Pyrazinamide
カタログ番号:
B1679903
CAS番号:
98-96-4
分子量:
123.11 g/mol
InChIキー:
IPEHBUMCGVEMRF-UHFFFAOYSA-N
注意:
研究専用です。人間または獣医用ではありません。
概要
説明
Pyrazinamide is an antimicrobial agent primarily used in the treatment of active tuberculosis. It is particularly effective during the initial phase of therapy, typically the first two months, and is used in combination with other antituberculous agents. This compound demonstrates significant antibacterial activity against Mycobacterium tuberculosis and Mycobacterium africanum .
作用機序
ピラジナミドは、細菌細胞内の酵素であるピラジナミダーゼによって、活性型であるピラジノ酸に変換されるプロドラッグです。ピラジノ酸は、細菌細胞膜の電位を乱し、脂肪酸合成を阻害することにより、結核菌の死滅につながります。 この薬物は、細菌が存在するマクロファージに見られるような酸性pHレベルでより活性があります .
類似化合物：
イソニアジド： 細菌細胞壁の必須成分であるミコール酸の合成を阻害する、もう1つの第一選択薬の抗結核剤です。
リファンピシン： 細菌のRNA合成を阻害する広域スペクトル抗生物質です。
エタンブトール： 結核菌細胞壁の成分であるアラビノガラクタンの合成を阻害します。
ピラジナミドの独自性： ピラジナミドは、マクロファージに見られるような酸性環境内にある結核菌を標的とする能力においてユニークです。 この性質により、増殖中の細菌集団と休眠中の細菌集団の両方に対して効果があり、短期間結核療法の重要な成分となります .
生化学分析
Biochemical Properties
Pyrazinamide is a prodrug that is converted into its active form, pyrazinoic acid, by the enzyme pyrazinamidase, which is expressed in active Mycobacterium tuberculosis . The conversion of this compound to pyrazinoic acid is a critical step in its biochemical activity .
Cellular Effects
This compound has a unique sterilizing effect, killing nonreplicating persisters that other TB drugs fail to kill . This makes it an essential drug for inclusion in any drug combinations for treating TB . It acts differently from common antibiotics by inhibiting multiple targets such as energy production, trans-translation, and perhaps pantothenate/coenzyme A required for persister survival .
Molecular Mechanism
The active form of this compound, pyrazinoic acid, exerts its effects at the molecular level through various mechanisms. It inhibits energy production, disrupts trans-translation, and may also affect the pantothenate/coenzyme A pathway, which is essential for the survival of persisters . Resistance to this compound is primarily driven by genetic variation in the pncA gene, which encodes the enzyme that converts this compound into pyrazinoic acid .
Temporal Effects in Laboratory Settings
The effects of this compound have been extensively studied in laboratory settings. It has been found to have high sterilizing activity, particularly in combination with other TB drugs
Metabolic Pathways
This compound is involved in the metabolic pathways of Mycobacterium tuberculosis. The pncA gene product, pyrazinamidase, is involved in the conversion of the prodrug this compound to its active form, pyrazinoic acid .
Transport and Distribution
This compound diffuses into active M. tuberculosis that express the pyrazinamidase enzyme. The active form, pyrazinoic acid, can leak out under acidic conditions to be converted to the protonated conjugate acid, which readily diffuses back into the bacilli and accumulates intracellularly .
準備方法
Synthetic Routes and Reaction Conditions: Pyrazinamide can be synthesized through several methods:
2-Cyanopyrazine Hydration: This method involves the hydration of 2-cyanopyrazine to produce this compound.
2-Pyrazinecarboxamide Formation: Another method involves the reaction of pyrazine with formamide in the presence of hydrogen peroxide and ferrous sulfate to yield this compound.
2-Pyrazinecarboxylate Ammonolysis: This method uses 2-pyrazinecarboxylate, which undergoes ammonolysis in the presence of ammonia to form this compound.
