Amodiaquina
Descripción general
Descripción
La amodiaquina es un compuesto sintético que pertenece a la clase de las 4-aminoquinolinas. Se utiliza principalmente como fármaco antimalárico, eficaz contra la malaria por Plasmodium falciparum, especialmente en regiones donde se ha desarrollado resistencia a otros fármacos antimaláricos como la cloroquina . La this compound se utiliza a menudo en combinación con artesunato para mejorar su eficacia y reducir el riesgo de resistencia .
Mecanismo De Acción
La amodiaquina ejerce sus efectos antimaláricos al inhibir la actividad de la hemopolimerasa en el parásito de la malaria. Esta inhibición provoca la acumulación de hemo libre, que es tóxico para el parásito. El fármaco se une al hemo libre, evitando que el parásito lo convierta en una forma menos tóxica, lo que interrumpe la función de la membrana y provoca la muerte del parásito . El principal objetivo molecular es la Fe(II)-protoporfirina IX .
Aplicaciones Científicas De Investigación
La amodiaquina tiene una amplia gama de aplicaciones en investigación científica:
Química: Se utiliza como compuesto modelo para estudiar la síntesis y la reactividad de las 4-aminoquinolinas.
Medicina: Se utiliza ampliamente en el tratamiento de la malaria, particularmente en terapias combinadas.
Industria: Se utiliza en la industria farmacéutica para la producción de medicamentos antimaláricos.
Análisis Bioquímico
Biochemical Properties
Amodiaquine interacts with various biomolecules in its role as an antimalarial agent. 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 the accumulation of free heme, which is toxic to the parasites. Amodiaquine 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
Amodiaquine 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 amodiaquine involves its interaction with free heme. Amodiaquine 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
Amodiaquine has shown consistent effects over time in laboratory settings. A study of the pharmacokinetic properties of amodiaquine 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 amodiaquine in animal models are limited, it is known that the cardiovascular effects of amodiaquine have been recognized from the earliest studies in animal models .
Metabolic Pathways
Amodiaquine is bioactivated hepatically to its primary metabolite, N-desethylamodiaquine, by the cytochrome p450 enzyme CYP2C8 . This metabolite is largely responsible for the antimalarial effect of the drug .
Transport and Distribution
Amodiaquine 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 amodiaquine is not well characterized. Given its mechanism of action, it is likely that amodiaquine and its active metabolite are localized in the cytoplasm where they can interact with free heme .
Métodos De Preparación
Rutas sintéticas y condiciones de reacción
La amodiaquina se sintetiza mediante un proceso de varios pasos que implica la reacción de 4,7-dicloroquinolina con 4-aminofenol en presencia de una base. La reacción procede a través de una sustitución nucleofílica aromática, lo que da lugar a la formación del compuesto intermedio, que luego se hace reaccionar con dietilamina para obtener this compound .
Métodos de producción industrial
La producción industrial de this compound implica la síntesis a gran escala utilizando condiciones de reacción similares a las de la síntesis de laboratorio. El proceso está optimizado para obtener un alto rendimiento y pureza, con estrictas medidas de control de calidad para garantizar que el producto final cumple con los estándares farmacéuticos .
Análisis De Reacciones Químicas
Tipos de reacciones
La amodiaquina experimenta diversas reacciones químicas, entre ellas:
Oxidación: La this compound se puede oxidar para formar su principal metabolito, la N-desetilamdodiaquina.
Reducción: Las reacciones de reducción son menos comunes, pero pueden ocurrir en condiciones específicas.
Sustitución: Las reacciones de sustitución nucleofílica participan en su síntesis y modificación.
Reactivos y condiciones comunes
Oxidación: Los agentes oxidantes comunes incluyen el peróxido de hidrógeno y el permanganato de potasio.
Reducción: Se pueden utilizar agentes reductores como el borohidruro de sodio.
Sustitución: Las bases como el hidróxido de sodio se utilizan en las reacciones de sustitución nucleofílica.
Principales productos formados
El principal producto formado a partir de la oxidación de la this compound es la N-desetilamdodiaquina, que conserva la actividad antimalárica .
Comparación Con Compuestos Similares
La amodiaquina es similar a otros compuestos de 4-aminoquinolina como la cloroquina, la mefloquina y la piperaquina . Tiene propiedades únicas que la hacen eficaz contra las cepas de Plasmodium falciparum resistentes a la cloroquina . A diferencia de la cloroquina, la this compound se utiliza a menudo en terapias combinadas para mejorar su eficacia y reducir la resistencia .
Lista de compuestos similares
- Cloroquina
- Mefloquina
- Piperaquina
- Lumefantrina
- Primaquina
- Tafenoquina
Propiedades
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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