Diloxanide
Overview
Description
Diloxanide is a medication primarily used to treat infections caused by protozoa, specifically amoebas. It is commonly used to manage and eliminate Entamoeba histolytica infections, which can cause amoebic dysentery and other gastrointestinal problems .
Scientific Research Applications
Diloxanide has several scientific research applications, including:
Chemistry: Used as a model compound to study hydrolysis and glucuronidation reactions.
Medicine: Used in clinical studies to evaluate its efficacy and safety in treating amoebic infections.
Industry: Employed in the development of new anti-protozoal drugs and formulations.
Mechanism of Action
Target of Action
Diloxanide primarily targets the protozoan parasite Entamoeba histolytica . This parasite is responsible for causing amoebiasis, a type of gastrointestinal infection. The drug acts as a luminal amebicide, meaning it works within the intestines to eliminate the parasite .
Mode of Action
histolytica, which are the active, feeding stage of the parasite . It is also suggested that this compound may inhibit protein synthesis .
Biochemical Pathways
This compound’s action leads to the destruction of E. histolytica trophozoites, which eventually form into cysts . These cysts are then excreted by individuals infected with asymptomatic amoebiasis
Pharmacokinetics
This compound furoate, the prodrug form of this compound, is hydrolyzed in the gastrointestinal tract to produce the active drug . The bioavailability of this compound is approximately 90% . After absorption, this compound is extensively metabolized, primarily through glucuronidation . About 90% of the drug is rapidly excreted in the urine as a glucuronide metabolite, and the remaining 10% is excreted in the feces as this compound . The half-life of this compound is approximately 3 hours .
Result of Action
The primary result of this compound’s action is the elimination of E. histolytica from the intestines of infected individuals . By destroying the trophozoites and preventing the formation of new cysts, this compound helps to stop the spread of the infection .
Action Environment
This compound is effective in the environment of the human gastrointestinal tract, where E. histolytica resides . The drug is designed to withstand the conditions of this environment, ensuring its stability and efficacy.
Safety and Hazards
Future Directions
While Diloxanide is not currently approved for use in the United States, it has been used effectively in the treatment of Entamoeba histolytica and some other protozoal infections . It is considered a second-line treatment after paromomycin when a person has no symptoms . For people who are symptomatic, it is used after treatment with metronidazole or tinidazole . Future research may focus on further understanding its mechanism of action and exploring its potential uses in treating other conditions.
Biochemical Analysis
Biochemical Properties
Diloxanide is a luminal amebicide, meaning it destroys the trophozoites of E. histolytica that eventually form into cysts .
Cellular Effects
This compound exerts its effects primarily on the cells of the protozoa E. histolytica. It destroys the trophozoites of this organism, which are the active, feeding stage of the life cycle . The destruction of these cells prevents the formation of cysts, which are the dormant stage that allows the protozoa to survive outside the host .
Molecular Mechanism
It is thought that this compound may inhibit protein synthesis . This would interfere with the growth and reproduction of the protozoa, leading to their destruction .
Temporal Effects in Laboratory Settings
The effects of this compound have been studied extensively in laboratory settings. This compound is a prodrug, and is hydrolyzed in the gastrointestinal tract to produce the active ingredient . It has a half-life of about 3 hours .
Dosage Effects in Animal Models
The effects of this compound in animal models have not been extensively studied. It is known that this compound is used in the treatment of asymptomatic (cyst passers) intestinal amebiasis caused by Entamoeba histolytica .
Metabolic Pathways
This compound is metabolized in the body by hydrolysis to furoic acid and this compound. The this compound is then extensively glucuronidated, with 99% of this compound occurring as glucuronide and 1% as free this compound in the systemic circulation .
Transport and Distribution
This compound is slowly absorbed from the gastrointestinal tract . It is then distributed throughout the body, where it exerts its effects on the cells of the protozoa E. histolytica .
Subcellular Localization
The subcellular localization of this compound is not well understood. As a luminal amebicide, it is likely that it exerts its effects primarily in the lumen of the intestine, where the protozoa E. histolytica reside .
Preparation Methods
Synthetic Routes and Reaction Conditions: Diloxanide can be synthesized through a multi-step process involving the reaction of 4-chloroaniline with dichloroacetyl chloride to form dichloroacetyl-4-chloroaniline. This intermediate is then reacted with furan-2-carboxylic acid to produce this compound .
