イソニアジド
概要
説明
イソニアジドは、イソニコチン酸ヒドラジドとしても知られる合成抗菌剤であり、主に結核の治療と予防に使用されます。イソニアジドは、1912年に初めて合成され、1950年代に臨床現場に導入されました。 イソニアジドは、結核の原因となる細菌である結核菌に対して高い有効性と選択性を持ち、結核の第一選択薬として使用されています .
2. 製法
合成経路と反応条件： イソニアジドは、通常、イソニコチン酸とヒドラジン水和物の反応によって合成されます。このプロセスは、イソニコチン酸をアルコールとアシル化試薬でエステル化し、イソニコチン酸エステルを生成することから始まります。 このエステルを次にヒドラジン水和物と反応させると、イソニアジドが生成されます .
工業的生産方法： 工業的な環境では、イソニアジドの製造には次の手順が含まれます。
エステル化： イソニコチン酸は、酸触媒の存在下でアルコール（メタノールなど）とエステル化されます。
ヒドラジン分解： その後、エステルを制御された温度条件下でヒドラジン水和物と反応させて、イソニアジドを得ます。
3. 化学反応の分析
反応の種類： イソニアジドは、次のものを含むさまざまな化学反応を起こします。
酸化： イソニアジドは酸化されて、イソニコチン酸を生成することができます。
還元： イソニアジドは還元されて、ヒドラジン誘導体を生成することができます。
一般的な試薬と条件：
酸化： 過マンガン酸カリウムまたは過酸化水素を酸化剤として使用できます。
還元： 水素化ホウ素ナトリウムまたは水素化リチウムアルミニウムを還元剤として使用できます。
主な生成物：
酸化： イソニコチン酸。
還元： ヒドラジン誘導体。
4. 科学研究における用途
イソニアジドは、科学研究において幅広い用途を持っています。
化学： 有機合成における試薬として、およびさまざまな誘導体を合成するための前駆体として使用されます。
生物学： 細菌細胞壁合成への影響、および細菌の耐性機構における役割について研究されています。
作用機序
イソニアジドは、細菌酵素カタラーゼ・ペルオキシダーゼ（KatG）による活性化を必要とするプロドラッグです。活性化されると、イソニアジドは、ミコバクテリアの細胞壁の必須成分であるミコール酸の合成を阻害します。この阻害は細胞壁の合成を阻害し、細菌の細胞死につながります。 イソニアジドは、DNA、脂質、炭水化物、ニコチンアミドアデニンジヌクレオチド（NAD）の合成を阻害することによっても、細菌殺傷効果に貢献しています .
類似化合物：
リファンピシン： 細菌RNA合成を阻害する、もう1つの結核の第一選択薬です。
エタンブトール： アラビノシル転移酵素を標的にすることで、ミコバクテリアの細胞壁の合成を阻害します。
ピラジナミド： ミコバクテリアの細胞膜の代謝と輸送機能を阻害します
イソニアジドの独自性： イソニアジドの独自性は、ミコバクテリアの細胞壁にとって重要なミコール酸合成を標的にする、特異的な作用機序にあります。 イソニアジドは、潜伏性結核の単剤療法として、および活動性結核に対する他の薬剤との併用療法として使用できるため、結核治療において汎用性が高く不可欠な薬剤となっています .
科学的研究の応用
Isoniazid has a wide range of scientific research applications:
Chemistry: Used as a reagent in organic synthesis and as a precursor for the synthesis of various derivatives.
Biology: Studied for its effects on bacterial cell wall synthesis and its role in bacterial resistance mechanisms.
Medicine: Primarily used in the treatment and prevention of tuberculosis. .
