfo
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- CN110464719A CN110464719A CN201910745591.8A CN201910745591A CN110464719A CN 110464719 A CN110464719 A CN 110464719A CN 201910745591 A CN201910745591 A CN 201910745591A CN 110464719 A CN110464719 A CN 110464719A
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- mycobacterium tuberculosis
- sunkatol
- acetamide
- chlorphenyl
- tuberculosis infection
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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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
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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Abstract
5- Sunkatol No. 1 replaces medical usage of the N- chlorphenyl-acetamide in Killing Mycobacterium Tuberculosis infection, is related to pharmaceutical field.5- Sunkatol No. 1 replaces N- chlorphenyl-acetamide to have the pharmaceutically acceptable salt of pharmaceutically acceptable salt or its pro-drug or its pro-drug, and the medical usage in Killing Mycobacterium Tuberculosis infection is with good prospect.5- Sunkatol No. 1 replaces N- chlorphenyl-acetamide to act on mycobacterium tuberculosis wild type RpsA and saltant type RpsA simultaneously, and action intensity is higher, show that 5- Sunkatol No. 1 replaces N- chlorphenyl-acetamide that can efficiently solve mycobacterium tuberculosis since RpsA is mutated bring resistance problems, also shows 5- Sunkatol No. 1 simultaneously and replace N- chlorphenyl-acetamide that can specifically act on wild type RpsA and saltant type RpsA.
Description
Technical field
The present invention relates to pharmaceutical fields, replace N- chlorphenyl-acetamide in treating tuberculosis branch more particularly, to 5- Sunkatol No. 1
Medical usage in bacillus infection.
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 in 2011 (Wanliang Shi etc.,
Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis:a
Potential mechanism for shortening the duration of tuberculosis chemotherapy,
Science, 2011, volume 333 (6049), 1630-1632) it proposes, PZA is hydrolyzed to through pyrazinamidase (PZase) in vivo
After pyrazine acid (POA), it is suppressed that the ribosomal protein S1 (RpsA) of mycobacterium tuberculosis, and then prevent mycobacterium tuberculosis
Trans- translation process achievees the purpose that Killing Mycobacterium Tuberculosis infects.It is outer caused by mycobacterium tuberculosis is in drug, environment
Under boundary's stimulation, mycobacterium tuberculosis ribosomes will be blocked, and trans- translating mechanism displaces retardance core by introducing tmRNA
RNA in sugared body, and the albumen that expression is interrupted introduces the implicit sequence label of tmRNA, to will likely have virose table
It degrades up to incomplete protein-specific.And in this trans- translation process, RpsA is played as rna binding protein
Key effect, but also RpsA becomes the important target spot of POA.
In addition, according to document (Yunbao Zhi etc., Lead compounds and key residues of
Ribosomal protein S1 in drug-resistant Mycobacterium tuberculosis, Bioorganic
Chemistry, 2019, volume 82,58-67), RpsA can be used as Killing Mycobacterium Tuberculosis infection, and especially anti-pyrazinamide is resistance to
The ideal targets of medicine mycobacterium tuberculosis infection.On the one hand, according to clinical statistics as a result, in the drug resistant part tuberculosis of pyrazinamide
In mycobacterium strain, No. 438 deletion of alanine mutation can occur for RpsA, and then POA can not inhibit RpsA and lose drug effect；Separately
On the one hand, the RpsA of mycobacterium tuberculosis is very low with the albumen homology of people and other mammals, and inhibitor will be to tuberculosis
Mycobacteria has specificity.Simultaneously using wild type RpsA and saltant type RpsA as target, tuberculosis branch will be efficiently solved
The pyrazinamide resistance problems of bacillus, while ensure that the specificity of its inhibitor.
Foundation books (L.R.Lakowicz, Principles of Fluorescence Spectroscopy, the third edition,
Springer publishing house, Boston, MA, 2006), fluorescence quenching titration is for verifying the common of protein ligand interaction
Experiment.The special interaction that ligand and albumen occur, so that static quenching occurs for the amino acid for generating fluorescence in albumen.Together
When, under certain protein concentration, the degree of fluorescence static quenching depends on ligand concentration, and then according to Hill equation, can intend
Close out the dissociation constant of ligand and albumen.This method can the interaction quickly and easily to ligand and albumen determine
Amount, thus the interaction of clear ligand and albumen.
