Amodiaquine
Vue d'ensemble
Description
L’amodiaquine est un composé synthétique appartenant à la classe des 4-aminoquinoléines. Il est principalement utilisé comme médicament antipaludique, efficace contre le paludisme à Plasmodium falciparum, en particulier dans les régions où une résistance à d’autres médicaments antipaludiques tels que la chloroquine s’est développée . L’this compound est souvent utilisée en association avec l’artésunate pour améliorer son efficacité et réduire le risque de résistance .
Mécanisme D'action
L’amodiaquine exerce ses effets antipaludiques en inhibant l’activité de la polymérase de l’hème dans le parasite du paludisme. Cette inhibition entraîne l’accumulation d’hème libre, qui est toxique pour le parasite. Le médicament se lie à l’hème libre, empêchant le parasite de le convertir en une forme moins toxique, perturbant ainsi la fonction membranaire et conduisant à la mort du parasite . La principale cible moléculaire est la Fe(II)-protoporphyrine IX .
Applications De Recherche Scientifique
Amodiaquine has a wide range of scientific research applications:
Analyse Biochimique
Biochemical Properties
Amodiaquine interacts with various biomolecules in its role as an antimalarial agent. The mechanism of plasmodicidal action of this compound is not completely certain. Like other quinoline derivatives, it is thought to inhibit heme polymerase activity . This results in the accumulation of free heme, which is toxic to the parasites. This compound binds the free heme, preventing the parasite from converting it to a form less toxic . This drug-heme complex is toxic and disrupts membrane function .
Cellular Effects
This compound has significant effects on various types of cells and cellular processes. It is known to depress cardiac muscle, impair cardiac conductivity, and produce vasodilatation with resultant hypotension . It also depresses respiration and can cause diplopia, dizziness, and nausea .
Molecular Mechanism
The molecular mechanism of action of this compound involves its interaction with free heme. This compound is thought to inhibit heme polymerase activity, leading to the accumulation of free heme . The drug then binds the free heme, preventing the parasite from converting it to a less toxic form . This drug-heme complex is toxic and disrupts membrane function .
Temporal Effects in Laboratory Settings
This compound has shown consistent effects over time in laboratory settings. A study of the pharmacokinetic properties of this compound provided evidence of high cure rates with exposure to the drug being remarkably consistent across all age groups .
Dosage Effects in Animal Models
While specific studies on the dosage effects of this compound in animal models are limited, it is known that the cardiovascular effects of this compound have been recognized from the earliest studies in animal models .
Metabolic Pathways
This compound is bioactivated hepatically to its primary metabolite, N-desethylthis compound, by the cytochrome p450 enzyme CYP2C8 . This metabolite is largely responsible for the antimalarial effect of the drug .
Transport and Distribution
This compound is likely to be widely distributed into body tissues, particularly in the liver, spleen, kidney, lungs, brain, and spinal cord .
Subcellular Localization
The subcellular localization of this compound is not well characterized. Given its mechanism of action, it is likely that this compound and its active metabolite are localized in the cytoplasm where they can interact with free heme .
Méthodes De Préparation
Voies de synthèse et conditions réactionnelles
L’amodiaquine est synthétisée par un processus en plusieurs étapes impliquant la réaction de la 4,7-dichloroquinoléine avec le 4-aminophénol en présence d’une base. La réaction se déroule par une substitution nucléophile aromatique, conduisant à la formation du composé intermédiaire, qui est ensuite réagi avec la diéthylamine pour donner l’this compound .
Méthodes de production industrielle
La production industrielle de l’this compound implique une synthèse à grande échelle utilisant des conditions réactionnelles similaires à celles de la synthèse en laboratoire. Le processus est optimisé pour un rendement et une pureté élevés, avec des mesures strictes de contrôle qualité pour garantir que le produit final répond aux normes pharmaceutiques .
Analyse Des Réactions Chimiques
Types de réactions
L’amodiaquine subit diverses réactions chimiques, notamment :
Oxydation : L’this compound peut être oxydée pour former son principal métabolite, la N-déséthylthis compound.
Réduction : Les réactions de réduction sont moins courantes mais peuvent se produire dans des conditions spécifiques.
Substitution : Des réactions de substitution nucléophile sont impliquées dans sa synthèse et sa modification.
Réactifs et conditions courantes
Oxydation : Les agents oxydants courants comprennent le peroxyde d’hydrogène et le permanganate de potassium.
Réduction : Des agents réducteurs comme le borohydrure de sodium peuvent être utilisés.
Substitution : Des bases comme l’hydroxyde de sodium sont utilisées dans les réactions de substitution nucléophile.
Principaux produits formés
Le principal produit formé par l’oxydation de l’this compound est la N-déséthylthis compound, qui conserve une activité antipaludique .
