羟氯喹
描述
羟氯喹是一种主要用于预防和治疗氯喹敏感地区疟疾的药物。它还用于治疗类风湿性关节炎、狼疮和迟发性皮肤卟啉症。 羟氯喹通常以硫酸羟氯喹的形式口服 . 它属于抗疟药和 4-氨基喹啉类药物 .
科学研究应用
Antimalarial Use
Primary Indication:
- Hydroxychloroquine is primarily indicated for the treatment and prophylaxis of malaria, particularly in regions where chloroquine resistance is not prevalent. It acts by inhibiting the growth of the malaria parasite within red blood cells.
Autoimmune Diseases
Rheumatological Applications:
- Systemic Lupus Erythematosus (SLE): HCQ is widely used in managing SLE due to its immunomodulatory effects. It helps reduce disease flares and improves overall prognosis by decreasing inflammation and preventing thrombotic events associated with antiphospholipid syndrome .
- Rheumatoid Arthritis (RA): HCQ serves as a disease-modifying antirheumatic drug (DMARD) that alleviates symptoms and slows disease progression in RA patients .
Infectious Diseases
COVID-19 Research:
- During the COVID-19 pandemic, hydroxychloroquine garnered attention for its potential antiviral properties against SARS-CoV-2. Several studies investigated its efficacy in critically ill patients:
- A retrospective study indicated that HCQ treatment was associated with decreased mortality rates and reduced inflammatory cytokine levels in critically ill COVID-19 patients .
- A systematic review highlighted mixed results regarding HCQ's effectiveness in treating COVID-19, emphasizing the need for larger, well-designed clinical trials to confirm its therapeutic role .
Emerging Applications
Other Potential Uses:
- Research is ongoing into HCQ's efficacy against various viral infections, including HIV, Zika virus, and chikungunya . Its immunomodulatory properties also suggest potential applications in treating other autoimmune conditions beyond SLE and RA.
Data Table: Summary of Hydroxychloroquine Applications
Case Studies
- COVID-19 Treatment Study:
- Lupus Management:
作用机制
生化分析
Biochemical Properties
Hydroxychloroquine is a weak base that accumulates in acidic compartments such as lysosomes and inflamed tissues . It interferes with lysosomal activity and autophagy, interacts with membrane stability, and alters signaling pathways and transcriptional activity . This can result in inhibition of cytokine production and modulation of certain co-stimulatory molecules .
Cellular Effects
Hydroxychloroquine has been shown to have a variety of effects on cells. It can inhibit terminal glycosylation of ACE2, the receptor that SARS-CoV and SARS-CoV-2 target for cell entry . ACE2 that is not in the glycosylated state may less efficiently interact with the SARS-CoV-2 spike protein, further inhibiting viral entry . Hydroxychloroquine also acts by suppressing Toll-like receptors to trigger important immunomodulatory effects .
Temporal Effects in Laboratory Settings
In laboratory settings, severe laboratory abnormalities while taking hydroxychloroquine are rare, even in a population with a high rate of comorbidities . Among the abnormalities observed, the majority of them were likely due to disease progression or a medication other than hydroxychloroquine .
Dosage Effects in Animal Models
In animal models, hydroxychloroquine has been shown to be ineffective in preventing or treating SARS-CoV-2 infection, regardless of the dosage used . The LD50 (lethal dose, 50%) of hydroxychloroquine is approximately twice as high as that of chloroquine .
Metabolic Pathways
Hydroxychloroquine is metabolized by CYP3A4, CYP2D6, and CYP2C8 in vitro . All three CYPs formed the primary metabolites desethylchloroquine (DCQ) and desethylhydroxychloroquine (DHCQ) to various degrees .
Transport and Distribution
Hydroxychloroquine is completely absorbed from the gastrointestinal tract, sequestered in peripheral tissues, metabolized in the liver to pharmacologically active by-products, and excreted via the kidneys and the feces . Plasma volumes of distribution up to 65,000 L for chloroquine and 44,257 L for hydroxychloroquine have been reported .
