molecular formula C12H15N3O2S B1528130 Albendazole-D3 CAS No. 1353867-92-1

Albendazole-D3

Cat. No.: B1528130
CAS No.: 1353867-92-1
M. Wt: 268.35 g/mol
InChI Key: HXHWSAZORRCQMX-BMSJAHLVSA-N
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Description

Albendazole-D3 is a deuterated form of Albendazole, a benzimidazole derivative widely used as an anthelmintic agent. This compound is chemically known as trideuteriomethyl N-(5-propylsulfanyl-1H-benzimidazol-2-yl)carbamate. The deuterium atoms replace the hydrogen atoms in the methyl group, which can enhance the compound’s stability and metabolic profile.

Scientific Research Applications

Albendazole-D3 has a wide range of scientific research applications:

    Chemistry: Used as a reference standard in analytical chemistry to study the metabolic pathways and degradation products of Albendazole.

    Biology: Employed in biological studies to investigate the pharmacokinetics and pharmacodynamics of deuterated drugs.

    Medicine: Used in clinical research to develop more stable and effective anthelmintic therapies.

    Industry: Applied in the development of new drug formulations with improved stability and bioavailability.

Mechanism of Action

Target of Action

Albendazole D3, also known as Albendazole-D3, primarily targets intestinal cells of parasitic worms, specifically helminths . The compound is particularly effective against many diseases caused by these parasites .

Mode of Action

Albendazole D3 interacts with its targets by binding to the colchicine-sensitive site of tubulin, a protein that forms the microtubules of the cellular cytoskeleton . This binding inhibits the polymerization or assembly of microtubules . The compound also interacts with DNA, potentially acting as a DNA intercalator .

Biochemical Pathways

The primary biochemical pathway affected by Albendazole D3 is the microtubule assembly process within the cells of the targeted parasites . By inhibiting tubulin polymerization, the compound causes degenerative alterations in the tegument and intestinal cells of the worm . This leads to a decrease in the worm’s energy production, ultimately resulting in the immobilization and death of the parasite .

Pharmacokinetics

Albendazole D3 exhibits poor absorption from the gastrointestinal tract . Its absorption may increase up to five times when administered with a fatty meal . Once absorbed, the compound is widely distributed throughout the body, including in the urine, bile, liver, cyst wall, cyst fluid, and cerebrospinal fluid . It undergoes extensive first-pass hepatic metabolism, with pathways including rapid sulfoxidation to its active metabolite . The compound is eliminated primarily in the urine .

Result of Action

The action of Albendazole D3 at the molecular level results in significant cellular effects. The compound induces CD8+ T cell activity and subsequent immunotherapy response associated with suppression of PD-L1 protein level . It also promotes ubiquitin-mediated degradation of PD-L1 via suppressing UBQLN4, which binds to PD-L1 and stabilizes PD-L1 protein .

Action Environment

Environmental factors can influence the action, efficacy, and stability of Albendazole D3. For instance, the compound, when administered to animals, enters the environment via excrements and may impact non-target organisms . Moreover, exposure of lower development stages of helminths to anthelmintics may encourage the development of drug-resistant strains of helminths . The count of eggs per gram of stool was identified as one of the variables that negatively and significantly influenced the efficacy of Albendazole D3 against A. lumbricoides .

Safety and Hazards

Albendazole may harm an unborn baby and cause damage to organs through prolonged or repeated exposure if swallowed . It is also very toxic to aquatic life with long-lasting effects .

Biochemical Analysis

Biochemical Properties

Albendazole D3 plays a crucial role in biochemical reactions by interacting with various enzymes, proteins, and other biomolecules. It primarily targets tubulin, a protein that polymerizes to form microtubules, which are essential for cell division and intracellular transport. By binding to the colchicine-sensitive site of tubulin, Albendazole D3 inhibits its polymerization, leading to the disruption of microtubule formation . This interaction results in the loss of cytoplasmic microtubules, ultimately causing cell death in parasitic worms . Additionally, Albendazole D3 interacts with cytochrome P450 enzymes, which are involved in its metabolism .

Cellular Effects

Albendazole D3 exerts significant effects on various types of cells and cellular processes. It disrupts cell division by inhibiting microtubule formation, leading to cell cycle arrest and apoptosis in parasitic cells . In cancer cells, Albendazole D3 has been shown to induce cell death by promoting the degradation of PD-L1 protein through ubiquitin-mediated pathways . This degradation enhances the immune response against tumor cells by increasing CD8+ T cell activity . Furthermore, Albendazole D3 influences cell signaling pathways, gene expression, and cellular metabolism by modulating the activity of key enzymes and proteins involved in these processes .

