Triclabendazole
Vue d'ensemble
Description
Le triclabendazole est un dérivé du benzimidazole utilisé principalement comme anthelminthique pour traiter les infections causées par les douves du foie, en particulier Fasciola hepatica et Fasciola gigantica . Il est commercialisé sous des noms de marque tels que Egaten et Fasinex . Le this compound est unique parmi les benzimidazoles en raison de son efficacité contre les stades immatures et matures des douves du foie .
Applications De Recherche Scientifique
Triclabendazole has a wide range of scientific research applications:
Chemistry: Used as a model compound to study benzimidazole derivatives and their chemical properties.
Biology: Investigated for its effects on liver flukes and other parasitic organisms.
Medicine: Primarily used to treat fascioliasis and paragonimiasis in humans and animals It is the only FDA-approved drug for fascioliasis in humans.
Industry: Used in veterinary medicine to treat liver fluke infections in livestock.
Mécanisme D'action
Target of Action
Triclabendazole is an anthelmintic drug primarily used to treat fascioliasis, a parasitic infection often caused by the helminths, Fasciola hepatica and Fasciola gigantica . These parasites, also known as “the common liver fluke” or “the sheep liver fluke”, can infect humans following ingestion of larvae in contaminated water or food .
Mode of Action
This compound and its metabolites are active against both the immature and mature worms of Fasciola hepatica and Fasciola gigantica . The drug and its active metabolites are absorbed by the tegument of the immature and mature worms, leading to a decrease of the resting membrane potential, inhibition of motility, and disruption of the surface as well as ultrastructure that include inhibition of spermatogenesis and vitelline cells .
Biochemical Pathways
This compound is a member of the benzimidazoles and is generally accepted to bind to beta-tubulin, therefore preventing the polymerization of microtubules . This inhibition of tubulin polymerization and protein and enzyme synthesis disrupts the cell’s structural and functional capacity . Additionally, this compound has been found to decrease the intracellular level of cyclic AMP by inhibiting adenylyl cyclase .
Pharmacokinetics
Following a single 10-mg/kg dose of oral this compound given with a meal, peak plasma concentrations of unchanged drug and active sulfoxide metabolite (this compound sulfoxide) are attained within 3–4 hours . Food enhances the absorption of this compound , indicating that its bioavailability is influenced by dietary intake.
Result of Action
The result of this compound’s action is the effective treatment of fascioliasis. The drug’s interaction with its targets leads to the death of the parasites, thereby curing the infection . This compound has been shown in clinical studies to be effective in the treatment of chronic and acute forms of fascioliasis and in both F. hepatica and F. gigantica infections .
Action Environment
The efficacy of this compound can be influenced by environmental factors. For instance, the drug is more effective when administered with food, which enhances its absorption . Furthermore, the prevalence of fascioliasis is higher in areas with contaminated water or food, indicating that environmental sanitation plays a crucial role in the control and prevention of the disease .
Analyse Biochimique
Biochemical Properties
Triclabendazole and its metabolites are active against both the immature and mature worms of Fasciola hepatica and Fasciola gigantica helminths . It is mainly metabolized by the CYP1A2 enzyme into its active sulfoxide metabolite and to a lesser extent by CYP2C9, CYP2C19, CYP2D6, CYP3A, and FMO (flavin containing monooxygenase) .
Cellular Effects
This compound has been found to induce lytic cell death in MCF-7 and MDA-MB-231 breast cancer cells, a typical sign of pyroptosis . It activates apoptosis by regulating the apoptotic protein levels including Bax, Bcl-2, and enhanced cleavage of caspase-8/9/3/7 and PARP . In addition, enhanced cleavage of GSDME was also observed, which indicates the secondary necrosis/pyroptosis is further induced by active caspase-3 .
Molecular Mechanism
The molecular mode of action of this compound consists in binding to beta-tubulin, therefore preventing the polymerization of microtubules . This disrupts the structural integrity of the helminths, leading to their death .