Summary of the invention
The purpose of the present invention is to provide 5- Sunkatol No. 1 replace N- chlorphenyl-acetamide Killing Mycobacterium Tuberculosis infect and
Medical usage in the drug resistant mycobacterium tuberculosis infection of pyrazinamide.
The 5- Sunkatol No. 1 replaces N- chlorphenyl-acetamide to have the following structure formula or its pharmaceutically acceptable salt, or
The pharmaceutically acceptable salt of its pro-drug or its pro-drug:
The 5- Sunkatol No. 1 replaces N- chlorphenyl-acetamide that can be used for by acting on wild type or saltant type RpsA
Prepare the drug of Killing Mycobacterium Tuberculosis infection, the preferably drug of the drug resistant Killing Mycobacterium Tuberculosis infection of pyrazinamide.
The drug of the Killing Mycobacterium Tuberculosis infection can replace N- chlorphenyl-acetamide or its medicine containing 5- Sunkatol No. 1
It the pharmaceutically acceptable salt of acceptable salt or its pro-drug or its pro-drug and other can pharmaceutically be connect on
The carrier received；
The pharmaceutical formulation of the Killing Mycobacterium Tuberculosis infection can be solid dosage forms, liquid dosage form, gas formulation, semisolid
One of dosage form etc..
The 5- Sunkatol No. 1 replaces N- chlorphenyl-acetamide pharmaceutically acceptable salt and its pro-drug pharmaceutically
Acceptable salt, wherein salt of the pharmaceutically acceptable salt containing innoxious negative ion, the salt for having non-toxic cation etc.；It is described to have
The salt of innoxious negative ion can be selected from chloride, bromide, iodide, sulfate, hydrochloride, maleate, fumarate, oxalic acid
One of salt, lactate, tartrate, gluconate, mesylate, 4- toluene fulfonate etc.；It is described have it is nontoxic sun from
The salt of son can be selected from sodium, potassium, calcium, magnesium, choline, ethanol amine, diethanol amine, benzyl ethamine, piperazine, N- methyl osamine, tromethamine
One of Deng.
Other pharmaceutically acceptable carriers that the drug of Killing Mycobacterium Tuberculosis infection contains can be selected from diluent,
In filler, excipient, adhesive, wetting agent, disintegrating agent, surfactant, sorbefacient, lubricant, absorption carrier etc.
One kind.
Further, by specific embodiment statistics indicate that, above-mentioned 5- Sunkatol No. 1 replaces N- chlorphenyl-acetamide
Medical usage in Killing Mycobacterium Tuberculosis infection has good prospect.5- Sunkatol No. 1 replaces N- chlorphenyl-acetamide simultaneously
Mycobacterium tuberculosis wild type RpsA and saltant type RpsA are acted on, and action intensity is higher, shows that 5- Sunkatol No. 1 replaces N- chlorine
Phenvl-acetamide can efficiently solve mycobacterium tuberculosis since RpsA is mutated bring resistance problems, also show simultaneously
5- Sunkatol No. 1 replaces N- chlorphenyl-acetamide that can specifically act on wild type RpsA and saltant type RpsA.
Specific embodiment
The present invention is further illustrated for following embodiment.
The 5- Sunkatol No. 1 replaces N- chlorphenyl-acetamide to have the following structure formula or its pharmaceutically acceptable salt, or
The pharmaceutically acceptable salt of its pro-drug or its pro-drug:
The 5- Sunkatol No. 1 replaces N- chlorphenyl-acetamide that can be used for by acting on wild type or saltant type RpsA
Prepare the drug of Killing Mycobacterium Tuberculosis infection, the preferably drug of the drug resistant Killing Mycobacterium Tuberculosis infection of pyrazinamide.
The drug of the Killing Mycobacterium Tuberculosis infection can replace N- chlorphenyl-acetamide or its medicine containing 5- Sunkatol No. 1
It the pharmaceutically acceptable salt of acceptable salt or its pro-drug or its pro-drug and other can pharmaceutically be connect on
The carrier received；
The pharmaceutical formulation of the Killing Mycobacterium Tuberculosis infection can be solid dosage forms, liquid dosage form, gas formulation, semisolid
One of dosage form etc..
