Praziquantel
Vue d'ensemble
Description
Praziquantel is a pyrazinoisoquinoline derivative used as an anthelmintic medication to treat parasitic worm infections in humans and animals. It is particularly effective against schistosomiasis, clonorchiasis, opisthorchiasis, and various tapeworm infections. This compound works by increasing the permeability of the parasite’s cell membranes to calcium ions, leading to muscle contraction and paralysis of the worm .
Applications De Recherche Scientifique
Praziquantel has a wide range of scientific research applications:
Chemistry: Used as a model compound for studying the synthesis and reactions of pyrazinoisoquinoline derivatives.
Biology: Used to study the biology and lifecycle of parasitic worms.
Medicine: Widely used in the treatment of parasitic infections, particularly schistosomiasis and tapeworm infections. It is also used in veterinary medicine.
Industry: Used in the production of antiparasitic medications and as a reference standard in pharmaceutical research
Mécanisme D'action
Target of Action
Praziquantel primarily targets the β subunits of voltage-gated Ca2+ channels, particularly in Schistosoma mansoni and Schistosoma . It also targets a flatworm transient receptor potential ion channel from the melastatin subfamily (TRPM PZQ) .
Mode of Action
It is hypothesized that this compound increases the permeability of the membranes of schistosome cells towards calcium ions . This leads to an influx of calcium ions, causing contraction of the parasites’ muscles, resulting in paralysis in the contracted state . It is also suggested that this compound disrupts an interaction between a voltage-gated calcium channel (SmCav1B) and an accessory protein, SmTAL1 .
Biochemical Pathways
This compound is believed to work by dysregulating calcium homeostasis in the worm . The influx of calcium ions into the schistosome cells is thought to alter the interaction between calmodulin and the calcium channel, resulting in the inhibition of calcium influx .
Pharmacokinetics
This compound is rapidly absorbed (80%) following oral administration with a Tmax of approximately 1−3 hours . When administered with food, the Cmax and AUC of this compound are higher relative to the fasting state, although the variability is also increased . This compound is metabolized by multiple CYPs, and drug-drug interactions within these CYP pathways could result in the formation and accumulation of metabolic by-products or a reduction of the drug’s therapeutic effect .
Result of Action
This compound is active against schistosoma (for example, Schistosoma mekongi, Schistosoma japonicum, Schistosoma mansoni and Schistosoma hematobium), and infections due to the liver flukes, Clonorchis sinensis/Opisthorchis . Following exposure to this compound, the tapeworm loses its ability to resist digestion by the mammalian host .
Action Environment
The efficacy of this compound can be influenced by various environmental factors. For instance, co-administered food can increase the bioavailability of this compound . Additionally, drug-drug interactions can potentially alter this compound efficacy . More comprehensive studies are needed to fully understand the influence of environmental factors on this compound’s action, efficacy, and stability.
Analyse Biochimique
Biochemical Properties
Praziquantel is known to interact with various enzymes and proteins. It has been found to have a specific effect on the permeability of the cell membrane of schistosomes . It also disrupts calcium ion homeostasis in the worm, and the current consensus is that it antagonizes voltage-gated calcium channels .
Cellular Effects
This compound induces a rapid contraction of schistosomes by a specific effect on the permeability of the cell membrane . The drug further causes vacuolization and disintegration of the schistosome tegument . It is also suggested that this compound works by dysregulating calcium homeostasis in the worm .
Molecular Mechanism
The molecular mechanism of this compound involves disruption of calcium ion homeostasis in the worm, leading to uncontrolled muscle contraction and paralysis . It is hypothesized that this compound disrupts an interaction between a voltage-gated calcium channel (SmCav1B) and an accessory protein, SmTAL1 .
Temporal Effects in Laboratory Settings
The efficacy of this compound has been maintained over four decades (from 1977 to 2018) according to a systematic review and meta-analysis .
Dosage Effects in Animal Models
In animal models, the effects of this compound vary with different dosages . Very rarely, animals may show signs of neurological distress, such as disorientation or seizures, particularly if there is an underlying health issue or in the case of overdose .
Metabolic Pathways
This compound undergoes first-pass metabolism and 80% of the dose is excreted mainly as metabolites in the urine within 24 hours . There was minimal information on this compound’s metabolic pathway, and no pharmacogenetics studies were identified .
Transport and Distribution
This compound is distributed throughout the body after oral administration . Alterations in the liver’s capacity to metabolize this compound as well as drug-drug interactions affected systemic levels of this compound .
Subcellular Localization
It is known that this compound affects the cell membrane of schistosomes, causing rapid contraction
Méthodes De Préparation
Synthetic Routes and Reaction Conditions: Praziquantel is synthesized through a multi-step process involving several key reactions. The synthesis generally includes the following steps:
Imino-Diels-Alder Reaction: This step involves the formation of a pyrazinoisoquinoline core.