Industry: Used in the production of pharmaceuticals and as an intermediate in the synthesis of other chemical compounds
生化学分析
Biochemical Properties
Isoniazid plays a crucial role in biochemical reactions, particularly in the inhibition of mycolic acid synthesis, which is essential for the bacterial cell wall. Isoniazid is a prodrug that requires activation by the bacterial enzyme catalase-peroxidase (KatG). Upon activation, isoniazid forms an adduct with nicotinamide adenine dinucleotide (NAD), which subsequently inhibits the enzyme InhA, an enoyl-acyl carrier protein reductase involved in mycolic acid synthesis . This inhibition disrupts the synthesis of mycolic acids, leading to the death of the mycobacteria.
Cellular Effects
Isoniazid exerts significant effects on various types of cells and cellular processes. In Mycobacterium tuberculosis, isoniazid inhibits cell wall synthesis, leading to cell lysis and death. In human cells, isoniazid can cause hepatotoxicity, which is believed to be mediated by the formation of reactive metabolites through the cytochrome P450 enzyme system . These metabolites can induce oxidative stress and damage cellular components, including lipids, proteins, and DNA. Additionally, isoniazid has been associated with pyridoxine (vitamin B6) deficiency, as it increases the excretion of pyridoxine, affecting cellular metabolism .
Molecular Mechanism
The molecular mechanism of isoniazid involves its activation by the bacterial enzyme KatG. The activated form of isoniazid interacts with NAD to form an adduct that inhibits the enzyme InhA . This inhibition prevents the synthesis of mycolic acids, which are vital components of the mycobacterial cell wall. The disruption of mycolic acid synthesis leads to the loss of cell wall integrity and ultimately the death of the bacterium. Additionally, isoniazid can induce the expression of genes involved in oxidative stress response, further contributing to its bactericidal effects .
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of isoniazid can change over time. Isoniazid is known to be relatively stable under standard storage conditions, but it can degrade when exposed to light and moisture . Over time, the degradation products of isoniazid can reduce its efficacy. Long-term exposure to isoniazid has been associated with hepatotoxicity in both in vitro and in vivo studies . The hepatotoxic effects are believed to be due to the accumulation of reactive metabolites that induce oxidative stress and liver damage.
Dosage Effects in Animal Models
The effects of isoniazid vary with different dosages in animal models. At therapeutic doses, isoniazid effectively inhibits the growth of Mycobacterium tuberculosis. At higher doses, isoniazid can cause toxic effects, including hepatotoxicity and neurotoxicity . In animal studies, high doses of isoniazid have been shown to induce liver damage, characterized by elevated liver enzymes and histopathological changes . Additionally, chronic administration of high doses of isoniazid can lead to peripheral neuropathy, which is attributed to pyridoxine deficiency .
Metabolic Pathways
Isoniazid undergoes extensive metabolism in the liver. The primary metabolic pathway involves acetylation by N-acetyltransferase 2 (NAT2) to form N-acetylisoniazid . N-acetylisoniazid is further hydrolyzed to isonicotinic acid and monoacetylhydrazine. Monoacetylhydrazine can be oxidized by cytochrome P450 enzymes to form reactive metabolites that contribute to hepatotoxicity . The rate of acetylation varies among individuals, leading to differences in drug clearance and susceptibility to adverse effects .
Transport and Distribution
Isoniazid is well-absorbed from the gastrointestinal tract and is widely distributed throughout the body, including the central nervous system . It has low protein binding and can penetrate tissues and cells effectively. Isoniazid is transported into cells via passive diffusion and is distributed to various tissues, including the liver, lungs, and kidneys . The distribution of isoniazid is influenced by its lipophilicity and the presence of transporters that facilitate its uptake into cells .
Subcellular Localization
Within cells, isoniazid is primarily localized in the cytoplasm, where it undergoes metabolic activation and exerts its effects . The activated form of isoniazid can interact with various cellular components, including enzymes and proteins involved in oxidative stress response . Additionally, isoniazid can induce the expression of genes involved in the detoxification of reactive metabolites, further influencing its subcellular localization and activity .