Industrial Production Methods: The industrial production of this compound primarily relies on the hydration of 2-cyanopyrazine due to its high yield and scalability. This method involves the use of catalysts and controlled reaction conditions to ensure high purity and efficiency .
Types of Reactions:
Oxidation: this compound can undergo oxidation reactions, particularly in the presence of strong oxidizing agents.
Reduction: It can be reduced to its corresponding amine derivative under specific conditions.
Substitution: this compound can participate in substitution reactions, where the amide group can be replaced by other functional groups.
Common Reagents and Conditions:
Oxidizing Agents: Hydrogen peroxide, potassium permanganate.
Reducing Agents: Sodium borohydride, lithium aluminum hydride.
Substitution Reagents: Various alkylating agents and nucleophiles.
Major Products:
Oxidation Products: Pyrazine-2-carboxylic acid.
Reduction Products: Pyrazine-2-carboxamide.
Substitution Products: Various substituted pyrazine derivatives.
科学的研究の応用
Pyrazinamide has a wide range of applications in scientific research:
Chemistry: It is used as a precursor in the synthesis of various pyrazine derivatives.
Biology: this compound is studied for its effects on bacterial cell walls and its role in inhibiting fatty acid synthesis.
Medicine: It is a crucial component in the treatment of tuberculosis, particularly in combination therapies.
Industry: this compound derivatives are explored for their potential use in agricultural chemicals and other industrial applications
類似化合物との比較
Isoniazid: Another first-line antituberculous agent that inhibits the synthesis of mycolic acids, essential components of the bacterial cell wall.
Rifampicin: A broad-spectrum antibiotic that inhibits bacterial RNA synthesis.
Ethambutol: Inhibits the synthesis of arabinogalactan, a component of the mycobacterial cell wall.
Uniqueness of Pyrazinamide: this compound is unique in its ability to target Mycobacterium tuberculosis within acidic environments, such as those found in macrophages. This property allows it to be effective against both replicating and dormant bacterial populations, making it a critical component of short-course tuberculosis therapy .
特性
IUPAC Name |
pyrazine-2-carboxamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C5H5N3O/c6-5(9)4-3-7-1-2-8-4/h1-3H,(H2,6,9) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
IPEHBUMCGVEMRF-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1=CN=C(C=N1)C(=O)N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C5H5N3O |
Source
|
| Record name | PYRAZINAMIDE | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/20970 | |
| Description | CAMEO Chemicals is a chemical database designed for people who are involved in hazardous material incident response and planning. CAMEO Chemicals contains a library with thousands of datasheets containing response-related information and recommendations for hazardous materials that are commonly transported, used, or stored in the United States. CAMEO Chemicals was developed by the National Oceanic and Atmospheric Administration's Office of Response and Restoration in partnership with the Environmental Protection Agency's Office of Emergency Management. | |
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| Record name | pyrazinamide | |
| Source | Wikipedia | |
| URL | https://en.wikipedia.org/wiki/Pyrazinamide | |
| Description | Chemical information link to Wikipedia. | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID9021215 |
Source
|
| Record name | Pyrazinamide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID9021215 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
123.11 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Pyrazinamide is a white powder. Sublimes from 318 °F. (NTP, 1992), Solid |
Source
|
| Record name | PYRAZINAMIDE | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/20970 | |
| Description | CAMEO Chemicals is a chemical database designed for people who are involved in hazardous material incident response and planning. CAMEO Chemicals contains a library with thousands of datasheets containing response-related information and recommendations for hazardous materials that are commonly transported, used, or stored in the United States. CAMEO Chemicals was developed by the National Oceanic and Atmospheric Administration's Office of Response and Restoration in partnership with the Environmental Protection Agency's Office of Emergency Management. | |
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| Record name | Pyrazinamide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014483 | |
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Boiling Point |
SUB (NTP, 1992) |
Source
|
| Record name | PYRAZINAMIDE | |
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Solubility |
