Pyrazinamide
Synonym(s):2-Pyrazinecarboxamide;Pyrazinamide;Pyrazine-2-carboxamide;Pyrazinecarboxamide;Pyrazinoic acid amide
- CAS NO.:98-96-4
- Empirical Formula: C5H5N3O
- Molecular Weight: 123.11
- MDL number: MFCD00006132
- EINECS: 202-717-6
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-11-19 23:02:33
What is Pyrazinamide?
Absorption
Rapidly and well absorbed from the gastrointestinal tract.
Toxicity
Side effects include liver injury, arthralgias, anorexia, nausea and vomiting, dysuria,malaise and fever, sideroblastic anemia, adverse effects on the blood clotting mechanism or vascular integrity, and hypersensitivity reactions such as urticaria, pruritis and skin rashes.
Description
Pyrazinamide was synthesized in 1952, and it is the nitrogen-analog of nicotinamide. It exhibits hepatotoxicity. Synonyms of this drug are dexambutol, miambutol, esnbutol, ebutol, and others.
Chemical properties
Crystalline Solid
The Uses of Pyrazinamide
Pyrazinamide is used therapeutically as an antitubercular agent. Pyrazinamide is used to form polymeric copper complexes, create pyrazine carboxamide scaffolds useful as FXs inhibitors, and as a component of mycobacteria identification kits. It is used to study liver toxicity prevention and mechanisms of resistance .
The Uses of Pyrazinamide
Antibacterial (tuberculostatic)
The Uses of Pyrazinamide
An antibacterial agent used to study liver toxicity prevention
Background
A pyrazine that is used therapeutically as an antitubercular agent.
Indications
For the initial treatment of active tuberculosis in adults and children when combined with other antituberculous agents.
What are the applications of Application
Pyrazinamide is an antibacterial agent used to study liver toxicity prevention
Indications
Pyrazinamide is a synthetic analogue of nicotinamide. Its exact mechanism of action is not known, although its target appears to be the mycobacterial fatty acid synthetase involved in mycolic acid biosynthesis. Pyrazinamide requires an acidic environment, such as that found in the phagolysosomes, to express its tuberculocidal activity. Thus, pyrazinamide is highly effective on intracellular mycobacteria. The mycobacterial enzyme pyrazinamidase converts pyrazinamide to pyrazinoic acid, the active form of the drug.A mutation in the gene (pncA) that encodes pyrazinamidase is responsible for drug resistance; resistance can be delayed through the use of drug combination therapy.
Definition
ChEBI: Pyrazinecarboxamide is a monocarboxylic acid amide resulting from the formal condensation of the carboxy group of pyrazinoic acid (pyrazine-2-carboxylic acid) with ammonia. A prodrug for pyrazinoic acid, pyrazinecarboxamide is used as part of multidrug regimens for the treatment of tuberculosis. It has a role as an antitubercular agent and a prodrug. It is a member of pyrazines, a N-acylammonia and a monocarboxylic acid amide.
Antimicrobial activity
It is principally active against actively metabolizing intracellular bacilli and those in acidic, anoxic inflammatory lesions. Activity against M. tuberculosis is highly pH dependent: at pH 5.6 the MIC is 8–16 mg/L, but it is almost inactive at neutral pH. Other mycobacterial species, including M. bovis, are resistant. Activity requires conversion to pyrazinoic acid by the mycobacterial enzyme pyrazinamidase, encoded for by the pncA gene, which is present in M. tuberculosis but not M. bovis. A few resistant strains lack mutations in pncA, indicating alternative mechanisms for resistance, including defects in transportation of the agent into the bacterial cell.
Acquired resistance
Drug resistance is uncommon and cross-resistance to other antituberculosis agents does not occur. Susceptibility testing is technically demanding as it requires very careful control of the pH of the medium, but molecular methods for detection of resistance-conferring mutations are available.
General Description
White powder. Sublimes from 318°F.
General Description
Pyrazinecarboxamide (PZA) occurs as a white crystalline powder that is sparingly soluble in water and slightly soluble in polar organic solvents. Its antitubercular properties were discovered as a result of an investigation of heterocyclic analogs of nicotinic acid, with which it is isosteric. Pyrazinamide has recently been elevated to first-line status in short-term tuberculosis treatment regimens because of its tuberculocidal activity and comparatively low short-term toxicity. Since pyrazinamide is not active against metabolically inactive tubercle bacilli, it is not considered suitable for long-term therapy. Potential hepatotoxicity also obviates long-term use of the drug. Pyrazinamide is maximally effective in the low pH environment that exists in macrophages (monocytes). Evidence suggests bioactivation of pyrazinamide to pyrazinoic acid by an amidase present in mycobacteria.
Air & Water Reactions
Water soluble.
Reactivity Profile
Pyrazinamide is a carbamate ester. Incompatible with strong acids and bases, and especially incompatible with strong reducing agents such as hydrides. May react with active metals or nitrides to produce flammable gaseous hydrogen. Incompatible with strongly oxidizing acids, peroxides, and hydroperoxides.
Pharmaceutical Applications
Like isoniazid, pyrazinamide is a synthetic nicotinamide analog, although its mode of action is quite distinct.
Biochem/physiol Actions
The active moiety of pyrazinamide is pyrazinoic acid (POA). POA is thought to disrupt membrane energetics and inhibit membrane transport function at acid pH in Mycobacterium tuberculosis. Iron enhances the antituberculous activity of pyrazinamide . Pyrazinamide and its analogs have been shown to inhibit the activity of purified FAS I.