Condensation: The intermediate is condensed with appropriate reagents.
Ugi Reaction: This multi-component reaction forms the core structure of this compound.
N-Acylation: The intermediate undergoes acylation to introduce the necessary functional groups.
Substitution and Cyclization: These steps complete the formation of the this compound molecule.
Crystallization: The final product is purified through crystallization.
Industrial Production Methods: Industrial production of this compound often employs flow-chemistry techniques to optimize yield and purity. The process involves continuous flow reactors, which allow for precise control of reaction conditions such as temperature, flow rate, and residence time. This method significantly reduces production time and increases the overall yield and purity of this compound .
Analyse Des Réactions Chimiques
Types of Reactions: Praziquantel undergoes various chemical reactions, including:
Reduction: Involves the removal of oxygen atoms or the addition of hydrogen atoms.
Substitution: Involves the replacement of one functional group with another.
Common Reagents and Conditions:
Oxidation: Common oxidizing agents include potassium permanganate and hydrogen peroxide.
Reduction: Common reducing agents include lithium aluminum hydride and sodium borohydride.
Substitution: Common reagents include halogens and nucleophiles under basic or acidic conditions.
Major Products: The major products formed from these reactions include various derivatives of this compound, which may have different pharmacological properties .
Comparaison Avec Des Composés Similaires
Oxamniquine: Another anthelmintic drug used to treat schistosomiasis.
Albendazole: Used to treat a variety of parasitic worm infections, including neurocysticercosis.
Mebendazole: Used to treat infections caused by roundworms, hookworms, and whipworms.
Comparison:
Praziquantel vs. Oxamniquine: this compound is effective against a broader range of parasitic infections compared to oxamniquine, which is primarily used for schistosomiasis.
This compound vs. Albendazole: While both drugs are used to treat parasitic infections, this compound is more effective against tapeworms and schistosomes, whereas albendazole is more effective against roundworms and other nematodes.
This compound vs. Mebendazole: this compound is preferred for treating schistosomiasis and tapeworm infections, while mebendazole is more commonly used for treating intestinal nematode infections .
This compound remains a crucial medication in the fight against parasitic infections, with ongoing research aimed at improving its efficacy and understanding its mechanism of action.
Propriétés
IUPAC Name |
2-(cyclohexanecarbonyl)-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C19H24N2O2/c22-18-13-20(19(23)15-7-2-1-3-8-15)12-17-16-9-5-4-6-14(16)10-11-21(17)18/h4-6,9,15,17H,1-3,7-8,10-13H2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
FSVJFNAIGNNGKK-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1CCC(CC1)C(=O)N2CC3C4=CC=CC=C4CCN3C(=O)C2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C19H24N2O2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID9021182 |
Source
|
| Record name | Praziquantel | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID9021182 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
312.4 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 | Praziquantel | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015191 | |
| 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 |
>46.9 [ug/mL] (The mean of the results at pH 7.4), 3.81e-01 g/L |
Source
|
| Record name | SID858012 | |
| 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 | Praziquantel | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01058 | |
| 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 | Praziquantel | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015191 | |
| 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. | |
Mechanism of Action |
Praziquantel works by causing severe spasms and paralysis of the worms' muscles. This paralysis is accompanied - and probably caused - by a rapid Ca 2+ influx inside the schistosome. Morphological alterations are another early effect of praziquantel. These morphological alterations are accompanied by an increased exposure of schistosome antigens at the parasite surface. The worms are then either completely destroyed in the intestine or passed in the stool. An interesting quirk of praziquantel is that it is relatively ineffective against juvenile schistosomes. While initially effective, effectiveness against schistosomes decreases until it reaches a minimum at 3-4 weeks. Effectiveness then increases again until it is once again fully effective at 6-7 weeks. Glutathione S-transferase (GST), an essential detoxification enzyme in parasitic helminths, is a major vaccine target and a drug target against schistosomiasis. Schistosome calcium ion channels are currently the only known target of praziquantel. |
Source
|
| Record name | Praziquantel | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01058 | |
| 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. |
55268-74-1 |
Source
|
| Record name | Praziquantel | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=55268-74-1 | |
| 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 | Praziquantel [USAN:USP:INN:BAN:JAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0055268741 | |
| 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 | Praziquantel | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01058 | |
| 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 | praziquantel | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=757285 | |
| 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 | Praziquantel | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID9021182 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Praziquantel | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.054.126 | |
| 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 | PRAZIQUANTEL | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/6490C9U457 | |
| 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 | Praziquantel | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015191 | |
| 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 |
136 °C |
Source
|
| Record name | Praziquantel | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01058 | |
| 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 | Praziquantel | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015191 | |
| 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
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