準備方法
Synthetic Routes and Reaction Conditions: Isoniazid is typically synthesized through the reaction of isonicotinic acid with hydrazine hydrate. The process involves the esterification of isonicotinic acid with an alcohol and an acylation reagent to form isonicotinic acid ester. This ester is then reacted with hydrazine hydrate to produce isoniazid .
Industrial Production Methods: In industrial settings, the preparation of isoniazid involves the following steps:
Esterification: Isonicotinic acid is esterified with an alcohol (e.g., methanol) in the presence of an acid catalyst.
Hydrazinolysis: The ester is then reacted with hydrazine hydrate under controlled temperature conditions to yield isoniazid.
Purification: The crude product is purified through recrystallization, decolorization, and washing to achieve high purity and yield
化学反応の分析
Types of Reactions: Isoniazid undergoes various chemical reactions, including:
Oxidation: Isoniazid can be oxidized to form isonicotinic acid.
Reduction: It can be reduced to form hydrazine derivatives.
Substitution: Isoniazid can participate in nucleophilic substitution reactions
Common Reagents and Conditions:
Oxidation: Potassium permanganate or hydrogen peroxide can be used as oxidizing agents.
Reduction: Sodium borohydride or lithium aluminum hydride can be used as reducing agents.
Substitution: Alkyl halides or acyl chlorides can be used for nucleophilic substitution reactions
Major Products:
Oxidation: Isonicotinic acid.
Reduction: Hydrazine derivatives.
Substitution: Various substituted isonicotinic acid derivatives
類似化合物との比較
Rifampicin: Another first-line antituberculosis drug that inhibits bacterial RNA synthesis.
Ethambutol: Inhibits the synthesis of the mycobacterial cell wall by targeting arabinosyl transferases.
Pyrazinamide: Disrupts mycobacterial cell membrane metabolism and transport functions
Uniqueness of Isoniazid: Isoniazid’s uniqueness lies in its specific mechanism of action, targeting mycolic acid synthesis, which is crucial for the mycobacterial cell wall. Its ability to be used both as a monotherapy for latent tuberculosis and in combination with other drugs for active tuberculosis makes it a versatile and essential medication in tuberculosis treatment .
特性
IUPAC Name |
pyridine-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) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
QRXWMOHMRWLFEY-UHFFFAOYSA-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 | |
Molecular Formula |
C6H7N3O |
Source
|
| Record name | ISONIAZID | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/20540 | |
| 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. | |
| Explanation | CAMEO Chemicals and all other CAMEO products are available at no charge to those organizations and individuals (recipients) responsible for the safe handling of chemicals. However, some of the chemical data itself is subject to the copyright restrictions of the companies or organizations that provided the data. | |
| Record name | ISONIAZID (OBSOLETE) | |
| Source | ILO-WHO International Chemical Safety Cards (ICSCs) | |
| URL | https://www.ilo.org/dyn/icsc/showcard.display?p_version=2&p_card_id=1258 | |
| Description | The International Chemical Safety Cards (ICSCs) are data sheets intended to provide essential safety and health information on chemicals in a clear and concise way. The primary aim of the Cards is to promote the safe use of chemicals in the workplace. | |
| Explanation | Creative Commons CC BY 4.0 | |
| Record name | isoniazid | |
| Source | Wikipedia | |
| URL | https://en.wikipedia.org/wiki/Isoniazid | |
| 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 |
DTXSID8020755 |
Source
|
| Record name | Isoniazid | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID8020755 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
137.14 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Isoniazid appears as odorless colorless or white crystals or white crystalline powder. Taste is slightly sweet at first and then bitter. pH (1% aqueous solution) 5.5-6.5. pH (5% aqueous solution) 6-8. (NTP, 1992), Solid, WHITE CRYSTALLINE ODOURLESS POWDER. |
Source
|
| Record name | ISONIAZID | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/20540 | |
| 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. | |
| Explanation | CAMEO Chemicals and all other CAMEO products are available at no charge to those organizations and individuals (recipients) responsible for the safe handling of chemicals. However, some of the chemical data itself is subject to the copyright restrictions of the companies or organizations that provided the data. | |
| Record name | Isoniazid | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015086 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
| Record name | ISONIAZID (OBSOLETE) | |
| Source | ILO-WHO International Chemical Safety Cards (ICSCs) | |
| URL | https://www.ilo.org/dyn/icsc/showcard.display?p_version=2&p_card_id=1258 | |
| Description | The International Chemical Safety Cards (ICSCs) are data sheets intended to provide essential safety and health information on chemicals in a clear and concise way. The primary aim of the Cards is to promote the safe use of chemicals in the workplace. | |