Temporal Effects in Laboratory Settings
In a study on 350 individuals with metabolic syndrome high-risk, after a 3-month proactive intervention, two-thirds of the phenotypic markers were significantly improved in the cohort . This suggests that this compound has a time-dependent effect on biochemical markers.
Dosage Effects in Animal Models
In veterinary medicine, this compound is typically administered at an oral dose of 10 or 12 mg/kg body weight to sheep and cattle, respectively . The effects of this compound vary with different dosages in animal models. For example, in a study on sheep naturally infected with Fasciola sp., treatment with this compound resulted in significant reduction in fecal egg count .
Metabolic Pathways
This compound is metabolized within the host, principally into its sulphoxide and sulphone metabolites . This biotransformation is carried out by the flavin monooxygenase (FMO) and cytochrome P450 (CYP 450) enzyme systems .
Transport and Distribution
This compound and its metabolites are absorbed by the outer body covering of the immature and mature worms, causing a reduction in the resting membrane potential . This suggests that this compound is transported and distributed within cells and tissues via absorption.
Subcellular Localization
Given its mechanism of action, it is likely that this compound and its metabolites localize to regions where beta-tubulin is abundant, such as the cytoskeleton of cells .
Méthodes De Préparation
Voies de synthèse et conditions de réaction
Le triclabendazole peut être synthétisé en utilisant diverses méthodes. Une méthode courante consiste à commencer par le 1,2,3-trichlorobenzène, qui subit une hydrolyse dans une liqueur alcaline à haute concentration pour former le 2,3-dichlorophénol de sodium . Cet intermédiaire réagit avec la 4,5-dichloro-2-nitroaniline dans une solution aqueuse de méthylbenzène pour former la 4-chloro-5-(2,3-dichlorophénoxy)-2-nitroaniline . Le groupe nitro est ensuite réduit par une méthode de transfert catalytique d'hydrogène, et le composé résultant subit une méthylation pour donner du this compound .
Une autre méthode consiste à utiliser la 3,4-dichloroaniline comme matière de départ, suivie d'une acylation, d'une nitration, d'une hydrolyse, d'une condensation, d'une réduction avec l'hydrate d'hydrazine et d'une fermeture de cycle avec le sulfate de S-méthylisothiourée . Cette méthode évite l'utilisation de réactifs dangereux et de réactions à haute pression, ce qui la rend plus sûre et plus respectueuse de l'environnement .
Méthodes de production industrielle
La production industrielle du this compound suit généralement les voies de synthèse mentionnées ci-dessus, avec des optimisations pour la fabrication à grande échelle. L'utilisation de matières de départ peu coûteuses et facilement disponibles, ainsi que de réactifs respectueux de l'environnement, rend le processus rentable et adapté à la production à grande échelle .
Analyse Des Réactions Chimiques
Types de réactions
Le triclabendazole subit diverses réactions chimiques, notamment :
Oxydation : Le this compound est métabolisé dans le foie pour former des métabolites sulfone et sulfoxyde.
Réduction : Le groupe nitro du composé intermédiaire est réduit en groupe amine pendant la synthèse.
Substitution : La synthèse implique des réactions de substitution nucléophile aromatique pour introduire le groupe dichlorophénoxy.
Réactifs et conditions courantes
Oxydation : Les enzymes hépatiques catalysent l'oxydation du this compound en ses métabolites.
Réduction : Le transfert catalytique d'hydrogène ou l'hydrate d'hydrazine est utilisé pour la réduction du groupe nitro
Substitution : Une liqueur alcaline à haute concentration et une solution aqueuse de méthylbenzène sont utilisées pour la substitution nucléophile aromatique.
Principaux produits formés
Métabolites sulfone et sulfoxyde : Formés lors de l'oxydation du this compound dans le foie.
4-chloro-5-(2,3-dichlorophénoxy)-2-nitroaniline : Un intermédiaire dans la synthèse du this compound.
Applications de la recherche scientifique
Le this compound a un large éventail d'applications de recherche scientifique :
Chimie : Utilisé comme composé modèle pour étudier les dérivés du benzimidazole et leurs propriétés chimiques.
