CN110403930A - Medical usage of 5- Sunkatol No. 1 substitution-N-3 ' the methylbenzyl acetamide in Killing Mycobacterium Tuberculosis infection - Google Patents
Medical usage of 5- Sunkatol No. 1 substitution-N-3 ' the methylbenzyl acetamide in Killing Mycobacterium Tuberculosis infection Download PDFInfo
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- CN110403930A CN110403930A CN201910745570.6A CN201910745570A CN110403930A CN 110403930 A CN110403930 A CN 110403930A CN 201910745570 A CN201910745570 A CN 201910745570A CN 110403930 A CN110403930 A CN 110403930A
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- mycobacterium tuberculosis
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- 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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- 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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Abstract
Medical usage of 5- Sunkatol No. 1 substitution-N-3 ' the methylbenzyl acetamide in Killing Mycobacterium Tuberculosis infection, is related to pharmaceutical field.5- Sunkatol No. 1 substitution-N-3 ' the methylbenzyl acetamide has the pharmaceutically acceptable salt of pharmaceutically acceptable salt or its pro-drug or its pro-drug.Medical usage in Killing Mycobacterium Tuberculosis infection has good prospect.5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide acts on mycobacterium tuberculosis wild type RpsA and saltant type RpsA simultaneously, and action intensity is higher, show that 5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide can efficiently solve mycobacterium tuberculosis since RpsA is mutated bring resistance problems, also wild type RpsA and saltant type RpsA can be specifically acted on by showing 5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide simultaneously.
Description
Technical field
The present invention relates to pharmaceutical fields, more particularly, to 5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide in treating tuberculosis
Medical usage in mycobacterial infections.
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, 2011,333:(6049), 1630-1632) and it proposes, PZA is hydrolyzed to pyrazine through pyrazinamidase (PZase) in vivo
After sour (POA), it is suppressed that the ribosomal protein S1 (RpsA) of mycobacterium tuberculosis, and then prevent the trans- of mycobacterium tuberculosis
Translation process achievees the purpose that Killing Mycobacterium Tuberculosis infects.The thorn of the external world caused by mycobacterium tuberculosis is in drug, environment
Under swashing, mycobacterium tuberculosis ribosomes will be blocked, and trans- translating mechanism displaces retardance ribosomes by introducing tmRNA
In RNA, and the albumen that expression is interrupted introduces the implicit sequence label of tmRNA, to will likely have virose expression not
Degrade to complete protein-specific.And in this trans- translation process, RpsA plays key as rna binding protein
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, 2019,82,58-67), RpsA can be used as Killing Mycobacterium Tuberculosis infection, especially anti-pyrazinamide drug resistance knot
The ideal targets of core mycobacterial infections.On the one hand, according to clinical statistics as a result, in the drug resistant part tuberculosis branch of pyrazinamide
In bacillus strain, No. 438 deletion of alanine mutation can occur for RpsA, and then POA can not inhibit RpsA and lose drug effect；Another party
Face, the RpsA of mycobacterium tuberculosis is very low with the albumen homology of people and other mammals, and inhibitor will be to tuberculosis branch
Bacillus has specificity.Simultaneously using wild type RpsA and saltant type RpsA as target, mycobacterium tuberculosis will be efficiently solved
Pyrazinamide resistance problems, 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 substitution-N-3 ' methylbenzyl acetamides in Killing Mycobacterium Tuberculosis sense
Medical usage in dye.
5- Sunkatol No. 1 substitution-N-3 ' the methylbenzyl acetamide has the following structure formula or its is pharmaceutically acceptable
The pharmaceutically acceptable salt of salt or its pro-drug or its pro-drug:
5- Sunkatol No. 1 substitution-N-3 ' the methylbenzyl acetamide can be by acting on wild type or saltant type RpsA, can
It is used to prepare the drug of Killing Mycobacterium Tuberculosis infection, the drug of the Killing Mycobacterium Tuberculosis infection is preferably that pyrazinamide is resistance to
The drug of the Killing Mycobacterium Tuberculosis infection of medicine.