| Explanation | Creative Commons CC BY 4.0 | |
Flash Point |
374 °F (NTP, 1992), > 250 °C |
Source
|
| Record name | ISONIAZID | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/20540 | |
| 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. | |
| Explanation | CAMEO Chemicals and all other CAMEO products are available at no charge to those organizations and individuals (recipients) responsible for the safe handling of chemicals. However, some of the chemical data itself is subject to the copyright restrictions of the companies or organizations that provided the data. | |
| Record name | ISONIAZID (OBSOLETE) | |
| Source | ILO-WHO International Chemical Safety Cards (ICSCs) | |
| URL | https://www.ilo.org/dyn/icsc/showcard.display?p_version=2&p_card_id=1258 | |
| Description | The International Chemical Safety Cards (ICSCs) are data sheets intended to provide essential safety and health information on chemicals in a clear and concise way. The primary aim of the Cards is to promote the safe use of chemicals in the workplace. | |
| Explanation | Creative Commons CC BY 4.0 | |
Solubility |
13.7 [ug/mL] (The mean of the results at pH 7.4), greater than or equal to 100 mg/mL at 77 °F (NTP, 1992), Solubility in alcohol at 25 °C: about 2, in boiling alcohol: about 10%; in chloroform: about 0.1%. Practically insoluble in ether, benzene., Sol in methyl ethyl ketone, acetone, In water, 1.4X10+5 mg/L at 25 °C, 3.49e+01 g/L, Solubility in water, g/100ml at 20 °C: 12.5 |
Source
|
| Record name | SID855769 | |
| 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 | ISONIAZID | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/20540 | |
| 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. | |
| Explanation | CAMEO Chemicals and all other CAMEO products are available at no charge to those organizations and individuals (recipients) responsible for the safe handling of chemicals. However, some of the chemical data itself is subject to the copyright restrictions of the companies or organizations that provided the data. | |
| Record name | Isoniazid | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00951 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | ISONIAZID | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/1647 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Isoniazid | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015086 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
| Record name | ISONIAZID (OBSOLETE) | |
| Source | ILO-WHO International Chemical Safety Cards (ICSCs) | |
| URL | https://www.ilo.org/dyn/icsc/showcard.display?p_version=2&p_card_id=1258 | |
| Description | The International Chemical Safety Cards (ICSCs) are data sheets intended to provide essential safety and health information on chemicals in a clear and concise way. The primary aim of the Cards is to promote the safe use of chemicals in the workplace. | |
| Explanation | Creative Commons CC BY 4.0 | |
Vapor Pressure |
Negligible (NTP, 1992), 4.6X10-5 mm Hg at 25 °C /Estimated/ |
Source
|
| Record name | ISONIAZID | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/20540 | |
| 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. | |
| Explanation | CAMEO Chemicals and all other CAMEO products are available at no charge to those organizations and individuals (recipients) responsible for the safe handling of chemicals. However, some of the chemical data itself is subject to the copyright restrictions of the companies or organizations that provided the data. | |
| Record name | ISONIAZID | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/1647 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Mechanism of Action |
Isoniazid is a prodrug and must be activated by bacterial catalase. Specficially, activation is associated with reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with oxygen to form an oxyferrous enzyme complex. Once activated, isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms. Specifically isoniazid inhibits InhA, the enoyl reductase from Mycobacterium tuberculosis, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA., Although the mechanism of action of isoniazid is unknown, several hypotheses have been proposed. These include effects on lipids, nucleic acid biosynthesis, and glycolysis. ... /It has been suggested that/ a primary action of isoniazid /is/ to inhibit the biosynthesis of mycolic acids, important constituents of the mycobacterial cell wall. Because mycolic acids are unique to mycobacteria, this action would explain the high degree of selectivity of the antimicrobial activity of isoniazid. Exposure to isoniazid leads to a loss of acid fastness and a decrease in the quantity of methanol-extractable lipid of the microorganisms., Isoniazid is bacteriostatic for "resting" bacilli but is bactericidal for rapidly dividing microorganisms. The minimal tuberculostatic concentration is 0.025 to 0.05 ug/ml. |
Source
|
| Record name | Isoniazid | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00951 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | ISONIAZID | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/1647 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Color/Form |