Industrial Production Methods: Industrial production of this compound typically involves large-scale synthesis using the same basic chemical reactions but optimized for efficiency and yield. This includes precise control of reaction conditions such as temperature, pressure, and pH to ensure high purity and consistency of the final product .
Chemical Reactions Analysis
Types of Reactions: Diloxanide undergoes several types of chemical reactions, including:
Hydrolysis: this compound furoate is hydrolyzed in the gastrointestinal tract to produce this compound and furoic acid.
Glucuronidation: this compound undergoes extensive glucuronidation in the liver, forming glucuronide conjugates that are excreted in the urine.
Common Reagents and Conditions:
Hydrolysis: Typically occurs under acidic or basic conditions in the presence of water.
Glucuronidation: Catalyzed by enzymes in the liver under physiological conditions.
Major Products Formed:
Hydrolysis: Produces this compound and furoic acid.
Glucuronidation: Produces this compound glucuronide.
Comparison with Similar Compounds
Paromomycin: Another luminal amebicide used to treat amoebic infections.
Metronidazole: Used to treat symptomatic amoebic infections and can penetrate tissues, unlike diloxanide.
Tinidazole: Similar to metronidazole, used for treating symptomatic amoebic infections.
Comparison:
This compound vs. Paromomycin: this compound is often used as a second-line treatment when paromomycin is not available or suitable.
This compound vs. Metronidazole/Tinidazole: this compound is used after treatment with metronidazole or tinidazole for symptomatic infections.
This compound’s unique role as a luminal amebicide makes it a valuable tool in the treatment of amoebic infections, particularly in cases where other treatments are not suitable or available.
Properties
IUPAC Name |
2,2-dichloro-N-(4-hydroxyphenyl)-N-methylacetamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C9H9Cl2NO2/c1-12(9(14)8(10)11)6-2-4-7(13)5-3-6/h2-5,8,13H,1H3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
GZZZSOOGQLOEOB-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CN(C1=CC=C(C=C1)O)C(=O)C(Cl)Cl |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C9H9Cl2NO2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID0022939 |
Source
|
| Record name | Diloxanide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID0022939 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
234.08 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Mechanism of Action |
Unknown. Diloxanide may inhibit protein synthesis. |
Source
|
| Record name | Diloxanide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08792 | |
| 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. |
579-38-4 |
Source
|
| Record name | Diloxanide | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=579-38-4 | |
| 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 | Diloxanide [INN:BAN:DCF] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000579384 | |
| 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 | Diloxanide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08792 | |
| 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 | Diloxanide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID0022939 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Diloxanide | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.008.583 | |
| 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 | DILOXANIDE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/89134SCM7M | |
| 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. | |
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
Q1: How does Diloxanide furoate exert its effects within the body?
A1: While the precise mechanism of action remains not fully elucidated, research suggests this compound furoate primarily targets the lumen of the intestine, exerting its effects directly on luminal amoebae. [] It is considered a luminal amoebicide, primarily active against Entamoeba histolytica trophozoites residing within the gut. [, ] This targeted action makes it particularly effective for treating asymptomatic intestinal amoebiasis. [, ]
Q2: What is the molecular formula and weight of this compound furoate?
A2: this compound furoate has the molecular formula C14H11Cl2NO4 and a molecular weight of 328.15 g/mol. []
Q3: Are there any spectroscopic data available for this compound furoate?
A3: Yes, several studies employ spectroscopic techniques for analysis:
- PMR Spectroscopy: A PMR spectroscopy method using tetramethylsilane (TMS) as an internal standard was developed to quantify this compound furoate in both pure powder and tablet formulations. The method relies on the N-CH3 protons singlet peak at δ = 3.23 for quantitative measurement. []
- UV Spectrophotometry: UV spectrophotometry plays a crucial role in analyzing this compound furoate. Studies use specific wavelengths for detection and quantification, including 258 nm, 270 nm, 280 nm, and 311 nm, depending on the analytical method and the other compounds present in the sample. [, , , , , ]
Q4: How does the presence of carbohydrates affect the stability of this compound furoate?
A4: Research indicates that certain carbohydrates can influence this compound furoate stability. In alkaline conditions, sucrose, glucose, fructose, and lactose were found to accelerate the hydrolysis of this compound furoate at 40°C. [] Interestingly, this compound furoate exhibited better stability in fructose, lactose, and sorbitol solutions at room temperature. []
Q5: How does light exposure impact the stability of this compound furoate?
