Isoniazid-d4
Overview
Description
Isoniazid-d4 is a deuterated form of isoniazid, an antibiotic primarily used for the treatment of tuberculosis. The deuterium atoms in this compound replace the hydrogen atoms, which can be useful in various scientific studies, particularly in the field of pharmacokinetics and metabolic research. This compound retains the antibacterial properties of isoniazid, making it a valuable tool in both clinical and research settings.
Scientific Research Applications
Isoniazid-d4 has a wide range of applications in scientific research:
Chemistry: Used as a tracer in reaction mechanisms and studies involving isotope effects.
Biology: Helps in studying metabolic pathways and enzyme kinetics.
Medicine: Utilized in pharmacokinetic studies to understand the metabolism and distribution of isoniazid in the body.
Industry: Employed in the development of new drugs and therapeutic agents.
Mechanism of Action
Target of Action
Isoniazid-d4, a deuterated form of Isoniazid, is primarily active against organisms of the genus Mycobacterium , specifically M. tuberculosis, M. bovis and M. kansasii . It is a highly specific agent, ineffective against other microorganisms .
Mode of Action
This compound is a prodrug and must be activated by bacterial catalase . Specifically, activation is associated with the reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with oxygen to form an oxyferrous enzyme complex . The antimicrobial activity of this compound is selective for mycobacteria, likely due to its ability to inhibit mycolic acid synthesis , which interferes with cell wall synthesis, thereby producing a bactericidal effect . It also disrupts DNA, lipid, carbohydrate, and nicotinamide adenine dinucleotide (NAD) synthesis and/or metabolism .
Biochemical Pathways
The biochemical pathways affected by this compound are primarily related to the synthesis of mycolic acids, an essential component of the bacterial cell wall . By inhibiting mycolic acid synthesis, this compound interferes with cell wall synthesis, leading to a bactericidal effect . It also disrupts DNA, lipid, carbohydrate, and NAD synthesis and/or metabolism .
Pharmacokinetics
For its parent compound isoniazid, the estimated absorption rate constant (k a ), oral clearance (cl/f), and apparent volume of distribution (v 2 /f) were reported as 394 ± 044 h −1, 182 ± 245 L⋅h −1, and 568 ± 553 L, respectively . The NAT2 genotypes had different effects on the CL/F and F M .
Result of Action
The result of this compound action is the inhibition of the growth of Mycobacterium species, specifically M. tuberculosis, M. bovis and M. kansasii . It is bactericidal when mycobacteria grow rapidly and bacteriostatic when they grow slowly .
Safety and Hazards
Biochemical Analysis
Biochemical Properties
Isoniazid-d4 plays a significant role in biochemical reactions. It interacts with various enzymes, proteins, and other biomolecules. The drug’s antimicrobial activity is selective for mycobacteria, likely due to its ability to inhibit mycolic acid synthesis, which interferes with cell wall synthesis . This interaction disrupts DNA, lipid, carbohydrate, and nicotinamide adenine dinucleotide (NAD) synthesis and/or metabolism .
Cellular Effects
This compound has profound effects on various types of cells and cellular processes. It influences cell function by disrupting DNA, lipid, carbohydrate, and NAD synthesis and/or metabolism . It is active against both intracellular and extracellular Mycobacterium tuberculosis .
Molecular Mechanism
The molecular mechanism of this compound involves its ability to inhibit mycolic acid synthesis, which interferes with cell wall synthesis, thereby producing a bactericidal effect . It also disrupts DNA, lipid, carbohydrate, and NAD synthesis and/or metabolism .
Temporal Effects in Laboratory Settings
It is known that the organism is most susceptible to this compound during its logarithmic phase of growth .
Dosage Effects in Animal Models
The effects of this compound vary with different dosages in animal models. For instance, in a mouse model of pellagra-related nausea induced by feeding mice a low-niacin diet and administering this compound, it was observed that the drug induced pica in mice fed a low-niacin diet .
Metabolic Pathways
This compound is involved in several metabolic pathways. Enzymatic acylation of this compound by N-arylaminoacetyl transferases (NATs) reduces the therapeutic effectiveness of the drug . This acetylation represents a major metabolic pathway for this compound in human beings .
Preparation Methods
Synthetic Routes and Reaction Conditions: The synthesis of isoniazid-d4 typically involves the introduction of deuterium atoms into the isoniazid molecule. One common method is the catalytic exchange of hydrogen with deuterium in the presence of a deuterium source such as deuterium oxide (D2O). The reaction is usually carried out under controlled conditions to ensure the selective incorporation of deuterium atoms.
Industrial Production Methods: Industrial production of this compound follows similar principles but on a larger scale. The process involves the use of specialized reactors and catalysts to achieve high yields and purity. The reaction conditions, such as temperature, pressure, and the concentration of deuterium source, are optimized to maximize the efficiency of the deuteration process.
Chemical Reactions Analysis
Types of Reactions: Isoniazid-d4 undergoes various chemical reactions similar to its non-deuterated counterpart. These include:
Oxidation: this compound can be oxidized to form isonicotinic acid.
Reduction: It can be reduced to form hydrazine derivatives.
Substitution: The compound can undergo nucleophilic substitution reactions, particularly at the hydrazide group.
Common Reagents and Conditions:
Oxidation: Common oxidizing agents include potassium permanganate and hydrogen peroxide.
Reduction: Reducing agents such as sodium borohydride or lithium aluminum hydride are used.
Substitution: Nucleophiles like amines or thiols can be used under basic conditions.
Major Products Formed:
Oxidation: Isonicotinic acid.
Reduction: Hydrazine derivatives.
Substitution: Various substituted hydrazides.
Comparison with Similar Compounds
Isoniazid: The non-deuterated form, widely used in tuberculosis treatment.
Rifampicin: Another first-line antituberculosis drug with a different mechanism of action.
Ethambutol: Used in combination with isoniazid for tuberculosis treatment.
Uniqueness of Isoniazid-d4: The incorporation of deuterium atoms in this compound provides unique advantages in research, such as improved stability and the ability to trace metabolic pathways more accurately. This makes it a valuable tool in both clinical and laboratory settings, offering insights that are not possible with non-deuterated compounds.
Properties
IUPAC Name |
2,3,5,6-tetradeuteriopyridine-4-carbohydrazide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C6H7N3O/c7-9-6(10)5-1-3-8-4-2-5/h1-4H,7H2,(H,9,10)/i1D,2D,3D,4D |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
QRXWMOHMRWLFEY-RHQRLBAQSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1=CN=CC=C1C(=O)NN |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
[2H]C1=C(N=C(C(=C1C(=O)NN)[2H])[2H])[2H] |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C6H7N3O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID60662042 |
Source
|
| Record name | (~2~H_4_)Pyridine-4-carbohydrazide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID60662042 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
141.16 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
CAS No. |
774596-24-6 |
Source
|
| Record name | (~2~H_4_)Pyridine-4-carbohydrazide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID60662042 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Synthesis routes and methods I
Procedure details
Synthesis routes and methods II
Procedure details
Q1: Why is Isoniazid-d4 used as an internal standard for Isoniazid quantification in this study?
A: this compound, a deuterated form of Isoniazid, serves as an ideal internal standard due to its similar chemical behavior to the analyte (Isoniazid) during sample preparation and analysis. Using a stable isotope-labeled analog like this compound helps correct for variability in extraction efficiency, ionization suppression, and other factors that can impact accurate quantification. [] This leads to more reliable and precise measurements of Isoniazid concentrations in serum samples.
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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.
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