Oxfendazole
Overview
Description
Oxfendazole is a broad-spectrum benzimidazole anthelmintic primarily used in veterinary medicine. It is effective against a variety of parasitic worms, including roundworms, strongyles, and pinworms. This compound is the sulfoxide metabolite of fenbendazole and is known for its efficacy in protecting livestock such as cattle, sheep, and goats .
Scientific Research Applications
Oxfendazole has a wide range of applications in scientific research:
Chemistry: Used as a model compound to study the behavior of benzimidazole derivatives.
Biology: Investigated for its effects on parasitic worms and its potential use in controlling parasitic infections in livestock.
Mechanism of Action
Target of Action
Oxfendazole, a sulfoxide metabolite of fenbendazole, is a broad-spectrum benzimidazole anthelmintic . Its primary targets are parasitic worms including roundworms, strongyles, and pinworms . These parasites are harmful to livestock and can cause significant health issues.
Mode of Action
The molecular mode of action of this compound, like all benzimidazoles, involves binding to tubulin , a structural protein of microtubules . This binding inhibits the polymerization or assembly of microtubules , causing degenerative alterations in the tegument and intestinal cells of the worm . This interaction disrupts the cell’s structure and function, leading to the death of the parasite.
Pharmacokinetics
This compound exhibits rapid absorption following oral administration, with the time to maximum concentration of drug in serum (Tmax) ranging from 1.92 to 2.56 hours . The half-life of this compound ranges from 8.5 to 11 hours , and it exhibits significant nonlinear pharmacokinetics with less than dose-proportional increases in exposure after single oral doses . The renal excretion of this compound is minimal .
Action Environment
The efficacy and stability of this compound can be influenced by various environmental factors. For instance, the drug’s absorption can be affected by the presence of food in the gastrointestinal tract . Additionally, the drug’s efficacy may vary depending on the specific species and life stage of the parasite. It’s also worth noting that this compound is primarily used in veterinary medicine, so factors such as the animal’s age, health status, and living conditions can also influence the drug’s action and efficacy .
Safety and Hazards
Future Directions
Biochemical Analysis
Biochemical Properties
Oxfendazole exhibits a range of notable biochemical and physiological effects. It inhibits parasite growth, curtails their reproductive capacity, and disrupts their energy production . It interacts with the colchicine-sensitive site of tubulin, thus inhibiting its polymerization or assembly into microtubules .
Cellular Effects
This compound has been shown to induce apoptosis in ovarian cancer cells by activating the JNK/MAPK pathway and inducing reactive oxygen species generation . It also inhibits the growth of non-small cell lung cancer cells .
Molecular Mechanism
This compound’s mechanism of action is primarily through its binding to the colchicine-sensitive site of tubulin, inhibiting its polymerization or assembly into microtubules . This disrupts the cytoskeleton of the cells, leading to cell death .
Temporal Effects in Laboratory Settings
In laboratory settings, this compound has been shown to have a substantial nonlinear pharmacokinetics, which complicates correlating this compound dose to exposure . An this compound nanocrystal suspension was prepared to overcome the challenge of its poor oral bioavailability .
Dosage Effects in Animal Models
The pharmacokinetics of this compound in healthy adults following single ascending oral doses from 0.5 to 60 mg/kg of body weight shows that this compound pharmacokinetics is substantially nonlinear . The apparent clearance and apparent volume of distribution were estimated to be 2.57 liters/h and 35.2 liters, respectively, at the lowest dose (0.5 mg/kg), indicating that this compound is a low extraction drug with moderate distribution .
Metabolic Pathways
This compound is a sulfoxide metabolite of fenbendazole . Fenbendazole formation from this compound was primarily through systemic metabolism, while both presystemic and systemic metabolism were critical to the formation of this compound sulfone .
Transport and Distribution
This compound’s pharmacokinetics was best described by a one-compartment model with nonlinear absorption and linear elimination . The disposition of both metabolites was adequately characterized by a one-compartment model with formation rate-limited elimination .
Subcellular Localization
Given its mechanism of action involving the disruption of microtubules, it is likely that this compound localizes to the cytoplasm where the microtubules are located .