Pharmacokinetics
Pyrazinamide kills or stops the growth of certain bacteria that cause tuberculosis (TB). It is used with other drugs to treat tuberculosis. It is a highly specific agent and is active only against Mycobacterium tuberculosis. In vitro and in vivo, the drug is active only at a slightly acid pH. Pyrazinamie gets activated to Pyrazinoic acid in the bacilli where it interferes with fatty acid synthase FAS I. This interferes with the bacteriums ability to synthesize new fatty acids, required for growth and replication.
Pharmacokinetics
Oral absorption: >90%
Cmax 20–22 mg/kg oral: 10–50 mg/L after 2 h
Plasma half-life: c. 9 h
Plasma protein binding: c. 50%
It readily crosses the blood–brain barrier, achieving CSF
concentrations similar to plasma levels. It is metabolized to
pyrazinoic acid in the liver and oxidized to inactive metabolites,
which are excreted in the urine, although about 70% of
an oral dose is excreted unchanged.
Pharmacology
Pyrazinamide is well absorbed from the GI tract and is widely distributed throughout the body. It penetrates tissues, macrophages, and tuberculous cavities and has excellent activity on the intracellular organisms; its plasma half-life is 9 to 10 hours in patients with normal renal function. The drug and its metabolites are excreted primarily by renal glomerular filtration.
Clinical Use
Tuberculosis (a component of the early, intensive phase of short-course therapy)
Clinical Use
Pyrazinamide is an essential component of the multidrug short-term therapy of tuberculosis. In combination with isoniazid and rifampin, it is active against the intracellular organisms that may cause relapse.
Side Effects
It is usually well tolerated. Moderate elevations of serum
transaminases occur early in treatment. Severe hepatotoxicity
is uncommon with standard dosage, except in patients with
pre-existing liver disease.
Its principal metabolite, pyrazinoic acid, inhibits renal
excretion of uric acid, but gout is extremely rare. An unrelated
arthralgia, notably of the shoulders and responsive to
analgesics, also occurs.
Other side effects include anorexia, nausea, mild flushing
of the skin and photosensitization.
Side Effects
Hepatotoxicity is the major concern in 15% of pyrazinamide recipients. It also can inhibit excretion of urates, resulting in hyperuricemia. Nearly all patients taking pyrazinamide develop hyperuricemia and possibly acute gouty arthritis. Other adverse effects include nausea, vomiting, anorexia, drug fever, and malaise. Pyrazinamide is not recommended for use during pregnancy.
Synthesis
Pyrazinamide, pyrazincarboxamide (34.1.11), is synthesized from quinoxaline (34.1.7) by reacting o-phenylendiamine with glyoxal. Oxidation of this compound with sodium permanganate gives pyrazin-2,3-dicarboxylic acid (34.1.8). Decarboxylation of the resulting product by heating gives pyrazin-2-carboxylic acid (34.1.9). Esterifying the resulting acid with methanol in the presence of hydrogen chloride and further reaction of this ester (34.1.10) with ammonia gives pyrazinamide.
Pyrazinamide was synthesized in 1952, and it is the nitrogen-analog of nicotinamide. It exhibits hepatotoxicity. Synonyms of this drug are dexambutol, miambutol, esnbutol, ebutol, and others.
Drug interactions
Potentially hazardous interactions with other drugs
Ciclosporin: on limited evidence, pyrazinamide
appears to reduce ciclosporin levels.
Metabolism
Hepatic.
Metabolism
Pyrazinamide is metabolised mainly in the liver by
hydrolysis to the major active metabolite pyrazinoic acid,
which is subsequently hydroxylated to the major excretory
product 5-hydroxypyrazinoic acid.
It is excreted via the kidneys mainly by glomerular
filtration. About 70% of a dose appears in the urine
within 24 hours mainly as metabolites.
Purification Methods
The amide crystallises from water, EtOH or 1:1 hexane/EtOH in four modifications viz -form, -form, -form and form. [R. & S.rum Acta Cryst 28B 1677 1972, Beilstein 25 III/IV 772.]
Properties of Pyrazinamide
Melting point: | 189-191 °C (lit.) |
Boiling point: | 229.19°C (rough estimate) |
Density | 1.3260 (rough estimate) |
refractive index | 1.5900 (estimate) |
Flash point: | >110°(230°F) |
storage temp. | 2-8°C |
solubility | H2O: soluble50mg/mL |
form | Crystalline Powder or Needles |
pka | 0.5(at 25℃) |
color | White |
PH | 7 (H2O) |
Water Solubility | 15 mg/mL |
Merck | 14,7956 |
BRN | 112306 |
CAS DataBase Reference | 98-96-4(CAS DataBase Reference) |
NIST Chemistry Reference | Pyrazine carboxamide(98-96-4) |
EPA Substance Registry System | Pyrazinamide (98-96-4) |
Safety information for Pyrazinamide
Signal word | Warning |
Pictogram(s) |
Exclamation Mark Irritant GHS07 |
GHS Hazard Statements |
H315:Skin corrosion/irritation H319:Serious eye damage/eye irritation H335:Specific target organ toxicity, single exposure;Respiratory tract irritation |
Precautionary Statement Codes |
P261:Avoid breathing dust/fume/gas/mist/vapours/spray. P271:Use only outdoors or in a well-ventilated area. P280:Wear protective gloves/protective clothing/eye protection/face protection. |
Computed Descriptors for Pyrazinamide
Abamectin manufacturer
Calyx Chemicals and Pharmaceuticals Ltd
Dr. Silviu Pharmachem Pvt., Ltd.
Ralington Pharma
Ishita Drugs And Industries Ltd
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