COLORLESS OR WHITE CRYSTALS, OR A WHITE, CRYSTALLINE POWDER, Crystals from alcohol | |
CAS No. |
54-85-3 |
Source
|
| Record name | ISONIAZID | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/20540 | |
| 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. | |
| Explanation | CAMEO Chemicals and all other CAMEO products are available at no charge to those organizations and individuals (recipients) responsible for the safe handling of chemicals. However, some of the chemical data itself is subject to the copyright restrictions of the companies or organizations that provided the data. | |
| Record name | Isoniazid | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=54-85-3 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Isoniazid [USP:INN:BAN:JAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000054853 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Isoniazid | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00951 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | isoniazid | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=757078 | |
| Description | The NCI Development Therapeutics Program (DTP) provides services and resources to the academic and private-sector research communities worldwide to facilitate the discovery and development of new cancer therapeutic agents. | |
| Explanation | Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source. | |
| Record name | isoniazid | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=9659 | |
| Description | The NCI Development Therapeutics Program (DTP) provides services and resources to the academic and private-sector research communities worldwide to facilitate the discovery and development of new cancer therapeutic agents. | |
| Explanation | Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source. | |
| Record name | 4-Pyridinecarboxylic acid, hydrazide | |
| Source | EPA Chemicals under the TSCA | |
| URL | https://www.epa.gov/chemicals-under-tsca | |
| Description | EPA Chemicals under the Toxic Substances Control Act (TSCA) collection contains information on chemicals and their regulations under TSCA, including non-confidential content from the TSCA Chemical Substance Inventory and Chemical Data Reporting. | |
| Record name | Isoniazid | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID8020755 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Isoniazid | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.000.195 | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | ISONIAZID | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/V83O1VOZ8L | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
| Record name | ISONIAZID | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/1647 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Isoniazid | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015086 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
| Record name | ISONIAZID (OBSOLETE) | |
| Source | ILO-WHO International Chemical Safety Cards (ICSCs) | |
| URL | https://www.ilo.org/dyn/icsc/showcard.display?p_version=2&p_card_id=1258 | |
| Description | The International Chemical Safety Cards (ICSCs) are data sheets intended to provide essential safety and health information on chemicals in a clear and concise way. The primary aim of the Cards is to promote the safe use of chemicals in the workplace. | |
| Explanation | Creative Commons CC BY 4.0 | |
Melting Point |
340.5 °F (NTP, 1992), 171.4 °C, 170-173 °C |
Source
|
| Record name | ISONIAZID | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/20540 | |
| 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. | |
| Explanation | CAMEO Chemicals and all other CAMEO products are available at no charge to those organizations and individuals (recipients) responsible for the safe handling of chemicals. However, some of the chemical data itself is subject to the copyright restrictions of the companies or organizations that provided the data. | |
| Record name | Isoniazid | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00951 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | ISONIAZID | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/1647 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Isoniazid | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015086 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
| Record name | ISONIAZID (OBSOLETE) | |
| Source | ILO-WHO International Chemical Safety Cards (ICSCs) | |
| URL | https://www.ilo.org/dyn/icsc/showcard.display?p_version=2&p_card_id=1258 | |
| Description | The International Chemical Safety Cards (ICSCs) are data sheets intended to provide essential safety and health information on chemicals in a clear and concise way. The primary aim of the Cards is to promote the safe use of chemicals in the workplace. | |
| Explanation | Creative Commons CC BY 4.0 | |
Synthesis routes and methods I
Procedure details
Synthesis routes and methods II
Procedure details
Retrosynthesis Analysis
AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.