Preparation Methods
Synthetic Routes and Reaction Conditions: Oxfendazole can be synthesized through the oxidation of fenbendazole. The process involves the use of hydrogen peroxide and acetic acid as oxidizing agents. The reaction is typically carried out at room temperature, and the product is purified through recrystallization .
Industrial Production Methods: In industrial settings, this compound is often produced by reacting fenbendazole with hydrogen peroxide in the presence of acetic acid. The reaction mixture is then subjected to filtration and recrystallization to obtain pure this compound. Another method involves the conversion of this compound into its hydrochloride form using hydrochloric acid, which enhances its solubility in various solvents .
Chemical Reactions Analysis
Types of Reactions: Oxfendazole undergoes several types of chemical reactions, including:
Oxidation: Conversion of fenbendazole to this compound using oxidizing agents like hydrogen peroxide.
Reduction: Although less common, reduction reactions can convert this compound back to fenbendazole.
Substitution: this compound can participate in substitution reactions where functional groups are replaced by other atoms or groups.
Common Reagents and Conditions:
Oxidation: Hydrogen peroxide and acetic acid at room temperature.
Reduction: Reducing agents such as sodium borohydride.
Substitution: Various nucleophiles under mild conditions.
Major Products:
Oxidation: this compound.
Reduction: Fenbendazole.
Substitution: Derivatives of this compound with different functional groups.
Comparison with Similar Compounds
Fenbendazole: The parent compound of oxfendazole, also a benzimidazole anthelmintic.
Albendazole: Another benzimidazole derivative with a similar mechanism of action.
Mebendazole: A benzimidazole anthelmintic used to treat a variety of parasitic worm infections.
Comparison:
Efficacy: this compound is more effective than fenbendazole due to its higher solubility and bioavailability. It also has a broader spectrum of activity compared to albendazole and mebendazole.
Mechanism of Action: All these compounds share a similar mechanism of action, targeting tubulin in parasitic worms.
Applications: While fenbendazole and this compound are primarily used in veterinary medicine, albendazole and mebendazole are more commonly used in human medicine
This compound stands out due to its enhanced solubility and broader spectrum of activity, making it a valuable compound in both veterinary and potential human medical applications.
Properties
IUPAC Name |
methyl N-[6-(benzenesulfinyl)-1H-benzimidazol-2-yl]carbamate |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C15H13N3O3S/c1-21-15(19)18-14-16-12-8-7-11(9-13(12)17-14)22(20)10-5-3-2-4-6-10/h2-9H,1H3,(H2,16,17,18,19) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
BEZZFPOZAYTVHN-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
COC(=O)NC1=NC2=C(N1)C=C(C=C2)S(=O)C3=CC=CC=C3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C15H13N3O3S |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID9044112 |
Source
|
| Record name | Oxfendazole | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID9044112 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
315.3 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 | Oxfendazole | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0031812 | |
| 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. | |
CAS No. |
53716-50-0 |
Source
|
| Record name | Oxfendazole | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=53716-50-0 | |
| 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 | Oxfendazole [USAN:USP:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0053716500 | |
| 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 | Oxfendazole | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB11446 | |
| 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 | Oxfendazole | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=758943 | |
| 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 | Oxfendazole | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID9044112 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Oxfendazole | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.053.358 | |
| 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 | OXFENDAZOLE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/OMP2H17F9E | |
| 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 | Oxfendazole | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0031812 | |
| 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 |
253 °C |
Source
|
| Record name | Oxfendazole | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0031812 | |
| 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. | |
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
Q1: What is the primary mechanism of action of oxfendazole?
A1: While the exact mechanism remains unclear, this compound is believed to primarily target β-tubulin in susceptible parasites. [, , ] This interaction disrupts microtubule formation, crucial for various cellular processes, ultimately leading to parasite death.
Q2: What types of parasites is this compound effective against?
