ニクロサミド
概要
説明
作用機序
科学的研究の応用
生化学分析
Biochemical Properties
Niclosamide plays a significant role in biochemical reactions by acting as a proton carrier. It interacts with acidic endosomes, neutralizing their pH and thereby inhibiting the entry of pH-dependent viruses such as human rhinoviruses and influenza virus . Niclosamide does not affect the vacuolar H±ATPase but neutralizes coated vesicles or synthetic liposomes, indicating a proton carrier mode-of-action independent of any protein target . Additionally, niclosamide has been shown to downregulate androgen receptor variants in prostate cancer cells, highlighting its interaction with specific proteins involved in cancer progression .
Cellular Effects
Niclosamide exerts various effects on different types of cells and cellular processes. In cancer cells, it downregulates androgen receptor variants, leading to reduced cell proliferation and tumor growth . Niclosamide also influences cell signaling pathways by neutralizing acidic compartments within cells, which can affect endosomal trafficking and virus entry . Furthermore, niclosamide disrupts the electron transport chain, leading to a decrease in adenosine triphosphate production and subsequent alterations in cellular metabolism .
Molecular Mechanism
The molecular mechanism of niclosamide involves its action as a proton carrier, which neutralizes acidic endosomes and inhibits the entry of pH-dependent viruses . Niclosamide also uncouples the electron transport chain from adenosine triphosphate synthase, preventing the production of adenosine triphosphate and disrupting cellular energy metabolism . Additionally, niclosamide downregulates androgen receptor variants in prostate cancer cells, which is achieved through its interaction with specific proteins involved in androgen receptor signaling .
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of niclosamide have been observed to change over time. Niclosamide is relatively stable, but its degradation products can influence its long-term effects on cellular function. In in vitro studies, niclosamide has shown sustained antiviral activity over extended periods, indicating its stability in neutralizing acidic compartments . In in vivo studies, the long-term effects of niclosamide on cellular function have been observed, with continued downregulation of androgen receptor variants in prostate cancer models .
Dosage Effects in Animal Models
The effects of niclosamide vary with different dosages in animal models. At lower doses, niclosamide effectively inhibits viral entry and downregulates androgen receptor variants without causing significant toxicity . At higher doses, niclosamide can exhibit toxic effects, including disruptions in cellular metabolism and potential adverse effects on normal cellular functions . Threshold effects have been observed, where the efficacy of niclosamide plateaus beyond a certain dosage, indicating the importance of optimizing dosage for therapeutic applications.
Metabolic Pathways
Niclosamide is involved in several metabolic pathways, primarily through its action as a proton carrier and uncoupler of the electron transport chain. It interacts with enzymes and cofactors involved in adenosine triphosphate production, leading to disruptions in metabolic flux and alterations in metabolite levels . Niclosamide’s interaction with androgen receptor variants also influences metabolic pathways related to cancer cell proliferation and survival .
Transport and Distribution
Within cells and tissues, niclosamide is transported and distributed through interactions with specific transporters and binding proteins. It accumulates in acidic compartments, such as endosomes, where it exerts its proton carrier activity . Niclosamide’s distribution within tissues can vary, with higher concentrations observed in target tissues such as the gastrointestinal tract and cancerous tissues .
Subcellular Localization
Niclosamide’s subcellular localization is primarily within acidic compartments, such as endosomes and lysosomes . Its activity and function are influenced by its localization, as it neutralizes the pH of these compartments and inhibits viral entry. Niclosamide’s targeting signals and post-translational modifications direct it to specific compartments, enhancing its efficacy in neutralizing acidic environments and disrupting cellular processes .
準備方法
化学反応の分析
ニクロサミドは、以下を含むさまざまな化学反応を起こします。
酸化: ニクロサミドは、酸化されてさまざまな誘導体を形成し、これらの誘導体は、生物活性が異なる可能性があります.
これらの反応で使用される一般的な試薬には、過マンガン酸カリウムなどの酸化剤、水素化ホウ素ナトリウムなどの還元剤、さまざまな求核剤（置換反応用）が含まれます . 生成される主要な生成物は、使用される特定の反応条件と試薬によって異なります。
類似化合物との比較
ニクロサミドは、プラジクアンテルやアルベンダゾールなどの他の駆虫薬と比較されることがよくあります . プラジクアンテルは、より広範囲の寄生虫感染症に効果がありますが、ニクロサミドは条虫に対して特に効果があります . ニクロサミドのユニークな作用機序は、酸化リン酸化の阻害を伴い、さまざまな代謝経路を標的とする可能性のある他の駆虫薬とは異なります .