The 5- Sunkatol No. 1 replaces N- chlorphenyl-acetamide pharmaceutically acceptable salt and its pro-drug pharmaceutically
Acceptable salt, wherein salt of the pharmaceutically acceptable salt containing innoxious negative ion, the salt for having non-toxic cation etc.；It is described to have
The salt of innoxious negative ion can be selected from chloride, bromide, iodide, sulfate, hydrochloride, maleate, fumarate, oxalic acid
One of salt, lactate, tartrate, gluconate, mesylate, 4- toluene fulfonate etc.；It is described have it is nontoxic sun from
The salt of son can be selected from sodium, potassium, calcium, magnesium, choline, ethanol amine, diethanol amine, benzyl ethamine, piperazine, N- methyl osamine, tromethamine
One of Deng.
Other pharmaceutically acceptable carriers that the drug of Killing Mycobacterium Tuberculosis infection contains can be selected from diluent,
In filler, excipient, adhesive, wetting agent, disintegrating agent, surfactant, sorbefacient, lubricant, absorption carrier etc.
One kind.
Pass through fluorescence quenching titration experimental fit compound and wild type RpsA [MtRpsA (285-476)] and saltant type
The dissociation constant of RpsA [MtRpsA (285-476) D438A], and interaction is further verified by nuclear-magnetism titration experiments.
Compound and reagent:
1) compound:
2) main agents: MtRpsA (285-476), MtRpsA (285-476) D438A, DMSO, drug 100%DMSO
100% liquid storage of liquid storage, POA.
3) key instrument: F-7000 sepectrophotofluorometer (Hitachi, Japan)
4) the quenching type decision of compound and albumen and dissociation constant (Kd) are measured:
4.1 experimentations: 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 wherein POA, PXYD2 are used for 0 μM, 5 μM, 10 μM, 20 μM, 40 μM, 80 μM, 160 μM, 250 μM, 350 μM,
500μM.Scan each concentration gradient of compound fluorescence emission spectrum, 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.
4.2 quenching type decisions: quenching constant is obtained with the fitting (as follows) of Stern-Volmer equation first:
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.
4.3Kd 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.
4.4 results: the Kq of PXYD1 compound and two albumen is all larger than 2.0 × 1010(mol·L-1)-1·s-1, show glimmering
Optical quenching is static quenching.The Kd of POA, PXYD2 and MtRpsA (285-476) compound is respectively 9.65 μM, 4.25 μM；
The Kd of PXYD2 and MtRpsA (285-476) D438A compound is 7.53 μM.PXYD2 compound and wild type RpsA [MtRpsA
(285-476)] interaction and POA it is quite even stronger, it is even more important that PXYD2 compound and saltant type RpsA
[MtRpsA (285-476) D438A] also has stronger interaction.
Claims (10)
1.5- Sunkatol No. 1 replaces medical usage of the N- chlorphenyl-acetamide in Killing Mycobacterium Tuberculosis infection.
2. 5- Sunkatol No. 1 as described in claim 1 replaces medicine of the N- chlorphenyl-acetamide in Killing Mycobacterium Tuberculosis infection
Purposes, it is characterised in that the 5- Sunkatol No. 1 substitution N- chlorphenyl-acetamide has the following structure formula or its is pharmaceutically acceptable
Salt or its pro-drug or its pro-drug pharmaceutically acceptable salt:
3. 5- Sunkatol No. 1 as described in claim 1 replaces medicine of the N- chlorphenyl-acetamide in Killing Mycobacterium Tuberculosis infection
Purposes, it is characterised in that the 5- Sunkatol No. 1 replaces N- chlorphenyl-acetamide by acting on wild type or saltant type RpsA, uses
In the drug of preparation Killing Mycobacterium Tuberculosis infection.
4. 5- Sunkatol No. 1 as claimed in claim 3 replaces medicine of the N- chlorphenyl-acetamide in Killing Mycobacterium Tuberculosis infection
Purposes, it is characterised in that the drug of the Killing Mycobacterium Tuberculosis infection is the drug resistant mycobacterium tuberculosis infection of pyrazinamide
Drug.