>18.5 [ug/mL] (The mean of the results at pH 7.4), Soluble (NTP, 1992), Solubility (mg/ml, 25 °C): methanol 13.8; absolute ethanol 5.7; isopropanol 3.8; ether 1.0; isooctane 0.01; chloroform 7.4, In water, 15 mg/ml @ 25 °C, 9.37e+01 g/L |
Source
|
| Record name | SID8139959 | |
| Source | Burnham Center for Chemical Genomics | |
| URL | https://pubchem.ncbi.nlm.nih.gov/bioassay/1996#section=Data-Table | |
| Description | Aqueous solubility in buffer at pH 7.4 | |
| Record name | PYRAZINAMIDE | |
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| Record name | Pyrazinamide | |
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| Record name | Pyrazinamide | |
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| URL | http://www.hmdb.ca/metabolites/HMDB0014483 | |
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Mechanism of Action |
Pyrazinamide diffuses into active _M. tuberculosis_ that express pyrazinamidase enzyme that converts pyrazinamide to the active form pyrazinoic acid. Pyrazinoic acid can leak out under acidic conditions to be converted to the protonated conjugate acid, which is readily diffused back into the bacilli and accumulate intracellularly. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH. Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesise fatty acids. However, this theory was thought to have been discounted. However, further studies reproduced the results of FAS I inhibition as the putative mechanism first in whole cell assay of replicating M. tuberculosis bacilli which have shown that pyrazinoic acid and its ester inhibit the synthesis of fatty acids. This study was followed by in vitro assay of tuberculous FAS I enzyme that tested the activity with pyrazinamide, pyrazinoic acid and several classes of pyrazinamide analogs. Pyrazinamide and its analogs inhibited the activity of purified FAS I. It has also been suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. Pyrazinoic acid has also been shown to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation. This may explain the ability of the drug to kill dormant mycobacteria., Pyrazinamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of the infection and the susceptibility of the infecting organism. In vitro and in vivo, the drug is active only at a slightly acidic pH. The exact mechanism of action of pyrazinamide has not been fully elucidated. The antimycobacterial activity of pyrazinamide appears to partly depend on conversion of the drug to pyrazinoic acid. Susceptible strains of Mycobacterium tuberculosis produce pyrazinamidase, an enzyme that deaminates pyrazinamide to pyrazinoic acid, and the in vitro susceptibility of a given strain of the organism appears to correspond to its pyrazinamidase activity. In vitro studies indicate that pyrazinoic acid has specific antimycobacterial activity against Mycobacterium tuberculosis. In addition, the fact that pyrazinoic acid lowers the pH of the environment below that which is necessary for growth of Mycobacterium tuberculosis appears to contribute to the drug's antimycobacterial activity in vitro., Unknown; pyrazinamide may be bacteriostatic or bactericidal, depending on its concentration and the susceptibility of the organism. It is active in vitro at an acidic pH of 5.6 or less, similar to that found in early, active tubercular inflammatory lesions. |
Source
|
| Record name | Pyrazinamide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00339 | |
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Color/Form |
Crystals, Crystals from water or alcohol, Crystals from water or ethyl alcohol | |
CAS No. |
98-96-4 |
Source
|
| Record name | PYRAZINAMIDE | |
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Melting Point |
376 to 379 °F (NTP, 1992), 192 °C |
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| Record name | PYRAZINAMIDE | |
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Synthesis routes and methods I
Procedure details
Diethylaniline (0.33 μL, 2.1 μmol, 1.1 equiv) was added in one portion to a stirred solution of the amine (1.0 mg, 1.9 μmol, 1 equiv) in THF (0.2 mL) at 0° C. under an argon atmosphere and the solution was stirred for 5 min. 2-Pyrazinecarboxylic acid (0.31 mg, 2.5 μmol, 1.3 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.48 mg, 2.5 μmol, 1.3 equiv) and 1-hydroxybenzotriazole (0.31 mg, 2.3 μmol, 1.2 equiv) were then added separately, each in one portion, to the above solution at 0° C. The reaction mixture was warmed to 23° C. over 17 h 40 min, then was quenched with saturated aqueous ammonium chloride solution (3 mL). The mixture was diluted with ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layer was dried over sodium sulfate. Concentration in vacuo left a white solid, which was purified by flash column chromatography (80% ethyl acetate-hexanes) to give the pyrazine-2-carboxylic acid amide derivative (1.1 mg, 92%) as a white solid.
