Clofazimine
Overview
Description
Clofazimine is a highly lipophilic antimicrobial riminophenazine dye used primarily in the treatment of leprosy. It was first described in 1957 and is known for its bright-red color, which can cause long-lasting discoloration of the skin and bodily fluids . This compound is used in combination with other agents, such as dapsone, to treat lepromatous leprosy, including dapsone-resistant cases .
Mechanism of Action
Target of Action
Clofazimine primarily targets Mycobacterium leprae , the bacterium responsible for leprosy . It is believed to act on the bacterial outer membrane, the bacterial respiratory chain, and ion transporters . It also has anti-inflammatory properties due to its suppression of T-lymphocyte activity .
Mode of Action
This compound exerts a slow bactericidal effect on Mycobacterium leprae due to its action on the bacterial outer membrane . It is also suggested that it interferes with DNA . The anti-inflammatory activity of this compound is the result of its inhibition of T-lymphocyte activation and proliferation . Several mechanisms have been proposed, including direct antagonism of T-cell Kv 1.3 potassium channels and indirect action by promoting the release of E-series prostaglandins and reactive oxygen species .
Biochemical Pathways
It is known to interfere with cellular respiration and ion transport in mycobacterium leprae . An in vitro study identified eight metabolites of this compound and the enzymatic pathways involved in their formation, including the important cytochrome P450 isoenzymes CYP3A4/A5 and CYP1A2 .
Pharmacokinetics
This compound is a highly lipophilic antimicrobial, which allows it to accumulate in skin and nerves . It has a relatively long duration of action owing to its long residence time in the body . The pharmacokinetics of this compound were well characterized by a three-compartment model, with a clearance of 11.5 L/h and peripheral volume of 10,500 L for a typical participant . Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction .
Result of Action
The bactericidal effect of this compound results in the elimination of Mycobacterium leprae from the body . Its anti-inflammatory properties help control harmful erythema nodosum leprosum and reversal immunity reactions, which may complicate antimicrobial chemotherapy .
Action Environment
The action of this compound can be influenced by environmental factors. For instance, its lipophilic nature allows it to accumulate in fatty tissues, which can affect its distribution and efficacy . Furthermore, its pharmacokinetics and resulting efficacy can be influenced by the patient’s body fat content .
Biochemical Analysis
Biochemical Properties
Clofazimine exerts a slow bactericidal effect on Mycobacterium leprae due to its action on the bacterial outer membrane . There is also evidence that it affects the bacterial respiratory chain and ion transporters . This compound is at least partially metabolized in the liver . An in vitro study using human liver microsomes identified eight metabolites of this compound and the enzymatic pathways involved in their formation, including the important cytochrome P450 isoenzymes CYP3A4/A5 and CYP1A2 .
Cellular Effects
This compound has been found to modulate the expression of lipid metabolism proteins in Mycobacterium leprae-infected macrophages . It also exerts anti-inflammatory properties due to the suppression of T-lymphocyte activity . In HepaRG cells, this compound was a weak inducer of CYP3A4 at low concentrations, but inhibited CYP3A4 at therapeutic concentrations .
Molecular Mechanism
This compound works by binding to the guanine bases of bacterial DNA, thereby blocking the template function of the DNA and inhibiting bacterial proliferation . It also increases the activity of bacterial phospholipase A2, leading to the release and accumulation of lysophospholipids, which are toxic and inhibit bacterial proliferation .
Temporal Effects in Laboratory Settings
In a study of patients with severe Mycobacterium avium complex pulmonary disease (MAC-PD), this compound demonstrated a relatively favorable efficacy, regardless of the maintenance dose . This effect was more pronounced when administered for a duration exceeding 6 months . In mice receiving this compound, the lungs’ bacterial load continued to grow during the first seven days of treatment .
Dosage Effects in Animal Models
In an orthotopic melanoma mouse model, this compound reduced tumor size by 90% . The specific effects of different dosages of this compound in animal models have not been extensively studied.
Metabolic Pathways
This compound is involved in several metabolic pathways. It has been found to modulate the expression of lipid metabolism proteins in Mycobacterium leprae-infected macrophages . It also affects the bacterial respiratory chain and ion transporters .
Transport and Distribution
This compound is a potential substrate of uptake and efflux transporters that might be involved in its disposition . The intracellular concentrations of this compound were significantly increased in the presence of selective inhibitors of P-gp and BCRP .