A5: Studies reveal this compound furoate is susceptible to photodegradation. Exposure to UV irradiation, artificial room light, and sunlight leads to degradation. The photodegradation process follows first-order kinetics in both quartz cells and glass bottles. Solvent choice also influences the rate of photodegradation. []
Q6: What strategies can enhance this compound furoate's photostability?
A6: The addition of photoprotective agents like para-aminobenzoic acid (PABA) and ascorbic acid significantly improves the photostability of this compound furoate solutions exposed to 254 nm UV irradiation. Commercially available Tang® preparation, containing sugars, buffers, stabilizers, and artificial colors, also demonstrated a photoprotective effect. []
Q7: What formulation strategies are explored to enhance this compound furoate's delivery and performance?
A7: Several approaches are under investigation to optimize this compound furoate delivery:
- Cyclodextrin Complexation: Complexation with β-cyclodextrin (βCD), methyl-β-cyclodextrin (MβCD), and hydroxypropyl-β-cyclodextrin (HPβCD) has been shown to significantly improve the solubility and dissolution rate of this compound furoate. [] This strategy holds promise for enhancing its bioavailability and therapeutic efficacy.
- pH-Dependent Polymers: Studies explore colon-targeted delivery using pH-sensitive polymers like Eudragit S100, Eudragit L 100, and Cellulose acetate phthallate. These polymers aim to control drug release in specific intestinal regions for optimal therapeutic effect. []
Q8: What analytical techniques are commonly employed in this compound furoate research?
A8: A range of analytical techniques are utilized to characterize and quantify this compound furoate:
- High-Performance Liquid Chromatography (HPLC): This versatile technique is frequently used to assay this compound furoate in pharmaceutical formulations, study its stability, and analyze its presence in biological samples. Different variations of HPLC, including RP-HPLC, are employed. [, , , , , , , , , , , , , ]
- Thin-Layer Chromatography (TLC): This method provides a rapid and cost-effective way to separate and quantify this compound furoate in mixtures. High-performance TLC (HPTLC) offers enhanced sensitivity and resolution for analysis. [, ]
- UV Spectrophotometry: This technique utilizes the absorption properties of this compound furoate at specific wavelengths to determine its concentration in various samples. [, , , ]
- Difference Spectrophotometry: This technique measures the absorbance difference at specific wavelengths, allowing the determination of this compound furoate in the presence of other components. []
Q9: How is the validity of these analytical methods ensured?
A9: The analytical methods employed in this compound furoate research undergo rigorous validation procedures following guidelines set by organizations like the International Conference on Harmonisation (ICH). [, , , , , , , ] The validation process typically involves assessing parameters like linearity, accuracy, precision, specificity, limit of detection (LOD), and limit of quantitation (LOQ). [, , , , , , ] This rigorous validation process ensures the reliability and reproducibility of the results obtained from these analytical methods.
Q10: What is the clinical significance of distinguishing pathogenic from non-pathogenic Entamoeba histolytica strains?
A10: The identification of distinct pathogenic and non-pathogenic Entamoeba histolytica strains has important implications for treatment decisions. While both strains can colonize the human gut, only pathogenic strains cause invasive disease. [] Therefore, treatment with this compound furoate, a luminal amebicide, is typically recommended only for infections confirmed to be caused by pathogenic strains. [, , ]
Q11: What challenges are associated with treating intestinal amoebiasis in specific populations?
A11: Difficulties in treatment can arise in settings where hygiene and sanitation are compromised, potentially leading to reinfection. This has been observed in institutions housing mentally disabled individuals. In such cases, combined therapeutic approaches, including metronidazole followed by this compound furoate, have proven effective in controlling the spread of infection. []
Q12: How does this compound furoate compare to other available treatments for amoebiasis?
A12: While this compound furoate effectively targets luminal amoebae, it might not be sufficient to completely eliminate amoebae residing within tissues. [, , , ] In such cases, a combination therapy approach, often involving metronidazole or other nitroimidazole derivatives followed by this compound furoate, is recommended. [, , , ] The choice of treatment often depends on the clinical presentation, the severity of infection, and the presence or absence of extraintestinal involvement.
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