The drug of Killing Mycobacterium Tuberculosis infection can contain 5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide or its
The pharmaceutically acceptable salt of pharmaceutically acceptable salt or its pro-drug or its pro-drug and other pharmaceutically may be used
The carrier of receiving；
The pharmaceutical formulation of the Killing Mycobacterium Tuberculosis infection can be solid dosage forms, liquid dosage form, gas formulation, semisolid
Dosage form etc..
The pharmaceutically acceptable salt of 5- Sunkatol No. 1 substitution-N-3 ' the methylbenzyl acetamide and its medicine of pro-drug
Acceptable salt on, wherein pharmaceutically acceptable salt can be selected from the salt etc. of the salt of innoxious negative ion, non-toxic cation；It is described
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.；The non-toxic cation
Salt can be selected from sodium, potassium, calcium, magnesium, choline, ethanol amine, diethanol amine, benzyl ethamine, piperazine, N- methyl osamine, tromethamine etc.
Middle one kind.
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 substitution-N-3 ' methylbenzyl second
Medical usage of the amide in Killing Mycobacterium Tuberculosis infection has good prospect.5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl second
Amide acts on mycobacterium tuberculosis wild type RpsA and saltant type RpsA simultaneously, and action intensity is higher, shows 5- Sunkatol No. 1
Substitution-N-3 ' methylbenzyl acetamide can efficiently solve mycobacterium tuberculosis due to RpsA be mutated bring resistance problems,
Also wild type RpsA and mutation can be specifically acted on by showing 5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide simultaneously
Type RpsA.
Specific embodiment
The present invention is further illustrated for following embodiment.
5- Sunkatol No. 1 substitution-N-3 ' the methylbenzyl acetamide has the following structure formula or its is pharmaceutically acceptable
The pharmaceutically acceptable salt of salt or its pro-drug or its pro-drug:
5- Sunkatol No. 1 substitution-N-3 ' the methylbenzyl acetamide can be by acting on wild type or saltant type RpsA, can
It is used to prepare the drug of Killing Mycobacterium Tuberculosis infection, the drug of the Killing Mycobacterium Tuberculosis infection is preferably that pyrazinamide is resistance to
The drug of the Killing Mycobacterium Tuberculosis infection of medicine.
The drug of Killing Mycobacterium Tuberculosis infection can contain 5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide or its
The pharmaceutically acceptable salt of pharmaceutically acceptable salt or its pro-drug or its pro-drug and other pharmaceutically may be used
The carrier of receiving；
The pharmaceutical formulation of the Killing Mycobacterium Tuberculosis infection can be solid dosage forms, liquid dosage form, gas formulation, semisolid
Dosage form etc..
The pharmaceutically acceptable salt of 5- Sunkatol No. 1 substitution-N-3 ' the methylbenzyl acetamide and its medicine of pro-drug
Acceptable salt on, wherein pharmaceutically acceptable salt can be selected from the salt etc. of the salt of innoxious negative ion, non-toxic cation；It is described
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.；The non-toxic cation
Salt can be selected from sodium, potassium, calcium, magnesium, choline, ethanol amine, diethanol amine, benzyl ethamine, piperazine, N- methyl osamine, tromethamine etc.
Middle one kind.
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 PXYD3 is used is 0 μM, 10 μM, 30 μM, 50 μM, 70 μM, 90 μM, 110 μM, 130 μM, 150 μM, 170 μ
The concentration gradient that M, POA are used is 0 μM, 5 μM, 10 μM, 20 μM, 40 μM, 80 μM, 160 μM, 250 μM, 350 μM, 500 μM.Scanning
The fluorescence emission spectrum of each concentration gradient of compound, parallel sweep 3 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.Fluorescence intensity level then is obtained in 330nm, takes three
The average value of secondary parallel determination is used for the fitting of subsequent equation.
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.
4.3 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.
4.4 results: the Kq of PXYD3 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, PXYD3 and MtRpsA (285-476) compound is respectively 9.65 μM, 5.66 μM；
The Kd of PXYD3 and MtRpsA (285-476) D438A compound is 6.91 μM.PXYD3 compound and wild type RpsA [MtRpsA
(285-476)] interaction and POA it is quite even stronger, it is even more important that PXYD3 compound and saltant type RpsA
[MtRpsA (285-476) d438A] also has stronger interaction.
