2-hydroxy-3-[(1r,4r)-4-(4-chlorophenyl)cyclohexyl]-1,4-dihydronaphthalene-1,4-dione

• ChemBase编号: 988
• 分子式: C22H19ClO3
• 平均质量: 366.83746
• 单一同位素质量: 366.10227215
• SMILES: C1(=C(C(=O)c2c(C1=O)cccc2)O)[C@@H]1CC[C@H](CC1)c1ccc(cc1)Cl
• Canonical SMILES: Clc1ccc(cc1)[C@@H]1CC[C@H](CC1)C1=C(O)C(=O)c2c(C1=O)cccc2
• InChI: InChI=1S/C22H19ClO3/c23-16-11-9-14(10-12-16)13-5-7-15(8-6-13)19-20(24)17-3-1-2-4-18(17)21(25)22(19)26/h1-4,9-13,15,26H,5-8H2/t13-,15-
• InChIKey: KUCQYCKVKVOKAY-CTYIDZIISA-N

名称和登记号

名称

• IUPAC标准名: 2-hydroxy-3-[(1r,4r)-4-(4-chlorophenyl)cyclohexyl]-1,4-dihydronaphthalene-1,4-dione
• IUPAC传统名: atovaquone; 2-hydroxy-3-[(1r,4r)-4-(4-chlorophenyl)cyclohexyl]-1,4-dihydronaphthalene-1,4-dione
• 商标名: Malarone; Malarone Pediatric; Mepron
• 别名: Atovaquone; Mepron; trans-2-[4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione; Atovaquone; Malarone

登记号

• CAS号: 94015-53-9; 95233-18-4
• PubChem SID: 46507298; 160964451
• PubChem CID: 74989
• CHEBI ID: 575568
• ATC码: P01AX06
• CHEMBL: 1450
• Chemspider ID: 10482034
• DrugBank ID: DB01117
• KEGG ID: D00236
• 美国药典/FDA物质标识码: Y883P1Z2LT
• 维基百科标题: Atovaquone
• Medline Plus: a693003

理论计算性质

JChem

• Acid pKa: 8.233868
• 质子受体: 3
• 质子供体: 1
• LogD (pH = 5.5): 4.9968457
• LogD (pH = 7.4): 4.9382534
• Log P: 4.9976463
• 摩尔折射率: 103.1065 cm^3
• 极化性: 39.141586 Å^3
• 极化表面积: 54.37 Å^2
• 可自由旋转的化学键: 2
• 里宾斯基五规则: true

ALOGPS 2.1

• Log P: 4.74
• LOG S: -5.66
• 溶解度: 7.96e-04 g/l

分子性质

理化性质

• 溶解度: DMSO: >10 mg/mL; Practically insoluble
• 外观: yellow powder
• 疏水性(logP): 5.8

安全信息

• RTECS编号: QJ5616500
• 欧盟危险性物质标志: 环境危害性(Nature polluting) (N)
• 德国WGK号: 3
• 危险公开号: 50/53
• 安全公开号: 60-61
• 保存温度: -20°C

药理学性质

• 给药途径: oral only
• 半衰期: 2.2 to 3.2 days
• 法定药品分级: PoM (UK), Rx [US]
• 生物活性机理: In Plasmodium species, the site of action appears to be the cytochrome bc1 complex (Complex III).; Inhibition of electron transport by atovaquone will result in indirect inhibition of these enzymes.; Several metabolic enzymes are linked to the mitochondrial electron transport chain via ubiquinone.; The mechanism of action against Pneumocystis carinii has not been fully elucidated; The ultimate metabolic effects of such blockade may include inhibition of nucleic acid and ATP synthesis.

产品相关信息

• 纯度: ≥98% (HPLC)
• 应用领域: Active (in animals and in vitro) against Pneumocystis carinii, Plasmodia, and tachyzoite and cyst forms of Toxoplasma gondii; Antiparasitic agent; Antiprotozoal; Orally active antiprotozoal used for treatment of AIDS-associated pneumonia
• Empirical Formula (Hill Notation): C22H19ClO3

详细说明

DrugBank - DB01117

• Drug Groups: approved
• Description: A hydroxynaphthoquinone that has antimicrobial activity and is being used in antimalarial protocols. [PubChem]
• Indication: For the treatment or prevention of Pneumocystis carinii pneumonia in patients who are intolerant to trimethoprim-sulfamethoxazole (TMP-SMX). Also indicated for the acute oral treatment of mild to moderate PCP in patients who are intolerant to TMP-SMX.
• Pharmacology: Atovaquone is a highly lipophilic drug that closely resembles the structure ubiquinone. Its inhibitory effect being comparable to ubiquinone, in sensitive parasites atovaquone can act by selectively affecting mitochondrial electron transport and parallel processes such as ATP and pyrimidine biosynthesis. For illustration, cytochrome bc1 complex (complex III) seems to serve as a highly discriminating molecular target for atovaquone in Plasmodia; atovaquone has the advantage of not causing myelosuppression, which is an important issue in patients who have undergone bone marrow transplantation.
• Toxicity: The median lethal dose is higher than the maximum oral dose tested in mice and rats (1825 mg/kg per day). Overdoses up to 31,500 mg of atovaquone have been reported. In one such patient who also took an unspecified dose of dapsone, methemoglobinemia occurred. Rash has also been reported after overdose.
• Affected Organisms: Plasmodium
• Biotransformation: Some evidence suggests limited metabolism (although no metabolites have been identified).
• Absorption: The bioavailability of atovaquone is low and variable and is highly dependent on formulation and diet. Bioavailability of the suspension increases two-fold when administered with meals. When administered with food, bioavailability is approximately 47%. Without food, the bioavailability is 23%.
• Half Life: 2.2 to 3.2 days
• Protein Binding: Atovaquone is extensively bound to plasma proteins (99.9%) over the concentration range of 1 to 90 µg/mL.
• Elimination: The half-life of atovaquone is long due to presumed enterohepatic cycling and eventual fecal elimination. There was little or no excretion of atovaquone in the urine (less than 0.6%).
• Distribution: * 0.60 ± 0.17 L/kg
• Clearance: * 10.4 +/- 5.5 ml/min [HIV-infected patients receiving IV administration]
• External Links: Wikipedia; RxList; Drugs.com

Sigma Aldrich - A7986

Application
Atovaquone inhibits the cytochrome bc(1) complex via interactions with the Rieske iron-sulfur protein and cytochrome b in the ubiquinol oxidation pocket. In addition to its use as a treatment for toxoplasmosis, atovaquone has antimalarial properties and prevents pneumocystis pneumonia post-renal transplant.
Biochem/physiol Actions
Atovaquone is an anti-protozoal mitochondrial electron transport inhibitor; Antimalarial; Antipneumocystic, and has also been used to treat toxoplasmosis. It is an analog of protozoan mitochondrial protein ubiquinone, and acts by inhibiting the cytochrome bc(1) complex via interactions with the Rieske iron-sulfur protein and cytochrome b in the ubiquinol oxidation pocket.

参考文献

• Eur. Pat., 1984, Wellcome, 123 238; CA, 102, 113082w, (synth, pharmacol)
• Hughes, W.T. et al., Antimicrob. Agents Chemother., 1990, 34, 225, (pharmacol)
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