One-Step Synthesis Focus: Specifically designed for one-step synthesis, it provides concise and direct routes for your target compounds, streamlining the synthesis process.
Accurate Predictions: Utilizing the extensive PISTACHIO, BKMS_METABOLIC, PISTACHIO_RINGBREAKER, REAXYS, REAXYS_BIOCATALYSIS database, our tool offers high-accuracy predictions, reflecting the latest in chemical research and data.
Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
Q1: How does isoniazid exert its anti-tubercular effect?
A1: Isoniazid acts as a prodrug, requiring activation by a bacterial catalase-peroxidase enzyme called KatG found in Mycobacterium tuberculosis [, ]. This activation leads to the formation of an isonicotinic acyl-NADH complex, which then inhibits InhA, an enoyl-acyl carrier protein reductase essential for mycolic acid biosynthesis [, ]. Mycolic acids are crucial components of the mycobacterial cell wall, and their disruption leads to bacterial death.
Q2: Does the activation process of isoniazid play a role in drug resistance?
A2: Yes, mutations in the katG gene, particularly in codon 315, are frequently observed in isoniazid-resistant M. tuberculosis strains [, ]. These mutations can alter the enzyme's structure, affecting its ability to activate isoniazid and leading to resistance.
Q3: What is the role of the inhA gene in isoniazid resistance?
A3: Mutations in the promoter region of the inhA gene, specifically at position -15, can lead to overexpression of the InhA enzyme, reducing isoniazid's effectiveness []. This overexpression counteracts the drug's inhibitory action on mycolic acid synthesis.
Q4: How does isoniazid treatment impact collagen in the body?
A4: Isoniazid can inhibit lysyl oxidase, an enzyme essential for collagen cross-linking []. This inhibition is linked to pyridoxal phosphate depletion in the liver as pyridoxal phosphate acts as a cofactor for lysyl oxidase. The reduction in lysyl oxidase activity leads to increased collagen solubility, potentially impacting connective tissue integrity.
Q5: What is the impact of acetylator status on isoniazid treatment?
A5: Isoniazid is primarily metabolized in the liver through acetylation [, ]. Individuals are categorized as slow, heterozygous rapid, or homozygous rapid acetylators based on their genetic predisposition []. The acetylator phenotype significantly influences the rate of isoniazid elimination, impacting the drug's half-life and ultimately influencing treatment efficacy, particularly in once-weekly regimens [, ].
Q6: Does food intake affect the pharmacokinetics of isoniazid?
A6: Studies suggest that food intake, particularly a light breakfast, can influence the pharmacokinetic parameters of isoniazid, including its peak plasma concentration (Cmax) and the area under the curve (AUC) [, ]. These findings highlight the importance of considering meal timing when administering isoniazid to optimize drug exposure.
Q7: Can isoniazid be transferred through breast milk?
A7: Yes, isoniazid can transfer from circulation to breast milk in lactating women undergoing tuberculosis treatment []. Studies have determined the milk-to-plasma ratio for isoniazid, providing insights into the potential exposure of the drug to nursing infants.
Q8: How is isoniazid distributed in the body?
