98-96-4 Usage
Uses
Used in Pharmaceutical Industry:
Pyrazinamide is used as an antitubercular agent for the treatment of tuberculosis. It is particularly effective against Mycobacterium tuberculosis, the causative agent of tuberculosis, and is often used in combination with other antitubercular drugs to enhance treatment efficacy.
Used in Chemical Research:
Pyrazinamide is used to form polymeric copper complexes and create pyrazine carboxamide scaffolds, which are useful as FXs inhibitors. These applications contribute to the development of new drugs and therapeutic agents.
Used in Diagnostic Industry:
Pyrazinamide serves as a component of mycobacteria identification kits, aiding in the accurate identification and diagnosis of mycobacterial infections.
Used in Toxicology Research:
Pyrazinamide is used to study liver toxicity prevention and the mechanisms of resistance, providing valuable insights into the development of safer and more effective treatments for various diseases.
Used in Antibacterial Research:
Pyrazinamide is employed as an antibacterial agent to study liver toxicity prevention, further expanding its applications in the field of medicine and healthcare.
Anti-tuberculosis drug
Pyrazinamide is a second-line anti-tuberculosis drug, also known as formamide pyrazine, carbamoyl pyrazine, and isonicotinic acid amine. At room temperature, it appears as a white crystalline powder and is slightly soluble in water and is odorless with slightly bitter taste. It has a good antibacterial effect against human type Mycobacterium tuberculosis with the strongest bactericidal effect at the range of pH value being between 5-5.5. It has especially optimal bactericidal effect against the Mycobacterium tuberculosis inside the slow-growing phagocytic cells in acidic environment. After pyrazinamide penetrates into the phagocytic cells and enter into the body of Mycobacterium tuberculosis, lactamase in vivo make it be de-amidated, being converted to pyrazine acid to play the antibacterial effect.
The in vivo inhibitory concentration is 12.5μg/ml with the concentration of 50 μg/ml being able to kill the Mycobacterium tuberculosis. The inhibitory concentration against Mycobacterium tuberculosis in vivo is 10 times lower than that in vitro with almost no inhibitory effect in a neutral, alkaline environment.
Its anti-bacterial effect is between streptomycin and paramisansodium. It has great toxicity and can easy to produce drug resistance and should be used in combination with other anti-TB drugs.
Pyrazinamide has similar chemical structure with nicotinamide and can interfere with the dehydrogenase through substitution of nicotinamide, therefore preventing the dehydrogenation and inhibiting the utilization of oxygen by Mycobacterium tuberculosis, causing death of the bacteria due to failure of normal metabolism.
It is oral easily absorbed and is widely distributed in body tissues and fluids including liver, lung, cerebrospinal fluid, kidney and bile. After 2 hours, its plasma concentration can reach peak. The concentration of cerebrospinal fluid is similar as blood concentrations. It can subject to hepatic metabolism to be hydrolyzed to the pyrazine acid that is a kind of metabolite having antimicrobial activity, then further being hydroxylated into inactive metabolites and excreted in urine after glomerular filtration. The t1/2 is about 8 to 10 hours. It can be used in combination with other kind of anti-TB drugs fro the treatment of some complex cases of tuberculosis and tubercular meningitis patients.
Drug Interactions
1, when being combined with allopurinol, colchicine, probenecid, and sulfinpyrazone, pyrazinamide can increase the serum uric acid concentration and further reduce the efficacy of the above drugs on gout. Therefore, when being combined with pyrazinamide, the above drugs should be subject to dose adjustment in order to control hyperuricemia and gout.
2, it can enhance the adverse reactions when combined with B sulfur isonicotinoyl amine.
3, when cyclosporine is used simultaneously with pyrazinamide, the blood concentration of the former drug may be reduced, and therefore the blood concentration needs to be monitored and we should adjust the dose if necessary.
4, it has synergistic effect when combined with isoniazid and rifampin and can delay the development of drug resistance.
The above information is edited by the lookchem of Dai Xiongfeng.
Indications
It can be used in combination with other anti-TB drugs for the treatment of tuberculosis that failed to be cured by first-line anti-TB drugs (such as streptomycin, isoniazid, rifampicin and ethambutol).
This product is only valid against mycobacteria.
In the past, pyrazinamide was used as second-line drugs, commonly applied to the patients undergoing retirement due to failure to be cured by other anti-TB drugs. A large number of clinical studies have shown: the short course regimen containing this product is suitable for being applied to the newly diagnosed sputum-positive cases. It is generally applied for 2 to 3 months. This protocol can enable a significant reduction of the re-positive rate of Mycobacterium tuberculosis after the end of treatment.
