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

• ChemBase ID: 988
• Molecular Formular: C22H19ClO3
• Molecular Mass: 366.83746
• Monoisotopic Mass: 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

NAMES AND DATABASE IDS

Names

• IUPAC name: 2-hydroxy-3-[(1r,4r)-4-(4-chlorophenyl)cyclohexyl]-1,4-dihydronaphthalene-1,4-dione
• IUPAC Traditional name: atovaquone; 2-hydroxy-3-[(1r,4r)-4-(4-chlorophenyl)cyclohexyl]-1,4-dihydronaphthalene-1,4-dione
• Brand Name: Malarone; Malarone Pediatric; Mepron
• Synonyms: Atovaquone; Mepron; trans-2-[4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione; Atovaquone; Malarone

Database IDs

• CAS Number: 94015-53-9; 95233-18-4
• PubChem SID: 46507298; 160964451
• PubChem CID: 74989
• CHEBI ID: 575568
• ATC CODE: P01AX06
• CHEMBL: 1450
• Chemspider ID: 10482034
• DrugBank ID: DB01117
• KEGG ID: D00236
• Unique Ingredient Identifier: Y883P1Z2LT
• Wikipedia Title: Atovaquone
• Medline Plus: a693003

CALCULATED PROPERTIES

JChem

• Acid pKa: 8.233868
• H Acceptors: 3
• H Donor: 1
• LogD (pH = 5.5): 4.9968457
• LogD (pH = 7.4): 4.9382534
• Log P: 4.9976463
• Molar Refractivity: 103.1065 cm^3
• Polarizability: 39.141586 Å^3
• Polar Surface Area: 54.37 Å^2
• Rotatable Bonds: 2
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 4.74
• LOG S: -5.66
• Solubility (Water): 7.96e-04 g/l

PROPERTIES

Physical Property

• Solubility: DMSO: >10 mg/mL; Practically insoluble
• Apperance: yellow powder
• Hydrophobicity(logP): 5.8

Safety Information

• RTECS: QJ5616500
• European Hazard Symbols: Nature polluting (N)
• German water hazard class: 3
• Risk Statements: 50/53
• Safety Statements: 60-61
• Storage Temperature: -20°C

Pharmacology Properties

• Admin Routes: oral only
• Half Life: 2.2 to 3.2 days
• Legal Status: PoM (UK), Rx [US]
• Mechanism of Action: 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.

Product Information

• Purity: ≥98% (HPLC)
• Application(s): 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

DETAILS

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.

REFERENCES

• Eur. Pat., 1984, Wellcome, 123 238; CA, 102, 113082w, (synth, pharmacol)
• Hughes, W.T. et al., Antimicrob. Agents Chemother., 1990, 34, 225, (pharmacol)
• Aranjo, F.G. et al., Antimicrob. Agents Chemother., 1991, 35, 293, (pharmacol)
• Falloon, J. et al., N. Engl. J. Med., 1991, 325, 1534, (use)
• Haile, L.G. et al., Ann. Pharmacother., 1993, 27, 1488, (rev)
• Drugs of Today (Barcelona), 1993, 29, 243, (rev)
• Martindale, The Extra Pharmacopoeia, 30th edn., Pharmaceutical Press, 1993, 510
• Hudson, A.T., Parasitol. Today, 1993, 9, 66, (rev)
• DeAngelis, D.V. et al., J. Chromatogr., 1994, 652, 211, (hplc)