Molecular Mechanism

The molecular mechanism of Albendazole D3 involves its binding to the colchicine-sensitive site of tubulin, inhibiting its polymerization and assembly into microtubules . This inhibition leads to the loss of cytoplasmic microtubules, causing degenerative alterations in the tegument and intestinal cells of parasitic worms . Additionally, Albendazole D3 promotes the ubiquitin-mediated degradation of PD-L1 protein by suppressing UBQLN4, a protein that stabilizes PD-L1 . This degradation enhances the immune response against tumor cells by increasing CD8+ T cell activity .

Temporal Effects in Laboratory Settings

In laboratory settings, the effects of Albendazole D3 change over time due to its stability, degradation, and long-term effects on cellular function. Albendazole D3 is rapidly metabolized in the liver to its primary metabolite, albendazole sulfoxide, which is further metabolized to albendazole sulfone . The half-life of Albendazole D3 and its metabolites varies, with albendazole sulfoxide having a half-life of approximately 7 to 8 hours . Long-term exposure to Albendazole D3 can lead to the induction of drug-metabolizing enzymes, which may affect its efficacy and toxicity .

Dosage Effects in Animal Models

The effects of Albendazole D3 vary with different dosages in animal models. In goats, dose-dependent plasma dispositions of albendazole sulfoxide were observed following subcutaneous administration at increased doses (10 and 15 mg/kg) . Higher doses of Albendazole D3 resulted in greater plasma concentrations and increased efficacy against target parasites . Exposure to high doses of Albendazole D3 can lead to toxic effects, including lethargy, loss of appetite, intestinal cramps, nausea, diarrhea, and vomiting .

Metabolic Pathways

Albendazole D3 is involved in various metabolic pathways, primarily in the liver. It is rapidly converted to its primary metabolite, albendazole sulfoxide, which is further metabolized to albendazole sulfone and other primary oxidative metabolites . These metabolites are excreted through urine, with albendazole sulfoxide being the major metabolite . The metabolism of Albendazole D3 involves cytochrome P450 enzymes, which play a crucial role in its biotransformation .

Transport and Distribution

Albendazole D3 is transported and distributed within cells and tissues through various mechanisms. It is rapidly absorbed and converted to albendazole sulfoxide in the liver . Albendazole sulfoxide is 70% bound to plasma proteins and is widely distributed throughout the body, including the liver, bile, cyst wall, cyst fluid, and cerebral tissue . The distribution of Albendazole D3 and its metabolites is influenced by their binding to plasma proteins and their solubility in different tissues .

Subcellular Localization

The subcellular localization of Albendazole D3 is primarily within the cytoplasm, where it exerts its effects on microtubule formation . Albendazole D3 targets the colchicine-sensitive site of tubulin, inhibiting its polymerization and assembly into microtubules . This inhibition leads to the loss of cytoplasmic microtubules, causing degenerative alterations in the tegument and intestinal cells of parasitic worms . Additionally, Albendazole D3 may localize to specific cellular compartments through targeting signals or post-translational modifications .

Preparation Methods

Synthetic Routes and Reaction Conditions

The synthesis of Albendazole-D3 involves the incorporation of deuterium atoms into the Albendazole molecule. One common method is the deuterium exchange reaction, where Albendazole is treated with deuterated reagents under specific conditions to replace hydrogen atoms with deuterium. This process typically involves the use of deuterated solvents and catalysts to facilitate the exchange.

Industrial Production Methods

Industrial production of this compound follows similar principles but on a larger scale. The process involves the use of high-purity deuterated reagents and advanced catalytic systems to ensure efficient and consistent deuterium incorporation. The final product is purified using techniques such as crystallization and chromatography to achieve the desired purity and isotopic enrichment.

Chemical Reactions Analysis

Types of Reactions

Albendazole-D3 undergoes various chemical reactions, including:

    Oxidation: The compound can be oxidized to form sulfoxides and sulfones.

    Reduction: Reduction reactions can convert this compound to its corresponding amine derivatives.

    Substitution: Nucleophilic substitution reactions can introduce different functional groups into the molecule.

Common Reagents and Conditions

    Oxidation: Common oxidizing agents include hydrogen peroxide and m-chloroperbenzoic acid.

    Reduction: Reducing agents such as lithium aluminum hydride and sodium borohydride are used.