This product has been well considered as the composition of triple or quadruple protocols in short course chemotherapy.
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.
Dosage
When used in combination therapy with other anti-TB drugs, the common dose of adult oral administration is: every 6 hours according to the weight 5-8.75mg/kg, or every eight hours according to the weight 6.7-11.7mg/kg; the highest value is 3 g daily.
Upon treatment of the infection of isoniazid resistant bacteria, you can increase the dose to 60 mg/kg daily.
Children should take with caution, the necessary reference amount should be: 20-25mg/kg daily, it should be separately orally administrated in 3 times with the maximum dose being 2 g daily, the treatment course is generally 2 to 3 months, it can not be more than six months.
First aid treatment
1. Misusage patients should be immediately subject to gastric lavage and catharsis.
2. If liver dysfunction occurs during the course of treatment, the drug should be discontinued and routine liver-protection therapy should be applied.
3. Patients of gout should be given 0.25g/time probenecid (carboxymethyl benzene with oral administration in 3 times daily and being able to promote the excretion of uric acid.
4. Allergic patients should be given treatment with antihistamines and corticosteroids.
Adverse reactions and side effects
Long-term or high-dose application of the product is easy to cause liver damage and increased blood uric acid and can also cause gastrointestinal irritation and allergic reactions.
For patients of relative high incidence: loss of appetite, fever, unusual fatigue or weakness, yellowing of the eyes or skin (liver toxicity).
Persons of low incidence: chills, joint pain (especially in the big toe, the condyle, knee) or diseased joints skin taut fever (acute gouty joint pain).
During the treatment course of this drug, the blood uric acid can increase and can cause acute gout that should be subject to determination of serum uric acid.
Adverse reactions are dose-related. After current application of conventional dosage, adverse reactions have been rarely observed.
Hepatic impairment: administration of drug for 3g daily with about 15% of patients getting liver damage, hepatomegaly, tenderness, elevated transaminases and jaundice. Currently upon applying 1.5 g daily for a 3-month treatment course, reactions of liver toxicity are rare.
Joint pain: PZA metabolites can inhibit the excretion of uric acid, causing hyperuricemia and gout-like performance with resumption after stopping drug.
Gastrointestinal reactions: loss of appetite, nausea, vomiting.
Allergies: occasionally fever and rash, and even jaundice.
Skin reactions: in some individual cases, the patients are light sensitive with the exposed parts of the skin being bright red brown. Patients subject to the long-term medication have their skins be bronze that can be gradually restored after the withdrawal of the drug.
For diabetic patients taking pyrazinamide, it is difficult to control the level of blood sugar.
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.
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.
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.
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.
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
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.
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.
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
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.]
Check Digit Verification of cas no
The CAS Registry Mumber 98-96-4 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 9 and 8 respectively; the second part has 2 digits, 9 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 98-96:
(4*9)+(3*8)+(2*9)+(1*6)=84
84 % 10 = 4
So 98-96-4 is a valid CAS Registry Number.
InChI:InChI=1/C5H5N3O/c6-5(9)4-3-7-1-2-8-4/h1-3H,(H2,6,9)
98-96-4Relevant articles and documents
A “universal” catalyst for aerobic oxidations to synthesize (hetero)aromatic aldehydes, ketones, esters, acids, nitriles, and amides
Bartling, Stephan,Beller, Matthias,Chandrashekhar, Vishwas G.,Jagadeesh, Rajenahally V.,Rabeah, Jabor,Rockstroh, Nils,Senthamarai, Thirusangumurugan
supporting information, p. 508 - 531 (2022/02/11)
Functionalized (hetero)aromatic compounds are indispensable chemicals widely used in basic and applied sciences. Among these, especially aromatic aldehydes, ketones, carboxylic acids, esters, nitriles, and amides represent valuable fine and bulk chemicals, which are used in chemical, pharmaceutical, agrochemical, and material industries. For their synthesis, catalytic aerobic oxidation of alcohols constitutes a green, sustainable, and cost-effective process, which should ideally make use of active and selective 3D metals. Here, we report the preparation of graphitic layers encapsulated in Co-nanoparticles by pyrolysis of cobalt-piperazine-tartaric acid complex on carbon as a most general oxidation catalyst. This unique material allows for the synthesis of simple, functionalized, and structurally diverse (hetero)aromatic aldehydes, ketones, carboxylic acids, esters, nitriles, and amides from alcohols in excellent yields in the presence of air.
