Niclosamide
Overview
Description
Niclosamide is a well-known anthelmintic medication primarily used to treat tapeworm infestations, including diphyllobothriasis, hymenolepiasis, and taeniasis . It was first synthesized in 1958 and has been listed as an essential medicine by the World Health Organization . This compound works by inhibiting glucose uptake, oxidative phosphorylation, and anaerobic metabolism in the tapeworm .
Mechanism of Action
Target of Action
Niclosamide primarily targets acidified endosomes and multiple oncogenic pathways such as Wnt/β-catenin, Ras, Stat3, Notch, E2F-Myc, NF-κB, and mTOR . It also activates tumor suppressor signaling pathways such as p53, PP2A, and AMPK . These targets play crucial roles in various cellular processes, including cell proliferation, differentiation, and survival.
Mode of Action
This compound works by killing tapeworms on contact. . The killed worms are then passed in the stool or sometimes destroyed in the intestine .
Biochemical Pathways
This compound affects several biochemical pathways. It inhibits the cellular mitochondrial oxidation and phosphorylation processes and uncouples the electron transmission chain . This prevents the creation of adenosine tri-phosphate (ATP), an essential molecule that supplies energy for metabolism . This compound also neutralizes acidic membrane-bounded compartments , which can inhibit infection with pH-dependent viruses .
Pharmacokinetics
This compound has low oral bioavailability and poor solubility, which limits its systemic absorption and distribution to tissues outside the gastrointestinal tract . When administered via nebulization, this compound exhibits dose-linear plasma pharmacokinetics and is described by a 3-compartmental model, estimating an absolute bioavailability of86% .
Result of Action
This compound has broad anti-cancer activity in a variety of contexts . It decreases the glutathione levels , inhibits proliferation , suppresses GPX4 expression , increases lipid peroxidation , and induces ferroptosis in TNBC cells . It also significantly reduces the growth of the TNBC cell line MB231 in mouse xenografts .
Action Environment
The action of this compound can be influenced by environmental factors. For instance, the extensive utilization and environmental pollution associated with this compound engender a potential hazard to both human health and the wellbeing of aquatic organisms . Furthermore, the efficacy of this compound can be influenced by the pH of the environment, as it targets acidified endosomes .
Biochemical Analysis
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 . This compound 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, this compound has been shown to downregulate androgen receptor variants in prostate cancer cells, highlighting its interaction with specific proteins involved in cancer progression .
Cellular Effects
This compound 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 . This compound also influences cell signaling pathways by neutralizing acidic compartments within cells, which can affect endosomal trafficking and virus entry . Furthermore, this compound 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 this compound involves its action as a proton carrier, which neutralizes acidic endosomes and inhibits the entry of pH-dependent viruses . This compound also uncouples the electron transport chain from adenosine triphosphate synthase, preventing the production of adenosine triphosphate and disrupting cellular energy metabolism . Additionally, this compound 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 this compound have been observed to change over time. This compound is relatively stable, but its degradation products can influence its long-term effects on cellular function. In in vitro studies, this compound has shown sustained antiviral activity over extended periods, indicating its stability in neutralizing acidic compartments . In in vivo studies, the long-term effects of this compound 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 this compound vary with different dosages in animal models. At lower doses, this compound effectively inhibits viral entry and downregulates androgen receptor variants without causing significant toxicity . At higher doses, this compound 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 this compound plateaus beyond a certain dosage, indicating the importance of optimizing dosage for therapeutic applications.
Metabolic Pathways
This compound 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 . This compound’s interaction with androgen receptor variants also influences metabolic pathways related to cancer cell proliferation and survival .
Transport and Distribution
Within cells and tissues, this compound 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 . This compound’s distribution within tissues can vary, with higher concentrations observed in target tissues such as the gastrointestinal tract and cancerous tissues .
Subcellular Localization
This compound’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. This compound’s targeting signals and post-translational modifications direct it to specific compartments, enhancing its efficacy in neutralizing acidic environments and disrupting cellular processes .
Preparation Methods
Niclosamide can be synthesized through various methods. One common synthetic route involves the reaction of 5-chlorosalicylic acid with o-chloro-p-nitroaniline in the presence of a quaternary alkylphosphonium salt . The reaction is typically carried out under melting conditions for 1-2 hours to obtain the crude product . Another method involves the use of thionyl chloride and xylene in a two-step reaction process . Industrial production methods focus on optimizing yield, purity, and cost-effectiveness, often involving similar reaction conditions but on a larger scale .
Chemical Reactions Analysis
Niclosamide undergoes various chemical reactions, including:
Oxidation: This compound can be oxidized to form different derivatives, which may have varying biological activities.
Reduction: Reduction reactions can modify the nitro group in this compound, leading to different analogs.
Substitution: This compound can undergo substitution reactions, where functional groups on the benzene ring are replaced with other groups.
Common reagents used in these reactions include oxidizing agents like potassium permanganate, reducing agents like sodium borohydride, and various nucleophiles for substitution reactions . The major products formed depend on the specific reaction conditions and reagents used.
Scientific Research Applications
Niclosamide has a wide range of scientific research applications:
Comparison with Similar Compounds
Niclosamide is often compared with other anthelmintic compounds such as praziquantel and albendazole . While praziquantel is effective against a broader range of parasitic infections, this compound is specifically effective against tapeworms . This compound’s unique mechanism of action, involving the inhibition of oxidative phosphorylation, sets it apart from other anthelmintics that may target different metabolic pathways .
Similar compounds include:
Praziquantel: Effective against a wide range of parasitic infections but works through a different mechanism.
Albendazole: Another broad-spectrum anthelmintic that inhibits microtubule synthesis in parasites.
This compound’s specificity and unique mechanism make it a valuable tool in both clinical and research settings.
Properties
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. | |
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| 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 | |
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| Record name | niclosamide | |
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| 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. | |
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| Record name | 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7040362 | |
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| Record name | Niclosamide | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.000.052 | |
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| Record name | NICLOSAMIDE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/8KK8CQ2K8G | |
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| 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
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