    Substitution: Reagents like alkyl halides and acyl chlorides are employed under basic or acidic conditions.

Major Products Formed

    Oxidation: Sulfoxides and sulfones.

    Reduction: Amine derivatives.

    Substitution: Various substituted benzimidazole derivatives.

Comparison with Similar Compounds

Similar Compounds

    Mebendazole: Another benzimidazole derivative with similar anthelmintic properties.

    Thiabendazole: A benzimidazole compound used to treat parasitic infections.

    Fenbendazole: A broad-spectrum anthelmintic used in veterinary medicine.

Uniqueness

Albendazole-D3 is unique due to the presence of deuterium atoms, which enhance its stability and metabolic profile. This makes it a valuable compound for research and therapeutic applications, offering potential advantages over non-deuterated analogs in terms of efficacy and safety.

Properties

IUPAC Name

trideuteriomethyl N-(6-propylsulfanyl-1H-benzimidazol-2-yl)carbamate
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

InChI

InChI=1S/C12H15N3O2S/c1-3-6-18-8-4-5-9-10(7-8)14-11(13-9)15-12(16)17-2/h4-5,7H,3,6H2,1-2H3,(H2,13,14,15,16)/i2D3
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

InChI Key

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

Canonical SMILES

CCCSC1=CC2=C(C=C1)N=C(N2)NC(=O)OC
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Isomeric SMILES

[2H]C([2H])([2H])OC(=O)NC1=NC2=C(N1)C=C(C=C2)SCCC
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Molecular Formula

C12H15N3O2S
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

DSSTOX Substance ID

DTXSID401016410
Record name Albendazole-(methyl-d3)
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Description DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.

Molecular Weight

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

CAS No.

1353867-92-1
Record name
Source CAS Common Chemistry
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Explanation The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
Record name Albendazole-(methyl-d3)
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Record name 1353867-92-1
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Synthesis routes and methods I

Procedure details

Preparation of methyl 5-propylthio-2-benzimidazole carbamate--A 1.82 g portion of cyanamide was dissolved in 10 ml of water. Methyl chloroformate, 4.64 g, and 6.34 g of 50% aqueous sodium hydroxide in 6 ml of water were added simultaneously so as to maintain the pH at approximately 7 as determined by a pH meter. The reaction mixture was stirred at 50° C. for one hour. A portion of 7.4 g of concentrated hydrochloric acid in 7 ml of water was added until the pH was 4. The methanol solution of 4-propylthio-o-phenylenediamine from Example IV was added at once. More of the hydrochloric acid solution was added to adjust the pH to 4. The reaction mixture was heated to distill the methanol. As methanol was nearly removed more hydrochloric acid solution was added to keep the pH at 4. Water was added from time to time to keep the slurry from becoming too thick. The reaction slurry was heated at 100° C. for one hour after the methanol had been removed. The reaction slurry was cooled, filtered and washed liberally with water. The solids were air dried to produce 8.77 g of crude methyl 5-propylthio-2-benzimidazole carbamate. The crude solids were washed 3 times with cold acetone and dried to produce 7.52 g of product assaying 97% methyl-5-propylthio-2-benzimidazole carbamate by HPLC, 73% yield from the 4-propylthio-2-nitroaniline employed in Example IV.
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Synthesis routes and methods II

Procedure details

SKOV-3 human cystadenocarcinoma cell line, obtained from the American Type Culture Collection (ATCC Accession No. HTB 77) were grown in McCoy's 5a medium with 1.5 mM L-glutamine, 100 units/ml penicillin, and 100 μg/ml streptomycin, supplemented with 10% FCS. Cells were grown to confluence and harvested by trypsinization with 0.25 mg/ml trypsin/EDTA and suspended in the medium before plating. These were then seeded (2×105) on plastic 6-well Corning culture plates. Cultures were maintained in a 37° C. incubator in a humidified atmosphere of 95% O2/5% CO2. Twenty-four hours later, the medium was removed. Subconfluent cultures were washed three times with phosphate buffer followed by incubation for 6 hours with culture medium containing various concentrations of albendazole (0, 0.1, 0.25 and 1.0 μM) dissolved in 1% ethanol. After completion of the treatment period, medium from the wells were individually collected and analysed for the VEGF concentration using an enzyme-linked immunosorbant assay (ELISA) that detects soluble VEGF121 and VEGF165 isoforms (Quantikine R&D systems, Minneapolis, USA).
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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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