Aerobic oxidation of primary amines to amides catalyzed by an annulated mesoionic carbene (MIC) stabilized Ru complex
Yadav, Suman,Reshi, Noor U Din,Pal, Saikat,Bera, Jitendra K.
, p. 7018 - 7028 (2021/11/17)
Catalytic aerobic oxidation of primary amines to the amides, using the precatalyst [Ru(COD)(L1)Br2] (1) bearing an annulated π-conjugated imidazo[1,2-a][1,8]naphthyridine-based mesoionic carbene ligand L1, is disclosed. This catalytic protocol is distinguished by its high activity and selectivity, wide substrate scope and modest reaction conditions. A variety of primary amines, RCH2NH2 (R = aliphatic, aromatic and heteroaromatic), are converted to the corresponding amides using ambient air as an oxidant in the presence of a sub-stoichiometric amount of KOtBu in tBuOH. A set of control experiments, Hammett relationships, kinetic studies and DFT calculations are undertaken to divulge mechanistic details of the amine oxidation using 1. The catalytic reaction involves abstraction of two amine protons and two benzylic hydrogen atoms of the metal-bound primary amine by the oxo and hydroxo ligands, respectively. A β-hydride transfer step for the benzylic C-H bond cleavage is not supported by Hammett studies. The nitrile generated by the catalytic oxidation undergoes hydration to afford the amide as the final product. This journal is
Substrate access tunnel engineering for improving the catalytic activity of a thermophilic nitrile hydratase toward pyridine and pyrazine nitriles
Cheng, Zhongyi,Jiang, Shijin,Zhou, Zhemin
, p. 8 - 13 (2021/08/30)
Nitrile hydratase (NHase) is able to bio-transform nitriles into amides. As nitrile hydration being an exothermic reaction, a NHase with high activity and stability is needed for amide production. However, the widespread use of NHase for amide bio-production is limited by an activity-stability trade-off. In this study, through the combination of substrate access tunnel calculation, residue conservative analysis and site-saturation mutagenesis, a residue located at the substrate access tunnel entrance of the thermophilic NHase from extremophile Caldalkalibacillus thermarum TA2. A1, βLeu48, was semi-rationally identified as a potential gating residue that directs the enzymatic activity toward various pyridine and pyrazine nitriles. The specific activity of the corresponding mutant βL48H towards 3-cyanopyridine, 2-cyanopyridine and cyanopyrazine were 2.4-fold, 2.8-fold and 3.1-fold higher than that of its parent enzyme, showing a great potential in the industrial production of high-value pyridine and pyrazine carboxamides. Further structural analysis demonstrated that the βHis48 could form a long-lasting hydrogen bond with αGlu166, which contributes to the expansion of the entrance of substrate access tunnel and accelerate substrate migration.
IRAK DEGRADERS AND USES THEREOF
-
Paragraph 00920; 002790-002791, (2021/01/23)
The present invention provides compounds, compositions thereof, and methods of using the same. The compounds include an IRAK binding moiety capable of binding to IRAK4 and a degradation inducing moiety (DIM). The DIM could be DTM a ligase binding moiety (LBM) or lysine mimetic. The compounds could be useful as IRAK protein kinase inhibitors and applied to IRAK mediated disorders.
Arene-ruthenium(II)-phosphine complexes: Green catalysts for hydration of nitriles under mild conditions
Vyas, Komal M.,Mandal, Poulami,Singh, Rinky,Mobin, Shaikh M.,Mukhopadhyay, Suman
, (2019/12/11)
Three new arene-ruthenium(II) complexes were prepared by treating [{RuCl(μ-Cl)(η6-arene)}2] (η6-arene = p-cymene) dimer with tri(2-furyl)phosphine (PFu3) and 1,3,5-triaza-7-phosphaadamantane (PTA), respectively to obtain [RuCl2(η6-arene)PFu3] [Ru]-1, [RuCl(η6-arene)(PFu3)(PTA)]BF4 [Ru]-2 and [RuCl(η6-arene)(PFu3)2]BF4 [Ru]-3. All the complexes were structurally identified using analytical and spectroscopic methods including single-crystal X-ray studies. The effectiveness of resulting complexes as potential homogeneous catalysts for selective hydration of different nitriles into corresponding amides in aqueous medium and air atmosphere was explored. There was a remarkable difference in catalytic activity of the catalysts depending on the nature and number of phosphorus-donor ligands and sites available for catalysis. Experimental studies performed using structural analogues of efficient catalyst concluded a structural-activity relationship for the higher catalytic activity of [Ru]-1, being able to convert huge variety of aromatic, heteroaromatic and aliphatic nitriles. The use of eco-friendly water as a solvent, open atmosphere and avoidance of any organic solvent during the catalytic reactions prove the reported process to be truly green and sustainable.