5. 5- Sunkatol No. 1 as claimed in claim 3 replaces medicine of the N- chlorphenyl-acetamide in Killing Mycobacterium Tuberculosis infection
Purposes, it is characterised in that the drug of Killing Mycobacterium Tuberculosis infection contain 5- Sunkatol No. 1 replace N- chlorphenyl-acetamide or
The pharmaceutically acceptable salt of its pharmaceutically acceptable salt or its pro-drug or its pro-drug and it is other pharmaceutically
Acceptable carrier.
6. 5- Sunkatol No. 1 as claimed in claim 3 replaces medicine of the N- chlorphenyl-acetamide in Killing Mycobacterium Tuberculosis infection
Purposes, it is characterised in that the pharmaceutical formulation of Killing Mycobacterium Tuberculosis infection be solid dosage forms, liquid dosage form, gas formulation,
One of semisolid dosage form.
7. 5- Sunkatol No. 1 as described in claim 1 replaces medicine of the N- chlorphenyl-acetamide in Killing Mycobacterium Tuberculosis infection
Purposes, it is characterised in that the 5- Sunkatol No. 1 replaces N- chlorphenyl-acetamide pharmaceutically acceptable salt and its pro-drug
Pharmaceutically acceptable salt, the salt that wherein pharmaceutically acceptable salt contains innoxious negative ion, the salt for having non-toxic cation.
8. 5- Sunkatol No. 1 as claimed in claim 7 replaces medicine of the N- chlorphenyl-acetamide in Killing Mycobacterium Tuberculosis infection
Purposes, it is characterised in that the salt for having innoxious negative ion is selected from chloride, bromide, iodide, sulfate, hydrochloride, horse
Come hydrochlorate, fumarate, oxalates, lactate, tartrate, gluconate, mesylate, one in 4- toluene fulfonate
Kind.
9. 5- Sunkatol No. 1 as claimed in claim 7 replaces medicine of the N- chlorphenyl-acetamide in Killing Mycobacterium Tuberculosis infection
Purposes, it is characterised in that the salt for having non-toxic cation is selected from sodium, potassium, calcium, magnesium, choline, ethanol amine, diethanol amine, benzyl second
One of amine, piperazine, N- methyl osamine, tromethamine.
10. 5- Sunkatol No. 1 as claimed in claim 3 replaces medicine of the N- chlorphenyl-acetamide in Killing Mycobacterium Tuberculosis infection
Purposes, it is characterised in that the drug of the Killing Mycobacterium Tuberculosis infection and the drug resistant mycobacterium tuberculosis infection of pyrazinamide contains
The other pharmaceutically acceptable carriers having are selected from diluent, filler, excipient, adhesive, wetting agent, disintegrating agent, surface
One of activating agent, sorbefacient, lubricant, absorption carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910745591.8A CN110464719B (en) | 2019-08-13 | 2019-08-13 | Medical application of 5-hydroxyflavone substituted N-chlorphenyl-acetamide in resisting mycobacterium tuberculosis infection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910745591.8A CN110464719B (en) | 2019-08-13 | 2019-08-13 | Medical application of 5-hydroxyflavone substituted N-chlorphenyl-acetamide in resisting mycobacterium tuberculosis infection |
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| Publication Number | Publication Date |
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| CN110464719A true CN110464719A (en) | 2019-11-19 |
| CN110464719B CN110464719B (en) | 2022-10-14 |
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| CN201910745591.8A Active CN110464719B (en) | 2019-08-13 | 2019-08-13 | Medical application of 5-hydroxyflavone substituted N-chlorphenyl-acetamide in resisting mycobacterium tuberculosis infection |
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| CN (1) | CN110464719B (en) |
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2019
- 2019-08-13 CN CN201910745591.8A patent/CN110464719B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| JUANJUAN YANG,ET AL: "Structural basis for targeting the ribosomal protein S1 of Mycobacterium tuberculosis by pyrazinamide", 《MOLECULAR MICROBIOLOGY》 * |
| YUNBAO ZHI,ET AL: "lead compounds and key residues of ribosomal protein S1 in drug-resistant Mycobacterium tuberculosis", 《BIOORGANIC CHEMISTRY》 * |
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| CN110464719B (en) | 2022-10-14 |
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