ペンタミジン
概要
説明
ペンタミジンは、主にアフリカトリパノソーマ症、リーシュマニア症、バラミシア感染症、バベシア症の治療、および免疫不全者の肺炎球菌肺炎の予防と治療に使用される抗菌薬です . この薬は、芳香族ジアミジン系薬物に属し、1937年から医療に使用されています . ペンタミジンはジェネリック医薬品として入手可能であり、世界保健機関の必須医薬品リストに含まれています .
2. 製法
合成経路と反応条件： ペンタミジンは、4,4'-ジヒドロキシベンゾフェノンとペンタメチレンブロミドを反応させて4,4'-ビス(ペンタメチレンジオキシ)ベンゾフェノンを形成する多段階プロセスによって合成できます。 この中間体は、塩化アンモニウムとシアン化ナトリウムとの反応によって、4,4'-ビス(ペンタメチレンジオキシ)ジベンザミジンに変換されます .
工業生産方法： 工業現場では、ペンタミジンは通常、注射用水を使用して薬物を再構成することによって調製されます。 再構成された溶液は、投与前にさらに希釈されます。 静脈内注入の場合、薬剤は電子制御の注入装置を使用して、60～120分かけて投与されます .
作用機序
ペンタミジンの正確な作用機序は完全には解明されていません。 DNA、RNA、リン脂質、タンパク質の合成を阻害することにより、核代謝を阻害すると考えられています . ペンタミジンは、その正に帯電したアミジニウムイオンを介して核酸に結合し、DNAとRNAの負に帯電したリン酸骨格に導きます . この相互作用は、核酸の正常な機能を阻害し、薬物の抗菌効果につながります .
類似の化合物：
ダプソン： 疱疹状皮膚炎、らい、その他の皮膚疾患の治療に使用されます.
スルファメトキサゾール/トリメトプリム： さまざまな細菌感染症の治療に使用される抗生物質の組み合わせ.
比較： ペンタミジンは、ダプソンやスルファメトキサゾール/トリメトプリムでは通常治療されない、アフリカトリパノソーマ症やリーシュマニア症などの幅広い原虫感染症を治療できるという点でユニークです . さらに、ペンタミジンの作用機序は、核酸合成の阻害に関与しており、他の抗菌剤とは異なります .
科学的研究の応用
Pentamidine has a wide range of scientific research applications:
生化学分析
Biochemical Properties
Pentamidine interacts with various biomolecules within the cell. It is thought to interfere with nuclear metabolism, inhibiting the synthesis of DNA, RNA, phospholipids, and proteins . This disruption of essential biochemical reactions is believed to contribute to its antifungal and antiprotozoal effects .
Cellular Effects
Pentamidine has significant effects on various types of cells and cellular processes. It is known to cause diabetes mellitus, central nervous system damage, and other toxic effects . In addition, it has been found to reduce mitochondrial protein abundance and trigger progressive loss of kinetoplast DNA and disruption of mitochondrial membrane potential .
Molecular Mechanism
It is believed to exert its effects at the molecular level through binding interactions with biomolecules, enzyme inhibition or activation, and changes in gene expression . For instance, it has been found to inhibit mitosis and cytokinesis .
Temporal Effects in Laboratory Settings
Over time, Pentamidine has been observed to have various effects in laboratory settings. For instance, it has been found to cause hypoglycemia and nephrotoxicity in up to 27% and 25% of treatment courses, respectively .
Dosage Effects in Animal Models
The effects of Pentamidine vary with different dosages in animal models. For instance, it has been found to effectively decrease the burden of Chlamydia trachomatis upon local or systemic application in mice .
Metabolic Pathways
Pentamidine is involved in various metabolic pathways. It is thought to change the metabolism of host cells, impairing chlamydia growth .
Transport and Distribution
Pentamidine is transported and distributed within cells and tissues via various mechanisms. It has been found to be involved in pentamidine transport at the human and mouse blood-brain barrier (BBB) via the organic cation transporter 1 (OCT1) .
Subcellular Localization
Pentamidine localizes in various subcellular compartments. It has been found to localize in parasite nuclei and kDNA, with greater intensity in the latter structure . Furthermore, it also concentrates in non-DNA-containing cytoplasmic organelles, possibly acidocalcisomes .
準備方法
Synthetic Routes and Reaction Conditions: Pentamidine can be synthesized through a multi-step process involving the reaction of 4,4’-dihydroxybenzophenone with pentamethylene bromide to form 4,4’-bis(pentamethylenedioxy)benzophenone. This intermediate is then converted to 4,4’-bis(pentamethylenedioxy)dibenzamidine through a reaction with ammonium chloride and sodium cyanide .