類似の化合物には、以下が含まれます。
プラジクアンテル: 幅広い寄生虫感染症に効果がありますが、異なるメカニズムで作用します.
アルベンダゾール: 寄生虫における微小管合成を阻害する、別の広域スペクトル駆虫薬.
ニクロサミドの特異性とユニークなメカニズムにより、臨床および研究の両方で貴重なツールとなっています。
特性
IUPAC Name |
5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C13H8Cl2N2O4/c14-7-1-4-12(18)9(5-7)13(19)16-11-3-2-8(17(20)21)6-10(11)15/h1-6,18H,(H,16,19) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
RJMUSRYZPJIFPJ-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1=CC(=C(C=C1[N+](=O)[O-])Cl)NC(=O)C2=C(C=CC(=C2)Cl)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C13H8Cl2N2O4 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Related CAS |
1420-04-8 (2-aminoethanol (1:1)) |
Source
|
| Record name | Niclosamide [USAN:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000050657 | |
| 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. | |
DSSTOX Substance ID |
DTXSID7040362 |
Source
|
| Record name | 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7040362 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
327.12 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Niclosamide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015679 | |
| 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. | |
Solubility |
SPARINGLY SOL IN CHLOROFORM, ETHER, ETHANOL, SOL IN ACETONE, Sol at 20 °C in 150 parts of alcohol, In water = 5-8 mg/L at 20 °C, For more Solubility (Complete) data for NICLOSAMIDE (8 total), please visit the HSDB record page. |
Source
|
| Record name | Niclosamide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB06803 | |
| 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 | NICLOSAMIDE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/1572 | |
| 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. | |
Vapor Pressure |
<9.87X10-9 mm Hg at 20 °C |
Source
|
| Record name | NICLOSAMIDE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/1572 | |
| 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 |
Niclosamide works by killing tapeworms on contact. Adult worms (but not ova) are rapidly killed, presumably due to uncoupling of oxidative phosphorylation or stimulation of ATPase activity. The killed worms are then passed in the stool or sometimes destroyed in the intestine. Niclosamide may work as a molluscicide by binding to and damaging DNA., Niclosamide has prominent activity against most of the cestodes that infect man; Enterobius (Oxyuris) vermicularis is also susceptible. At low concn, niclosamide stimulates oxygen uptake by Hymenolepis diminuta, but at higher concn respiration is inhibited and glucose uptake is blocked. The principal action of the drug may be to inhibit anaerobic phosphorylation of adenosine diphosphate (ADP) by the mitochondria of the parasite, an energy producing process that is dependent on CO2 fixation ... ., Cestocidal activity is due to inhibition of absorption of glucose by the tapeworm and uncoupling of the oxidative phosphorylation process in the mitochondria of cestodes. Resultant blocking of the Krebs cycle leads to accumulation of lactic acid, which kills the tapeworm. ... overstimulation of adenosine triphosphatase (ATPase) activity of the mitochondria may be related to cestodal action of niclosamide. |
Source
|
| Record name | Niclosamide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB06803 | |
| 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 | NICLOSAMIDE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/1572 | |
| 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 |
PALE, YELLOW CRYSTALS, ALMOST COLORLESS CRYSTALS, A cream-colored or yellowish-white powder, Bright yellow crystalline solid | |
CAS No. |
50-65-7 |
Source
|
| Record name | Niclosamide | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=50-65-7 | |
| 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 | Niclosamide [USAN:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000050657 | |
| 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 | Niclosamide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB06803 | |
| 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 | niclosamide | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=758440 | |
| 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 | niclosamide | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=178296 | |
| 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 | 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7040362 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Niclosamide | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.000.052 | |
| 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 | NICLOSAMIDE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/8KK8CQ2K8G | |
| 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 | NICLOSAMIDE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/1572 | |
| 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 | Niclosamide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015679 | |
| 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. | |
Melting Point |
225-230 °C |
Source
|
| Record name | Niclosamide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB06803 | |
| 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 | NICLOSAMIDE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/1572 | |
| 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. | |
Retrosynthesis Analysis
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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
試験管内研究製品の免責事項と情報
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