molecular formula C19H24N2O2 B1678089 Praziquantel CAS No. 55268-74-1

Praziquantel

Número de catálogo: B1678089
Número CAS: 55268-74-1
Peso molecular: 312.4 g/mol
Clave InChI: FSVJFNAIGNNGKK-UHFFFAOYSA-N
Atención: Solo para uso de investigación. No para uso humano o veterinario.
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Descripción

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 .

Aplicaciones Científicas De Investigación

Praziquantel has a wide range of scientific research applications:

Mecanismo De Acción

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.

Análisis Bioquímico

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

Métodos De Preparación

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 .

Análisis De Reacciones Químicas

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 .

Comparación Con Compuestos Similares

    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:

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.

Propiedades

IUPAC Name

2-(cyclohexanecarbonyl)-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one
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 PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

InChI Key

FSVJFNAIGNNGKK-UHFFFAOYSA-N
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 PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Molecular Formula

C19H24N2O2
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

DSSTOX Substance ID

DTXSID9021182
Record name Praziquantel
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Molecular Weight

312.4 g/mol
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Physical Description

Solid
Record name Praziquantel
Source Human Metabolome Database (HMDB)
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Solubility

>46.9 [ug/mL] (The mean of the results at pH 7.4), 3.81e-01 g/L
Record name SID858012
Source Burnham Center for Chemical Genomics
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Description Aqueous solubility in buffer at pH 7.4
Record name Praziquantel
Source DrugBank
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Record name Praziquantel
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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.
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CAS No.

55268-74-1
Record name Praziquantel
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Record name Praziquantel [USAN:USP:INN:BAN:JAN]
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Record name PRAZIQUANTEL
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Record name Praziquantel
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Melting Point

136 °C
Record name Praziquantel
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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

AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.

One-Step Synthesis Focus: Specifically designed for one-step synthesis, it provides concise and direct routes for your target compounds, streamlining the synthesis process.

Accurate Predictions: Utilizing the extensive PISTACHIO, BKMS_METABOLIC, PISTACHIO_RINGBREAKER, REAXYS, REAXYS_BIOCATALYSIS database, our tool offers high-accuracy predictions, reflecting the latest in chemical research and data.

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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