Applications de la recherche scientifique
L’this compound a une large gamme d’applications de recherche scientifique :
Chimie : Utilisé comme composé modèle pour étudier la synthèse et la réactivité des 4-aminoquinoléines.
Médecine : Largement utilisé dans le traitement du paludisme, en particulier dans les thérapies combinées.
Industrie : Employé dans l’industrie pharmaceutique pour la production de médicaments antipaludiques.
Comparaison Avec Des Composés Similaires
L’amodiaquine est similaire à d’autres composés de la 4-aminoquinoléine tels que la chloroquine, la méfloquine et la pipéraquine . Il possède des propriétés uniques qui le rendent efficace contre les souches de Plasmodium falciparum résistantes à la chloroquine . Contrairement à la chloroquine, l’this compound est souvent utilisée dans des thérapies combinées pour améliorer son efficacité et réduire la résistance .
Liste des composés similaires
- Chloroquine
- Mefloquine
- Piperaquine
- Lumefantrine
- Primaquine
- Tafenoquine
Propriétés
IUPAC Name |
4-[(7-chloroquinolin-4-yl)amino]-2-(diethylaminomethyl)phenol |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C20H22ClN3O/c1-3-24(4-2)13-14-11-16(6-8-20(14)25)23-18-9-10-22-19-12-15(21)5-7-17(18)19/h5-12,25H,3-4,13H2,1-2H3,(H,22,23) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
OVCDSSHSILBFBN-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CCN(CC)CC1=C(C=CC(=C1)NC2=C3C=CC(=CC3=NC=C2)Cl)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C20H22ClN3O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID2022597 |
Source
|
| Record name | Amodiaquine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID2022597 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
355.9 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 | Amodiaquine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014751 | |
| 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 |
24.9 [ug/mL] (The mean of the results at pH 7.4), 8.80e-03 g/L |
Source
|
| Record name | SID50085969 | |
| 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 | Amodiaquine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014751 | |
| 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 |
The mechanism of plasmodicidal action of amodiaquine is not completely certain. Like other quinoline derivatives, it is thought to inhibit heme polymerase activity. This results in accumulation of free heme, which is toxic to the parasites. The drug binds the free heme preventing the parasite from converting it to a form less toxic. This drug-heme complex is toxic and disrupts membrane function., Amodiaquine is a Mannich base 4-aminoquinoline with a mode of action similar to that of chloroquine. It is effective against some chloroquine-resistant strains of P. falciparum, although there is cross-resistance., The 4-aminoquinoline derivatives appear to bind to nucleoproteins and interfere with protein synthesis in susceptible organisms; the drugs intercalate readily into double-stranded DNA and inhibit both DNA and RNA polymerase. In addition, the drugs apparently concentrate in parasite digestive vacuoles, increase the pH of the vacuoles, and interfere with the parasite's ability to metabolize and utilize erythrocyte hemoglobin. Plasmodial forms that do not have digestive vacuoles and do not utilize hemoglobin, such as exoerythrocytic forms, are not affected by /these medications/., The 4-aminoquinoline derivatives ... have anti-inflammatory activity; however, the mechanism(s) of action of the drugs in the treatment of rheumatoid arthritis and lupus erythematosus has not been determined. /4-aminoquinoline derivatives/ reportedly antagonizes histamine in vitro, has antiserotonin effects, and inhibits prostaglandin effects in mammalian cells presumably by inhibiting conversion of arachidonic acid to prostaglandin F2., The mode of action of amodiaquine has not yet been determined. 4-Aminoquinolines depress cardiac muscle, impair cardiac conductivity, and produce vasodilatation with resultant hypotension; they depress respiration and cause diplopia, dizziness and nausea. |
Source
|
| Record name | Amodiaquine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00613 | |
| 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 | AMODIAQUINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7457 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Color/Form |
Crystals from absolute ethanol | |
CAS No. |
86-42-0 |
Source
|
| Record name | Amodiaquine | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=86-42-0 | |
| 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 | Amodiaquine [USP:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000086420 | |
| 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 | Amodiaquine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00613 | |
| 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 | amodiaquine | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=13453 | |
| 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 | Amodiaquine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID2022597 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Amodiaquine | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.001.518 | |
| 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 | AMODIAQUINE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/220236ED28 | |
| 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 | AMODIAQUINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7457 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Amodiaquine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014751 | |
| 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 |
206-208, 208 °C (decomposes), Yellow crystals from methanol. Melting point 243 °C. Slightly soluble in water and alcohol /Amodiaquine dihydrochloride hemihydrate/, 208 °C |
Source
|
| Record name | Amodiaquine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00613 | |
| 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 | AMODIAQUINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7457 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Amodiaquine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014751 | |
| 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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