Subcellular Localization
This compound has been found to accumulate in macrophages in an intracellular liquid crystal-like structure This suggests that this compound may be localized in specific subcellular compartments within these cells
Preparation Methods
Synthetic Routes and Reaction Conditions: Clofazimine is synthesized through a multi-step process involving the condensation of 3-chloro-4-nitroaniline with 4-chlorobenzaldehyde to form a Schiff base. This intermediate is then cyclized to form the phenazine core structure. The final step involves the reduction of the nitro group to an amine .
Industrial Production Methods: Industrial production of this compound involves high-pressure homogenization to produce nanosuspensions suitable for intravenous use. This method ensures that the particle size is appropriate for passive targeting to the reticuloendothelial system .
Chemical Reactions Analysis
Types of Reactions: Clofazimine undergoes various chemical reactions, including oxidation, reduction, and substitution. It is known to interact with membrane phospholipids, leading to the generation of antimicrobial lysophospholipids .
Common Reagents and Conditions: Common reagents used in the synthesis and reactions of this compound include 3-chloro-4-nitroaniline, 4-chlorobenzaldehyde, and reducing agents for the final step .
Major Products: The major product formed from the synthesis of this compound is the riminophenazine core structure, which is essential for its antimicrobial activity .
Scientific Research Applications
Clofazimine has a wide range of scientific research applications, including:
Chemistry: Used as a model compound for studying lipophilic antimicrobial agents.
Biology: Investigated for its effects on bacterial DNA and membrane phospholipids.
Medicine: Primarily used in the treatment of leprosy and multidrug-resistant tuberculosis.
Industry: Utilized in the development of novel drug delivery systems, such as nanosuspensions.
Comparison with Similar Compounds
Dapsone: Another antimicrobial agent used in the treatment of leprosy.
Rifampin: Used in combination with clofazimine for the treatment of leprosy and tuberculosis.
Uniqueness of this compound: this compound is unique due to its dual antimicrobial and anti-inflammatory properties, as well as its ability to accumulate in skin and nerves, making it particularly effective in treating leprosy .
Properties
IUPAC Name |
N,5-bis(4-chlorophenyl)-3-propan-2-yliminophenazin-2-amine |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C27H22Cl2N4/c1-17(2)30-24-16-27-25(15-23(24)31-20-11-7-18(28)8-12-20)32-22-5-3-4-6-26(22)33(27)21-13-9-19(29)10-14-21/h3-17,31H,1-2H3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
WDQPAMHFFCXSNU-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC(C)N=C1C=C2C(=NC3=CC=CC=C3N2C4=CC=C(C=C4)Cl)C=C1NC5=CC=C(C=C5)Cl |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C27H22Cl2N4 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID7022839 |
Source
|
| Record name | Clofazimine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7022839 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
473.4 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 | Clofazimine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014983 | |
| 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 |
0.3 [ug/mL] (The mean of the results at pH 7.4), 1.51e-03 g/L |
Source
|
| Record name | SID49681815 | |
| 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 | Clofazimine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00845 | |
| 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 | Clofazimine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014983 | |
| 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 |
Although the precise mechanism(s) of action of clofazimine have not been elucidated, its antimicrobial activity appears to be membrane-directed. It was previously thought that, due to its lipophilicity, clofazimine participated in the generation of intracellular reactive oxygen species (ROS) via redox cycling, specifically H2O2 and superoxide, which then exerted an antimicrobial effect. A more recent and compelling theory involves clofazimine interacting with bacterial membrane phospholipids to generate antimicrobial lysophospholipids - bactericidal efficacy may, then, arise from the combined membrane-destabilizing effects of both clofazimine and lysophospholipids, which interfere with K+ uptake and, ultimately, ATP production. The anti-inflammatory activity of clofazimine is the result of its inhibition of T-lymphocyte activation and proliferation. Several mechanisms have been proposed, including direct antagonism of T-cell Kv 1.3 potassium channels and indirect action by promoting the release of E-series prostaglandins and reactive oxygen species from bystander neutrophils and monocytes. |
Source
|
| Record name | Clofazimine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00845 | |
| 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. |
2030-63-9 |
Source
|
| Record name | Clofazimine | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=2030-63-9 | |
| 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. | |
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| Record name | Clofazimine [USAN:USP:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0002030639 | |
| 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 | Clofazimine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00845 | |
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| Record name | clofazimine | |
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| Record name | clofazimine | |
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| Record name | Clofazimine | |
| Source | EPA DSSTox | |
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| Record name | Clofazimine | |
| Source | European Chemicals Agency (ECHA) | |
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| Record name | CLOFAZIMINE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/D959AE5USF | |
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| Record name | Clofazimine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014983 | |
| 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 |
210-212 °C, 210 - 212 °C |
Source
|
| Record name | Clofazimine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00845 | |
| 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 | Clofazimine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014983 | |
| 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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