A8: Isoniazid exhibits good penetration into various body fluids, including cerebrospinal fluid (CSF) []. Studies have investigated the pharmacokinetic parameters associated with isoniazid transfer into CSF, particularly in patients with tuberculous meningitis. Understanding drug distribution patterns is crucial for optimizing treatment strategies, especially for infections affecting different body compartments.
Q9: What are the common adverse events associated with isoniazid treatment?
A9: The most frequently reported adverse events associated with isoniazid treatment are hepatotoxicity, gastric intolerance, and neuropathy [, , ]. The incidence of these adverse events can vary significantly. Close monitoring of liver function and neurological symptoms is crucial during isoniazid therapy.
Q10: Are there specific patient groups at higher risk of isoniazid-induced hepatotoxicity?
A10: Research suggests that certain factors might increase the risk of isoniazid-induced hepatotoxicity. These include elderly patients, individuals with pre-existing liver disease like hepatitis C infection, and those with low serum albumin levels [, ]. Careful patient selection and monitoring are essential to minimize the risk of hepatotoxicity.
Q11: Is there a treatment for isoniazid overdose?
A11: Yes, high-dose pyridoxine hydrochloride (vitamin B6) is an effective treatment for acute isoniazid overdose []. Pyridoxine, administered intravenously, can counteract the toxic effects of isoniazid and prevent potentially fatal complications.
Q12: How effective is isoniazid prophylaxis in individuals exposed to isoniazid-resistant tuberculosis?
A12: There have been reports of isoniazid chemoprophylaxis failure in preventing active pulmonary tuberculosis and tuberculin conversion in individuals exposed to isoniazid-resistant strains of M. tuberculosis []. These observations highlight the limitations of isoniazid prophylaxis in such situations and emphasize the need to consider alternative prophylactic agents.
Q13: What analytical methods are commonly used to determine isoniazid concentrations?
A13: Several analytical techniques have been employed to quantify isoniazid concentrations in various matrices. These include spectrophotometry, high-performance liquid chromatography (HPLC), and chemiluminescence-based methods [, ]. Each method offers advantages and limitations in terms of sensitivity, selectivity, and practicality.
Q14: Are there specific formulation strategies to enhance isoniazid delivery or stability?
A14: Yes, researchers have explored different formulation approaches to improve isoniazid delivery and stability. These include the development of slow-release preparations to sustain drug release, enhance patient compliance, and potentially reduce the dosing frequency [, ].
Q15: What is the historical significance of isoniazid in tuberculosis treatment?
A15: The discovery and introduction of isoniazid marked a significant milestone in the fight against tuberculosis. This potent drug, particularly when combined with other anti-tuberculosis agents, revolutionized treatment strategies and significantly improved patient outcomes. Isoniazid remains a cornerstone of tuberculosis treatment regimens worldwide, underscoring its enduring importance in global health.
Q16: What are the potential areas for future research on isoniazid?
A16: Future research endeavors could focus on several aspects, including:
- Developing novel isoniazid derivatives with improved efficacy and safety profiles [].
- Exploring alternative drug delivery systems to enhance targeted delivery and minimize side effects [].
- Investigating new strategies to combat emerging drug resistance and ensure the long-term effectiveness of isoniazid-containing regimens [, ].
試験管内研究製品の免責事項と情報
BenchChemで提示されるすべての記事および製品情報は、情報提供を目的としています。BenchChemで購入可能な製品は、生体外研究のために特別に設計されています。生体外研究は、ラテン語の "in glass" に由来し、生物体の外で行われる実験を指します。これらの製品は医薬品または薬として分類されておらず、FDAから任何の医療状態、病気、または疾患の予防、治療、または治癒のために承認されていません。これらの製品を人間または動物に体内に導入する形態は、法律により厳格に禁止されています。これらのガイドラインに従うことは、研究と実験において法的および倫理的な基準の遵守を確実にするために重要です。