Subcellular Localization
Hydroxychloroquine and its metabolites are primarily localized in the cytoplasm . In some cell lines, they accumulate in a specific region of the cytoplasm .
准备方法
合成路线和反应条件： 羟氯喹的制备涉及多个步骤。一种方法包括使用硅烷化试剂对 5-(N-乙基-N-羟乙基)-2-氨基戊烷进行羟基保护。然后使用双(三甲基硅烷基)锂酰胺溶液在四氢呋喃或甲苯中去除氨基质子以形成氨基阴离子。 这些阴离子与 4,7-二氯喹啉发生取代反应生成羟氯喹 . 然后在醇溶液中用硫酸盐化硫酸盐化生成硫酸羟氯喹 .
工业生产方法： 硫酸羟氯喹的工业生产方法包括在催化剂作用下使 4,7-二氯喹啉与羟氯喹侧链缩合以得到羟氯喹。 然后将羟氯喹与硫酸反应制备硫酸羟氯喹 .
化学反应分析
反应类型： 羟氯喹会发生各种化学反应，包括氧化、还原和取代反应。
常用试剂和条件： 这些反应中常用的试剂包括用于去除氨基质子的双(三甲基硅烷基)锂酰胺和用于盐化的硫酸 .
主要生成物： 这些反应的主要产物包括羟氯喹和硫酸羟氯喹 .
相似化合物的比较
生物活性
Hydroxychloroquine (HCQ) is a medication traditionally used for treating malaria and autoimmune diseases such as lupus and rheumatoid arthritis. Its biological activity has garnered significant attention, particularly in the context of viral infections, including COVID-19. This article explores the diverse mechanisms through which HCQ exerts its effects, supported by research findings, data tables, and case studies.
HCQ operates through several biological pathways, which can be categorized into five major mechanisms:
- Alkalinization of Lysosomes and Endosomes : HCQ increases the pH within lysosomes and endosomes, inhibiting the processing of immune complexes and viral particles. This alkalinization disrupts critical cellular pathways necessary for viral replication .
- Inhibition of TLR7 and TLR9 : HCQ accumulates in endosomal compartments, inhibiting Toll-like receptors (TLR7 and TLR9) that play a crucial role in the immune response. By preventing these receptors from binding to immune complexes, HCQ reduces the transcription of type-1 interferons, leading to immunomodulatory effects .
- Downregulation of CXCR4 Expression : HCQ has been shown to downregulate C-X-C chemokine receptor type 4 (CXCR4), which is involved in various inflammatory processes .
- Alteration of Intracellular Calcium Levels : The drug affects calcium signaling pathways within cells, potentially influencing various cellular responses, including apoptosis and inflammation .
- Prevention of Thrombus Formation : HCQ may also inhibit platelet aggregation and thrombus formation, contributing to its anti-inflammatory properties .
Research Findings
Numerous studies have investigated the efficacy of HCQ in various contexts, particularly concerning COVID-19. The following table summarizes key findings from significant clinical trials:
Case Studies
Several observational studies have highlighted both the potential benefits and limitations of HCQ:
- Chen et al. (2020) conducted a prospective randomized clinical trial with 62 hospitalized patients, finding that those treated with HCQ had significantly shorter recovery times compared to the control group .
- Sbidian et al. (2020) analyzed data from over 4600 patients and found no difference in mortality rates between those receiving HCQ and those receiving usual care; however, discharge rates were significantly higher in the HCQ group .
Controversies and Limitations
Despite initial hopes for HCQ as a treatment for COVID-19, subsequent large-scale studies have largely discredited its efficacy against the virus:
- The RECOVERY trial , one of the largest studies conducted, concluded that there was no meaningful benefit from HCQ treatment in hospitalized patients .
- Observational studies often suffered from methodological flaws such as small sample sizes and lack of randomization, leading to overinterpretation of results .