Hydration of nitriles using a metal-ligand cooperative ruthenium pincer catalyst
Guo, Beibei,Otten, Edwin,De Vries, Johannes G.
, p. 10647 - 10652 (2019/12/02)
Nitrile hydration provides access to amides that are important structural elements in organic chemistry. Here we report catalytic nitrile hydration using ruthenium catalysts based on a pincer scaffold with a dearomatized pyridine backbone. These complexes catalyze the nucleophilic addition of H2O to a wide variety of aliphatic and (hetero)aromatic nitriles in tBuOH as solvent. Reactions occur under mild conditions (room temperature) in the absence of additives. A mechanism for nitrile hydration is proposed that is initiated by metal-ligand cooperative binding of the nitrile.
Modular Continuous Flow Synthesis of Imatinib and Analogues
Fu, Wai Chung,Jamison, Timothy F.
supporting information, p. 6112 - 6116 (2019/08/26)
A modular continuous flow synthesis of imatinib and analogues is reported. Structurally diverse imatinib analogues are rapidly generated using three readily available building blocks via a flow hydration/chemoselective C-N coupling sequence. The newly developed continuous flow hydration and amidation modules each exhibit a broad scope with good to excellent yields. Overall, the method described does not require solvent switches, in-line purifications, or packed-bed apparatuses due to the judicious manipulation of flow setups and solvent mixtures.
A Facile Synthesis of Substituted 2-(5-(Benzylthio)-1,3,4-oxadiazol-2-yl)pyrazine Using Microwave Irradiation and Conventional Method with Antioxidant and Anticancer Activities
Patil, Sanjeev R.,Sarkate, Aniket P.,Karnik, Kshipra S.,Arsondkar, Ashish,Patil, Vrushali,Sangshetti, Jaiprakash N.,Bobade, Anil S.,Shinde, Devanand B.
, p. 859 - 866 (2019/02/01)
A series of novel substituted 2-(5-(benzylthio)-1,3,4-oxadiazol-2-yl)pyrazine derivatives (6a–n) were synthesized under microwave irradiation and conventional conditions with less reaction time with good to excellent yields. All the synthesized compounds were screened for antioxidant and anticancer activities. Out of the 14 prepared derivatives, compounds 6f and 6m were most potent and active with antioxidant and anticancer activities, respectively. Also, the developed technique was simple, easy, and less time consuming.
Method for preparing pyrazinamide
-
Paragraph 0022-0032, (2019/06/30)
The invention discloses a method for preparing pyrazinamide. The method comprises the steps that 2-methyl pyrazine serves as a raw material, a metal catalyst is added, oxidation is conducted through an oxidant to obtain 2-aldehyde pyrazine, after oxidation is finished, ammonia serving as an aminating agent is added for an amination reaction, and pyrazinamide is obtained; the metal catalyst is ferrous salt. Accordingly, the reaction conditions of high temperature and high pressure in an original process are avoided, use of highly toxic raw materials is avoided, and the process is simplified. Bymeans of experiment and exploration, it is found that under the catalysis of the ferrous salt, the 2-methylpyrazine is oxidized through the oxidant and then reacts with the ammonia to produce the pyrazinamide, special reaction equipment is not needed for the reaction, and the yield is high (the yield can reach 85-95%). The method has the advantages of being safe and reliable on the whole, good ineconomic benefit and suitable for industrial production.
Corresponding amine nitrile and method of manufacturing thereof
-
Paragraph 0135; 0136; 0137; 0145, (2018/05/07)
The invention relates to a manufacturing method of nitrile. Compared with the prior art, the manufacturing method has the characteristics of significantly reduced using amount of an ammonia source, low environmental pressure, low energy consumption, low production cost, high purity and yield of a nitrile product and the like, and nitrile with a more complex structure can be obtained. The invention also relates to a method for manufacturing corresponding amine from nitrile.