Biologie : Étudié pour ses effets sur les douves du foie et autres organismes parasites.
Médecine : Principalement utilisé pour traiter la fascioliase et la paragonimiase chez l'homme et l'animal C'est le seul médicament approuvé par la FDA pour la fascioliase chez l'homme.
Industrie : Utilisé en médecine vétérinaire pour traiter les infections par les douves du foie chez le bétail.
Mécanisme d'action
Le this compound et ses métabolites sont absorbés par le tégument des douves du foie, entraînant une diminution du potentiel de membrane au repos et une inhibition de la motilité . Cette perturbation affecte la surface et l'ultrastructure des douves, conduisant finalement à leur mort . Le this compound se lie à la bêta-tubuline, empêchant la polymérisation des microtubules, ce qui est essentiel à la survie des douves .
Comparaison Avec Des Composés Similaires
Le triclabendazole est unique parmi les benzimidazoles en raison de son efficacité contre les douves du foie immatures et matures . Des composés similaires incluent :
Albendazole : Utilisé pour traiter une variété d'infections parasitaires, mais moins efficace contre les douves du foie.
Thiabendazole : Un autre dérivé du benzimidazole avec un mécanisme d'action différent, principalement utilisé pour traiter la strongyloïdose.
Closantel : Efficace contre les douves du foie immatures, mais pas aussi large spectre que le this compound.
La structure unique du this compound, y compris un noyau benzénique chloré et l'absence de groupe carbamate, contribue à son mécanisme d'action et à son efficacité distincts .
Propriétés
IUPAC Name |
6-chloro-5-(2,3-dichlorophenoxy)-2-methylsulfanyl-1H-benzimidazole |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C14H9Cl3N2OS/c1-21-14-18-9-5-8(16)12(6-10(9)19-14)20-11-4-2-3-7(15)13(11)17/h2-6H,1H3,(H,18,19) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
NQPDXQQQCQDHHW-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CSC1=NC2=CC(=C(C=C2N1)Cl)OC3=C(C(=CC=C3)Cl)Cl |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C14H9Cl3N2OS |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID7043952 |
Source
|
| Record name | Triclabendazole | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7043952 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
359.7 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Solubility |
0.5 [ug/mL] (The mean of the results at pH 7.4) |
Source
|
| Record name | SID50085431 | |
| 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 | Triclabendazole | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB12245 | |
| 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) | |
Mechanism of Action |
Triclabendazole is an anthelmintic agent against _Fasciola_ species. The mechanism of action against Fasciola species is not fully understood at this time. In vitro studies and animal studies suggest that triclabendazole and its active metabolites (_sulfoxide_ and _sulfone_) are absorbed by the outer body covering of the immature and mature worms, causing a reduction in the resting membrane potential, the inhibition of tubulin function as well as protein and enzyme synthesis necessary for survival. These metabolic disturbances lead to an inhibition of motility, disruption of the worm outer surface, in addition to the inhibition of spermatogenesis and egg/embryonic cells. **A note on resistance** In vitro studies, in vivo studies, as well as case reports suggest a possibility for the development of resistance to triclabendazole. The mechanism of resistance may be multifactorial and include changes in drug uptake/efflux mechanisms, target molecules, and changes in drug metabolism. The clinical significance of triclabendazole resistance in humans is not yet elucidated. |
Source
|
| Record name | Triclabendazole | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB12245 | |
| 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) | |
CAS No. |
68786-66-3 |
Source
|
| Record name | Triclabendazole | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=68786-66-3 | |
| 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 | Triclabendazole [USAN:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0068786663 | |
| 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 | Triclabendazole | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB12245 | |
| 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 | Triclabendazole | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=759250 | |
| 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 | Triclabendazole | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7043952 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | 1H-Benzimidazole, 6-chloro-5-(2,3-dichlorophenoxy)-2-(methylthio) | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.127.414 | |
| 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 | TRICLABENDAZOLE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/4784C8E03O | |
| 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. | |
Melting Point |
189-191 |
Source
|
| Record name | Triclabendazole | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB12245 | |
| 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) | |
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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