三氯苯咪唑
描述
科学研究应用
Treatment of Fascioliasis
Clinical Efficacy
Triclabendazole is the drug of choice for treating fascioliasis. Studies have demonstrated high cure rates following treatment:
- Cure Rates by Dosage :
In a retrospective cohort study involving children in Peru, the initial treatment with triclabendazole resulted in a 55% cure rate , which decreased with subsequent treatments, indicating potential resistance or treatment failure in endemic areas .
Case Studies
- Case Study Example : In a report involving multiple cases of chronic fascioliasis, patients underwent several rounds of treatment with varying dosages of triclabendazole. Despite initial improvements, many continued to shed Fasciola eggs post-treatment, highlighting challenges in achieving complete parasitological cure .
Potential Applications in Schistosomiasis
Recent studies have evaluated triclabendazole's efficacy against Schistosoma mansoni , particularly in patients with co-infections of fascioliasis and schistosomiasis. A field survey showed that:
- Cure Rate for Schistosomiasis :
- In Vitro Studies : Triclabendazole demonstrated significant effects on adult schistosomes, leading to rapid destruction of their tegument within hours .
Cancer Research
Emerging research suggests that triclabendazole may have applications in oncology:
- Mechanism of Action : It has been shown to induce pyroptosis—a form of programmed cell death—in breast cancer cells by activating caspase-3 pathways. This mechanism involves the elevation of reactive oxygen species and the regulation of apoptotic proteins .
- Tumor Volume Reduction : In xenograft models, triclabendazole significantly reduced tumor volumes, indicating its potential as an anti-cancer agent .
Resistance and Treatment Challenges
Despite its efficacy, there are growing concerns regarding resistance to triclabendazole:
作用机制
生化分析
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
Triclabendazole 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 triclabendazole 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 triclabendazole has a time-dependent effect on biochemical markers.
Dosage Effects in Animal Models
In veterinary medicine, triclabendazole is typically administered at an oral dose of 10 or 12 mg/kg body weight to sheep and cattle, respectively . The effects of triclabendazole vary with different dosages in animal models. For example, in a study on sheep naturally infected with Fasciola sp., treatment with triclabendazole resulted in significant reduction in fecal egg count .
Metabolic Pathways
Triclabendazole 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
Triclabendazole 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 triclabendazole is transported and distributed within cells and tissues via absorption.
Subcellular Localization
Given its mechanism of action, it is likely that triclabendazole and its metabolites localize to regions where beta-tubulin is abundant, such as the cytoskeleton of cells .
准备方法
合成路线和反应条件
三氯苯咪唑可以通过多种方法合成。 一种常用的方法是使用1,2,3-三氯苯作为起始原料，在高浓度碱液中进行水解反应生成2,3-二氯酚钠 . 该中间体与4,5-二氯-2-硝基苯胺在甲苯水溶液中反应生成4-氯-5-(2,3-二氯苯氧基)-2-硝基苯胺 . 然后使用氢催化转移法还原硝基，得到的化合物进行甲基化反应得到三氯苯咪唑 .
另一种方法是使用3,4-二氯苯胺作为起始原料，然后进行酰化、硝化、水解、缩合、用水合肼还原以及与硫酸甲基异硫脲环合 . 这种方法避免了使用危险的试剂和高压反应，使其更安全、更环保 .
工业生产方法
三氯苯咪唑的工业生产通常遵循上述合成路线，并针对大规模生产进行了优化。 使用廉价易得的起始原料，以及环保的试剂，使得该工艺具有成本效益，适合大规模生产 .
化学反应分析
反应类型
三氯苯咪唑会发生各种化学反应，包括：
氧化： 三氯苯咪唑在肝脏中代谢生成砜和亚砜代谢物.
常用试剂和条件
氧化： 肝脏酶催化三氯苯咪唑氧化生成其代谢物.
还原： 氢催化转移或水合肼用于还原硝基
取代： 高浓度碱液和甲苯水溶液用于亲核芳香取代.
主要生成物
砜和亚砜代谢物： 在三氯苯咪唑在肝脏中氧化过程中形成.
4-氯-5-(2,3-二氯苯氧基)-2-硝基苯胺： 三氯苯咪唑合成过程中的中间体.
相似化合物的比较
三氯苯咪唑在苯咪唑类药物中是独一无二的，因为它对肝吸虫的幼虫和成虫阶段都有效 . 类似化合物包括：
阿苯达唑： 用于治疗多种寄生虫感染，但对肝吸虫的效果较差.
噻苯达唑： 另一种苯咪唑衍生物，作用机制不同，主要用于治疗钩虫病.
克罗桑特： 对肝吸虫幼虫有效，但不如三氯苯咪唑广谱.
生物活性
Triclabendazole (TCBZ) is a benzimidazole derivative that is primarily used as an anthelmintic agent for the treatment of infections caused by Fasciola hepatica and Fasciola gigantica. This compound exhibits a range of biological activities, particularly against helminths, and has garnered attention for its potential applications beyond parasitic infections. This article delves into the biological activity of triclabendazole, presenting research findings, case studies, and a comprehensive analysis of its mechanisms of action.
The precise mechanism of action of triclabendazole remains partially understood; however, several key pathways have been identified:
- Microtubule Disruption : TCBZ disrupts microtubule formation in helminths, leading to tegumental damage and impaired motility. This effect has been demonstrated in studies involving F. hepatica, where TCBZ exposure resulted in autophagic changes and loss of tubulin immunoreactivity in the tegumental syncytium .
- Metabolite Activity : The sulphoxide metabolite of TCBZ is believed to play a significant role in its efficacy. This metabolite exhibits delayed but potent effects on parasite motility and may act through multiple targets, including inhibition of adenylate cyclase activity .
- Oxidative Phosphorylation : There is evidence suggesting that TCBZ may uncouple oxidative phosphorylation, which could contribute to its anthelmintic effects .
Efficacy in Treating Fascioliasis
Triclabendazole is notably effective against all stages of Fasciola infections. A review of clinical studies indicates high cure rates following treatment with TCBZ:
| Study | Dose Regimen | Cure Rate (%) |
|---|---|---|
| Talaie et al. (2019) | 10 mg/kg (1 dose) | 63.9% |
| Talaie et al. (2019) | 10 mg/kg (2 doses) | 68.6% |
| Talaie et al. (2019) | 10 mg/kg (3 doses) | 63.9% |
| Villegas et al. (2020) | 10 mg/kg (single dose) | 70% - 100% |
Despite these high efficacy rates, treatment failures have been documented, particularly in cases with high baseline egg counts or lower socioeconomic status . A retrospective cohort study in Peru found that only 55% of children achieved parasitologic cure after the first round of treatment, with cure rates declining significantly after multiple doses .
Case Studies
Several case studies highlight the variability in treatment outcomes with triclabendazole:
- Case Study 1 : A 51-year-old female farmer experienced significant weight loss and abdominal pain due to Fasciola infection. After initial treatment with TCBZ (10 mg/kg), her symptoms improved; however, she relapsed after eight months and continued shedding Fasciola eggs despite subsequent treatments .
- Case Study 2 : In another case involving chronic fascioliasis, a patient received multiple courses of TCBZ but failed to achieve sustained parasitologic cure, emphasizing the need for ongoing research into resistance mechanisms and alternative treatments .
Broader Biological Activities
Recent studies have also explored the antibacterial properties of triclabendazole. Research indicates that TCBZ exhibits activity against certain Gram-positive bacteria, including methicillin-resistant strains. In combination with other agents, it has demonstrated synergistic effects against Gram-negative pathogens like E. coli and Klebsiella pneumoniae .
属性
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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