A2: this compound exhibits broad-spectrum activity against various helminths, including gastrointestinal nematodes like Haemonchus contortus, Ostertagia ostertagi, and Trichostrongylus spp., as well as cestodes like Taenia solium and trematodes. [, , , , , , , , ]
Q3: Does this compound show promise against tissue-dwelling parasites?
A3: Yes, this compound demonstrates potential against tissue-dwelling parasites. Studies show promising efficacy against larval cestodes in hydatid disease models and trematodes in models of cystic echinococcosis. [, , ]
Q4: How does this compound reach tissue-dwelling parasites?
A4: Research using a Trichuris suis-pig infection model suggests that this compound, after being absorbed from the gastrointestinal tract, reaches the parasite via the blood-enterocyte pathway. []
Q5: What are the key pharmacokinetic parameters of this compound in animals?
A5: this compound is absorbed rapidly following oral administration in various animal species. Its half-life ranges from 8.5 to 11 hours in healthy human volunteers. [, ] Notably, it exhibits nonlinear pharmacokinetics, with exposure not increasing proportionally with dose. [, , ]
Q6: Does food intake affect the pharmacokinetics of this compound?
A6: Yes, food, particularly a fatty meal, significantly impacts this compound pharmacokinetics. It delays the time to reach maximum concentration (Tmax) and increases both the maximum concentration (Cmax) and the area under the concentration-time curve (AUC). [, ]
Q7: What are the major metabolites of this compound?
A7: The primary metabolites of this compound are this compound sulfone and fenbendazole, both possessing anthelmintic activity. [, , , , ] Fenbendazole further metabolizes to fenbendazole sulfone.
Q8: What is the significance of this compound's metabolites?
A8: Both this compound sulfone and fenbendazole contribute to the overall anthelmintic effect. The prolonged presence of active metabolites contributes to this compound's efficacy, particularly against immature or inhibited parasite stages. [, , ]
Q9: Are there any strategies to improve this compound delivery?
A9: Research explores nanosuspension formulations to enhance this compound bioavailability. Studies in sheep show that this compound nanosuspensions significantly increase Cmax and AUC compared to conventional granular formulations. []
Q10: What are the potential target organs for this compound toxicity?
A10: In a 2-week rat study, target organs included bone marrow, epididymis, liver, spleen, testis, and thymus. [] Notably, female rats exhibited greater this compound exposure and toxicity at lower doses compared to males. []
Q11: Does this compound pose any genetic toxicity risks?
A11: this compound did not exhibit mutagenic potential in standard Ames bacterial, mouse lymphoma, or rat micronucleus assays. []
Q12: Is there evidence of this compound resistance in parasites?
A12: Yes, studies report emerging resistance to this compound in various nematode species, including Haemonchus contortus and Teladorsagia circumcincta. [, ]
Q13: What are the potential factors contributing to this compound resistance?
A13: Factors potentially contributing to resistance include frequent anthelmintic treatments, inadequate dosing, and lack of rotation among different drug classes. []
Q14: What are the future directions for this compound research?
A14: Future research should focus on:
- Exploring this compound's potential for treating human parasitic infections, particularly those with limited therapeutic options. []
Q15: What analytical methods are used to detect and quantify this compound?
A15: Several methods are employed for this compound analysis:
- High-Performance Liquid Chromatography (HPLC): This method, often coupled with UV or mass spectrometry detection, is widely used to determine this compound concentrations in various matrices, including plasma, tissue, and feed. [, , , , ]
- Radioimmunoassay (RIA): This highly sensitive method uses antibodies to detect and quantify this compound in biological samples, particularly plasma and fat. [, ]
- Spectrophotometry: Techniques like derivative spectrophotometry and Vierordt's method allow for the simultaneous determination of this compound in combination with other drugs in veterinary formulations. []
- Gas Chromatography (GC): Coupled with headspace analysis, GC offers a sensitive approach to quantify residual solvents in this compound active pharmaceutical ingredients. []
Q16: Are there any concerns about this compound residues in food products?
A16: The extensive use of this compound in livestock raises concerns about potential residues in food products. Studies are conducted to determine the concentration of this compound and its metabolites in edible tissues to ensure compliance with maximum residue limits (MRLs). [, ]
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