[Compound]
Name
amine
Quantity
1 mg
Type
reactant
Reaction Step One
Quantity
0.48 mg
Type
reactant
Reaction Step Two
Yield
92%
Synthesis routes and methods II
Procedure details
To a 15-mL polypropylene centrifuge tube was added 3.73 mL of 50 mM potassium phosphate buffer (pH 7.0), 1.0 mL of a suspension of 22.1 mg dry cell weight E. coli SW132 wet cells (prepared as described in Example 10) in 50 mM potassium phosphate buffer (pH 7.0), and 0.2694 g of pyrazinecarbonitrile. The final concentration of pyrazinecarbonitrile was 0.512 M. The reaction mixture was mixed on a rotating platform at 23° C. After 15 min, 7.50 mL of 95:5 acetonitrile/water containing 0.30 M N,N-dimethylbenzamide (HPLC external standard) was added to the reaction, the resulting mixture centrifuged, and a 0.100 mL of the supernatant mixed with 0.900 mL of acetonitrile and analyzed by HPLC. The conversion of pyrazinecarbonitrile was 100%, and the yields of pyrazinamide and pyrazinecarboxylic acid were 100% and 0%, respectively.
Name
potassium phosphate
Quantity
3.73 mL
Type
reactant
Reaction Step One
[Compound]
Name
suspension
Quantity
1 mL
Type
reactant
Reaction Step One
Name
Synthesis routes and methods III
Procedure details
The mixture of (R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87, 240 mg, 0.71 mmol), 4-(1-methylpiperidin-4-yl)aniline (280 mg, 1.42 mmol), fine-powder cesium carbonate (930 mg, 2.84 mmol), Pd(OAc)2 (32 mg, 0.14 mmol), BINAP (88 mg, 0.14 mmol) in 20 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 2 hours. The mixture was cooled to RT, diluted with 100 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 15% MeOH in chloroform to isolate (R)-tert-butyl 1-(5-cyano-6-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (204) in >90% yield. It was dissolved in 30 mL MeOH and 3 mL DMSO. To it were added two NaOH solid bead (about 200 mg) and then 1 mL 30% H2O2. The mixture was stirred at RT for 2 hours, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 120 mL EtOAc, washed with water, concentrated in vacuo to dryness to give crude (R)-tert-butyl 1-(5-carbamoyl-6-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (205). It was treated with 40 mL commercial 4N HCl in dioxane for 40 min, and concentrated in vacuo to afford crude (R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (206) hydrochloride. Crude 206 hydrochloride (60 mg, 0.12 mmol) was dissolved in 3 mL DMF. To it were added DIEA (210 μL, 1.2 mmol) and dimethylcarbamoyl chloride (34 μL, 0.36 mmol). The mixture was stirred at RT for 1.5 hour, acidified with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-O-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (207) as HCl salt (36 mg). MS found for C25H36N8O2 as (M+H)+ 481.2, (M−H)− 479.3. UV: λ=268, 277, 306, 336, 372 nm.
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
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| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
Reactant of Route 1
Reactant of Route 1
Pyrazinamide
Reactant of Route 2
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Reactant of Route 3
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Reactant of Route 4
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Reactant of Route 5
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Reactant of Route 6
Pyrazinamide
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