Industrial Production Methods: In industrial settings, pentamidine is typically prepared by reconstituting the drug using water for injections. The reconstituted solution is then diluted further prior to administration. For intravenous infusion, the drug is administered using an electronically controlled infusion device over a period of 60 to 120 minutes .
化学反応の分析
反応の種類： ペンタミジンは、還元反応や置換反応など、さまざまな化学反応を起こします。 注目すべき反応の1つは、サイクリックボルタンメトリーを使用して研究されてきた電気化学的還元です .
一般的な試薬と条件：
還元： pH 8.5のリン酸緩衝液中では、ペンタミジンは-1.56 V（vs. ）の電位で感度の高い還元波を生成します。
置換： ペンタミジンは、求核剤との置換反応を起こし、さまざまな誘導体を形成することができます。
主な生成物： これらの反応から生成される主な生成物には、ペンタミジンの還元型およびそのさまざまな置換誘導体が含まれます .
4. 科学研究への応用
ペンタミジンは、幅広い科学研究への応用があります：
類似化合物との比較
Dapsone: Used for the treatment of dermatitis herpetiformis, leprosy, and other skin conditions.
Sulfamethoxazole/Trimethoprim: An antibiotic combination used to treat various bacterial infections.
Comparison: Pentamidine is unique in its ability to treat a wide range of protozoal infections, including African trypanosomiasis and leishmaniasis, which are not typically treated with dapsone or sulfamethoxazole/trimethoprim . Additionally, pentamidine’s mechanism of action, involving the inhibition of nucleic acid synthesis, sets it apart from other antimicrobial agents .
特性
IUPAC Name |
4-[5-(4-carbamimidoylphenoxy)pentoxy]benzenecarboximidamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C19H24N4O2/c20-18(21)14-4-8-16(9-5-14)24-12-2-1-3-13-25-17-10-6-15(7-11-17)19(22)23/h4-11H,1-3,12-13H2,(H3,20,21)(H3,22,23) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
XDRYMKDFEDOLFX-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1=CC(=CC=C1C(=N)N)OCCCCCOC2=CC=C(C=C2)C(=N)N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C19H24N4O2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID7023431 |
Source
|
| Record name | Pentamidine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7023431 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
340.4 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 | Pentamidine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014876 | |
| 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 |
Complete, Mol wt: 592.69. Hygroscopic, very bitter crystals, mp approx 180 °C. Slight butyric odor. Sol in water (approx 1 in 10 at 25 °C, approx 1 in 4 at 100 °C); sol in glycerol, more readily on warming; slightly sol in alcohol. Insol in ether, acetone, chloroform, liq petr. pH of a 5% w/v soln in water: 4.5 to 6.5. /Isethioante/, 2.36e-02 g/L |
Source
|
| Record name | Pentamidine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00738 | |
| 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 | PENTAMIDINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7474 | |
| 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 | Pentamidine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014876 | |
| 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 mode of action of pentamidine is not fully understood. It is thought that the drug interferes with nuclear metabolism producing inhibition of the synthesis of DNA, RNA, phospholipids, and proteins., ... Up to now, it has been thought that therapeutic compounds causing QT prolongation are associated with direct block of the cardiac potassium channel human ether a-go-go-related gene (hERG), which encodes the alpha subunit of cardiac I(Kr) currents. /The authors/ show that pentamidine has no acute effects on currents produced by hERG, KvLQT1/mink, Kv4.3, or SCNA5. Cardiac calcium currents and the guinea pig cardiac action potential were also not affected. After overnight exposure, however, pentamidine reduced hERG currents and inhibited trafficking and maturation of hERG with IC(50) values of 5 to 8 uM similar to therapeutic concentrations. Surface expression determined in a chemiluminescence assay was reduced on exposure to 10, 30, and 100 uM pentamidine by about 30, 40, and 70%, respectively. These effects were specific for hERG since expression of hKv1.5, KvLQT1/minK, and Kv4.3 was not altered. In isolated guinea pig ventricular myocytes, 10 uM pentamidine prolonged action potential duration APD(90) from 374.3 or + or - 57.1 to 893.9 + or - 86.2 ms on overnight incubation. I(Kr) tail current density was reduced from 0.61 + or - 0.09 to 0.39 + or - 0.04 pA/pF. /The authors/ conclude that pentamidine prolongs the cardiac action potential by block of hERG trafficking and reduction of the number of functional hERG channels at the cell surface. /The authors/ propose that pentamidine, like arsenic trioxide, produces QT prolongation and torsades de pointes in patients by inhibition of hERG trafficking., ... Inhibition in vitro of trypanosomal mitochondrial topoisomerase II and plasma Ca+2, Mg+2-ATPase also has been reported ... Pentamidine promotes linearization of trypanosome kinetoplast DNA, consistent with its being a type II topoisomerase inhibitor ... The drug also inhibits ATP-dependent topoisomerases in extracts of Pneumocystis carinii ..., Not clearly defined; pentamidine may interfere with