Claims (10)
- Medical usage of 1.5- Sunkatol No. 1 substitution-N-3 ' the methylbenzyl acetamide in Killing Mycobacterium Tuberculosis infection.
- 2. 5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide as described in claim 1 is in Killing Mycobacterium Tuberculosis infection Medical usage, it is characterised in that 5- Sunkatol No. 1 substitution-N-3 ' the methylbenzyl acetamide has the following structure formula or its pharmacy The pharmaceutically acceptable salt of upper acceptable salt or its pro-drug or its pro-drug:
- 3. 5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide as described in claim 1 is in Killing Mycobacterium Tuberculosis infection Medical usage, it is characterised in that 5- Sunkatol No. 1 substitution-N-3 ' the methylbenzyl acetamide is by acting on wild type or mutation Type RpsA is used to prepare the drug of Killing Mycobacterium Tuberculosis infection.
- 4. 5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide as claimed in claim 3 is in Killing Mycobacterium Tuberculosis infection Medical usage, it is characterised in that the drug of the Killing Mycobacterium Tuberculosis infection is the drug resistant Killing Mycobacterium Tuberculosis of pyrazinamide The drug of infection.
- 5. 5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide as claimed in claim 3 is in Killing Mycobacterium Tuberculosis infection Medical usage, it is characterised in that drug substitution-N-3 ' the methylbenzyl second of Sunkatol No. 1 containing 5- of the Killing Mycobacterium Tuberculosis infection The pharmaceutically acceptable salt of amide or its pharmaceutically acceptable salt or its pro-drug or its pro-drug and other Pharmaceutically acceptable carrier.
- 6. 5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide as claimed in claim 3 is in Killing Mycobacterium Tuberculosis infection Medical usage, it is characterised in that the pharmaceutical formulation of the Killing Mycobacterium Tuberculosis infection is solid dosage forms, liquid dosage form, agent gas Type, semisolid dosage form.
- 7. 5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide as described in claim 1 is in Killing Mycobacterium Tuberculosis infection Medical usage, it is characterised in that the pharmaceutically acceptable salt of 5- Sunkatol No. 1 substitution-N-3 ' the methylbenzyl acetamide and its The pharmaceutically acceptable salt of pro-drug, wherein pharmaceutically acceptable salt is selected from salt, the non-toxic cation of innoxious negative ion Salt.
- 8. 5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide as claimed in claim 7 is in Killing Mycobacterium Tuberculosis infection Medical usage, it is characterised in that the salt of the innoxious negative ion be selected from chloride, bromide, iodide, sulfate, hydrochloride, Maleate, fumarate, oxalates, lactate, tartrate, gluconate, mesylate, in 4- toluene fulfonate It is a kind of.
- 9. 5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide as claimed in claim 7 is in Killing Mycobacterium Tuberculosis infection Medical usage, it is characterised in that the salt of the non-toxic cation is selected from sodium, potassium, calcium, magnesium, choline, ethanol amine, diethanol amine, benzyl It is ethamine, piperazine, N- methyl osamine, a kind of in tromethamine.
- 10. 5- Sunkatol No. 1 substitution-N-3 ' methylbenzyl acetamide as claimed in claim 3 is in Killing Mycobacterium Tuberculosis infection Medical usage, it is characterised in that other pharmaceutically acceptable carriers choosing that the drug of the Killing Mycobacterium Tuberculosis infection contains From diluent, filler, excipient, adhesive, wetting agent, disintegrating agent, surfactant, sorbefacient, lubricant, absorption One of carrier.
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| CN201910745570.6A CN110403930B (en) | 2019-08-13 | 2019-08-13 | Medical application of 5-hydroxyflavone substituted-N-3' methylbenzylacetamide in resisting mycobacterium tuberculosis infection |
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| CN201910745570.6A CN110403930B (en) | 2019-08-13 | 2019-08-13 | Medical application of 5-hydroxyflavone substituted-N-3' methylbenzylacetamide in resisting mycobacterium tuberculosis infection |
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| CN110403930B CN110403930B (en) | 2022-10-28 |
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Non-Patent Citations (2)
| Title |
|---|
| JUANJUAN YANG，ET AL: "Structural basis for targeting the ribosomal protein S1 of", 《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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