属性
IUPAC Name |
2-[4-[(7-chloroquinolin-4-yl)amino]pentyl-ethylamino]ethanol |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C18H26ClN3O/c1-3-22(11-12-23)10-4-5-14(2)21-17-8-9-20-18-13-15(19)6-7-16(17)18/h6-9,13-14,23H,3-5,10-12H2,1-2H3,(H,20,21) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
XXSMGPRMXLTPCZ-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CCN(CCCC(C)NC1=C2C=CC(=CC2=NC=C1)Cl)CCO |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C18H26ClN3O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Related CAS |
747-36-4 (sulfate (1:1) salt) |
Source
|
| Record name | Hydroxychloroquine [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000118423 | |
| 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. | |
DSSTOX Substance ID |
DTXSID8023135 |
Source
|
| Record name | Hydroxychloroquine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID8023135 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
335.9 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 | Hydroxychloroquine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015549 | |
| 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 |
2.61e-02 g/L |
Source
|
| Record name | Hydroxychloroquine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015549 | |
| 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 exact mechanisms of hydroxychloroquine are unknown. It has been shown that hydroxychloroquine accumulates in the lysosomes of the malaria parasite, raising the pH of the vacuole. This activity interferes with the parasite's ability to proteolyse hemoglobin, preventing the normal growth and replication of the parasite. Hydroxychloroquine can also interfere with the action of parasitic heme polymerase, allowing for the accumulation of the toxic product beta-hematin. Hydroxychloroquine accumulation in human organelles also raise their pH, which inhibits antigen processing, prevents the alpha and beta chains of the major histocompatibility complex (MHC) class II from dimerizing, inhibits antigen presentation of the cell, and reduces the inflammatory response. Elevated pH in the vesicles may alter the recycling of MHC complexes so that only the high affinity complexes are presented on the cell surface. Self peptides bind to MHC complexes with low affinity and so they will be less likely to be presented to autoimmune T cells. Hydroxychloroquine also reduces the release of cytokines like interleukin-1 and tumor necrosis factor, possibly through inhibition of Toll-like receptors. The raised pH in endosomes, prevent virus particles (such as SARS-CoV and SARS-CoV-2) from utilizing their activity for fusion and entry into the cell. Hydroxychloroquine inhibits terminal glycosylation of ACE2, the receptor that SARS-CoV and SARS-CoV-2 target for cell entry. ACE2 that is not in the glycosylated state may less efficiently interact with the SARS-CoV-2 spike protein, further inhibiting viral entry. |
Source
|
| Record name | Hydroxychloroquine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01611 | |
| 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. |
118-42-3 |
Source
|
| Record name | Hydroxychloroquine | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=118-42-3 | |
| 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 | Hydroxychloroquine [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000118423 | |
| 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 | Hydroxychloroquine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01611 | |
| 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 | Hydroxychloroquine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID8023135 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Hydroxychloroquine | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.003.864 | |
| 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 | HYDROXYCHLOROQUINE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/4QWG6N8QKH | |
| 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 | Hydroxychloroquine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015549 | |
| 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 |
89-91, 90 °C |
Source
|
| Record name | Hydroxychloroquine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01611 | |
| 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 | Hydroxychloroquine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015549 | |
| 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
体外研究产品的免责声明和信息
请注意，BenchChem 上展示的所有文章和产品信息仅供信息参考。 BenchChem 上可购买的产品专为体外研究设计，这些研究在生物体外进行。体外研究，源自拉丁语 "in glass"，涉及在受控实验室环境中使用细胞或组织进行的实验。重要的是要注意，这些产品没有被归类为药物或药品，他们没有得到 FDA 的批准，用于预防、治疗或治愈任何医疗状况、疾病或疾病。我们必须强调，将这些产品以任何形式引入人类或动物的身体都是法律严格禁止的。遵守这些指南对确保研究和实验的法律和道德标准的符合性至关重要。