incorporation of nucleotides into RNA and DNA and inhibit oxidative phosphorylation and biosynthesis of DNA, RNA, protein, and phospholipid; may also interfere with folate transformation., ... The cytotoxic properties of pentamidine isethionate (2) towards the promastigotes of the protozoan parasite Leishmania infantum /was determined/. The leishmanicidal activity of 2 was 60 times higher after 72 hr of incubation than that of cisplatin. The pentamidine salt 2 induced a higher amount of programmed cell death (PCD) than cisplatin, which is associated with inhibition of DNA synthesis and cell-cycle arrest in the G2/M phase. Circular dichroism (CD) data indicate that binding of 2 to calf-thymus DNA (CT-DNA) induces conformational changes in the DNA double helix, consistent with a B-->A transition. Moreover, the interaction of 2 with ubiquitin led to a 6% increase in the beta-sheet content of the protein as observed by CD spectroscopy. Fluorescence-spectroscopy studies agreed with the CD data, showing that the pentamidine portion of 2 induces a significant decrease in the fluorescence of the Ub residues Phe4 and Phe45 located on the beta-cluster of the molecule, but not of Tyr59 on the alpha-cluster. These data indicate that pentamidine specifically modifies the beta-cluster, i.e., the 'basic face' of ubiquitin. ... /The/ results suggest that the biochemical mechanism of action of pentamidine may be a consequence of its dual binding to DNA and proteins., In this work pentamidine is shown to exhibit characteristics of a cationic uncoupler of oxidative phosphorylation in isolated rat liver mitochondria: it released respiratory control, enhanced the latent ATPase activity, and released the inhibition of State 3 respiration by oligomycin. Maximal stimulation of respiration and ATPase activity was observed at a concentration of pentamidine of 200-300 microM. Higher concentrations had an inhibitory effect on mitochondrial respiration. As it happens with other cationic uncouplers, the uncoupling effect of pentamidine required inorganic phosphate. Pentamidine-induced uncoupling of oxidative phosphorylation was accompanied by an efflux of Ca2+ from the mitochondria and partial collapse of the mitochondrial membrane potential. |
Source
|
| Record name | Pentamidine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00738 | |
| 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 | PENTAMIDINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7474 | |
| 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 |
Crystallizes as colorless plates from water | |
CAS No. |
100-33-4 |
Source
|
| Record name | Pentamidine | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=100-33-4 | |
| 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 | Pentamidine [INN:BAN:DCF] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000100334 | |
| 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 | Pentamidine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00738 | |
| 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 | pentamidine | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=9921 | |
| 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. | |
| Explanation | Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source. | |
| Record name | Pentamidine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7023431 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Pentamidine | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.002.583 | |
| 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 | PENTAMIDINE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/673LC5J4LQ | |
| 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 | PENTAMIDINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7474 | |
| 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 | Pentamidine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014876 | |
| 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 |
Decomposes at 186 °C, 186.0 °C (decomposes) |
Source
|
| Record name | Pentamidine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00738 | |
| 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 | PENTAMIDINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7474 | |
| 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 | Pentamidine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014876 | |
| 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. | |
Synthesis routes and methods
Procedure details
Retrosynthesis Analysis
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|---|---|
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| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
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Feasible Synthetic Routes
試験管内研究製品の免責事項と情報
BenchChemで提示されるすべての記事および製品情報は、情報提供を目的としています。BenchChemで購入可能な製品は、生体外研究のために特別に設計されています。生体外研究は、ラテン語の "in glass" に由来し、生物体の外で行われる実験を指します。これらの製品は医薬品または薬として分類されておらず、FDAから任何の医療状態、病気、または疾患の予防、治療、または治癒のために承認されていません。これらの製品を人間または動物に体内に導入する形態は、法律により厳格に禁止されています。これらのガイドラインに従うことは、研究と実験において法的および倫理的な基準の遵守を確実にするために重要です。
