Atovaquone CAS 95233-18-4
Introduction：Basic information about Atovaquone CAS 95233-18-4, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Atovaquone Basic informationAntimalarial Agent
| Product Name: | Atovaquone |
| Synonyms: | trans-2-[4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione;3-Hydroxy-2-[4β-(4-chlorophenyl)cyclohexan-1α-yl]naphthalene-1,4-dione;Atovaquone (200 mg);Atovaquone, USP;1,4-Naphthalenedione, 2-[trans-4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-;Atavaquone;Atovaquone for system suitability;566C80 |
| CAS: | 95233-18-4 |
| MF: | C22H19ClO3 |
| MW: | 366.84 |
| EINECS: | 000-000-0 |
| Product Categories: | Intermediates & Fine Chemicals;Pharmaceuticals;Heterocycles;LEVATOL;Coronavirus |
| Mol File: | 95233-18-4.mol |
Atovaquone Chemical Properties
| Melting point | 216-2190C |
| Boiling point | 535.0±50.0 °C(Predicted) |
| density | 1.349±0.06 g/cm3(Predicted) |
| storage temp. | 2-8°C |
| solubility | DMSO: >10mg/mL |
| pka | 5.01±0.10(Predicted) |
| form | powder |
| color | yellow |
| λmax | 494nm(aq. Buffer)(lit.) |
| Merck | 14,866 |
| Major Application | pharmaceutical (small molecule) |
| 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 |
| SMILES | C1(=O)C2=C(C=CC=C2)C(=O)C(O)=C1[C@@H]1CC[C@@H](C2=CC=C(Cl)C=C2)CC1 |
| CAS DataBase Reference | 95233-18-4(CAS DataBase Reference) |
Safety Information
| Hazard Codes | N |
| Risk Statements | 50/53 |
| Safety Statements | 60-61 |
| RIDADR | 3077 |
| WGK Germany | 3 |
| RTECS | QJ5616500 |
| HS Code | 29147000 |
| Storage Class | 11 - Combustible Solids |
| Hazardous Substances Data | 95233-18-4(Hazardous Substances Data) |
| Antimalarial Agent | The hydroxynaphthoquinone atovaquone, which exhibits antimalarial and anti-Pneumocystis activity, is an electron transport inhibitor that causes depletion of the ATP pool. The primary effect is on the iron flavoprotein dihydro-orotate dehydrogenase, an essential enzyme in the production of pyrimidines. Mammalian cells are able to avoid undue toxicity by use of preformed pyrimidines. Dihydro-orotate dehydrogenase from Plasmodium falciparum is inhibited by concentrations of atovaquone that are very much lower than those needed to inhibit the Pneumocystis enzyme, raising the possibility that the antimicrobial consequences might differ in the two organisms. Although atovaquone was originally developed as a monotherapy for malaria, high level resistance readily emerges in Plasmodium falciparum when the drug is used alone. Consequently, atovaquone is now combined with proguanil. |
| Description | Atovaquone is an orally active antiprotozoal agent indicated for patients with mild tomoderate AIDS-associated Pneumocystis carinii pneumonia who are intolerant to thefist-line therapy of trimethoprim-sulfamethoxazole. It is also under investigation as atreatment for malaria and AIDS-associated toxoplasmosis. |
| Chemical Properties | Yellow to Orange Crystalline Solid |
| Originator | Wellcome (United Kingdom) |
| Uses | Hydroxynaphthoquinone derivative that inhibits mitochondrial electron transport. Antipneumocystic |
| Uses | beta-adrenergic blocker |
| Uses | 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. |
| Definition | ChEBI: A naphthoquinone compound having a 4-(4-chlorophenyl)cyclohexyl group at the 2-position and a hydroxy substituent at the 3-position. |
| Indications | Atovaquone is a naphthoquinone whose mechanism ofaction involves inhibition of the mitochondrial electrontransport system in the protozoa. Malaria parasites dependon de novo pyrimidine biosynthesis through dihydroorotatedehydrogenase coupled to electron transport.Plasmodia are unable to salvage and recyclepyrimidines as do mammalian cells. Atovaquone is poorly absorbed from the gastrointestinaltract, but absorption is increased with a fattymeal. Excretion of the drug, mostly unchanged, occursin the feces.The elimination half-life is 2 to 3 days. Lowplasma levels persist for several weeks. Concurrent administrationof metoclopramide, tetracycline, or rifampinreduces atovaquone plasma levels by 40 to 50%. Atovaquone has good initial activity against theblood but not the hepatic stage of P. vivax and P. ovalemalaria parasites. It is effective against erythrocytic andexoerythrocytic P. falciparum, and therefore, daily suppressivedoses need to be taken for only 1 week uponleaving endemic areas.When used alone, it has an unacceptable(30%) rate of recrudescence and selects for resistantorganisms. It and proguanil are synergistic whencombined and no atovaquone resistance is seen. Thiscombination (Malarone) is significantly more effectivethan mefloquine, amodiaquine, chloroquine, and combinationsof chloroquine, pyrimethamine, and sulfadoxine.In addition to using the combination of atovaquoneand proguanil for the treatment and prophylaxis of P.falciparum malaria, atovaquone is also used for thetreatment and prevention of P. carinii pneumonia andbabesiosis therapy. Atovaquone is well tolerated and produces onlyrare instances of nausea, vomiting, diarrhea, abdominalpain, headache, and rash of mild to moderate intensity. |
| Manufacturing Process | Preparation of intermediate 4-(4-chlorophenyl)cyclohexane-1-carboxylic acidwas needed at first. It was made as follows: acetyl chloride (30 g), aluminiumchloride (60 g) in carbon disulfide (120 ml) were stirred at -50°C. Cyclohexen(30 g) previously cooled to -50°C was added dropwise during 10 minutes andthe mixture was stirred for 60 minutes at -50°C. The solvent was decantedand 300 ml chlorobenzene was added, the so-obtained solution heated at40°C for 3 hours with stirring, poured onto a mixture of ice and concentratedhydrochloric acid and the organic layer washed with 2 M HCl, 2 M NaOH andwater, dried over anhydrous Na2SO4. The product was distilled in vacuo, thefraction boiling at 140°-154°C (0.1 mm Hg) collected, diluted with an equalvolume of petroleum ether, cooled to -6°C and a stream of nitrogen gasbubbled through. 3.1 g above obtained hexahydroacetophenone was dissolved in dioxan (15 ml)and the fresh preparated hypobromite (8 ml) in a solution of NaOH (6.2 g) inwater (42 ml) at 0°C was added at below 20°C. The mixture was stirred atambient temperature for 6 hours then allowed to stand overnight. Excesshypobromite was destroyed with sodium metabisulphite, cooled and thenacidified to give a colourless solid. It was filtered off, washed with water, driedand recrystallysed from ethanol to give 4-(4-chlorophenyl)cyclohexane-1-carboxylic acid, m.p. 254°-256°C. A mixture of this acid, 2-chloro-1,4-naphthoquinone and silver nitrate was added to ammonium persulfate to givethe corresponding naphthoquinone which was saponificated with KOH and wasyielded 2-trans-4-(p-chlorophenyl)cyclohexyl)-3-hydroxy-1,4 naphthoquinone,m.p. 216°-219°C, shown by NMR to be the pure trans isomer. |
| Brand name | Mepron (GlaxoSmithKline). |
| Therapeutic Function | Antiprotozoal |
| Antimicrobial activity | It is active against erythrocytic, liver and sexual stages ofmalaria parasites. It shows synergy with proguanil and tetracyclinesin vitro. It is also active against Babesia spp. and bothtachyzoites and cysts of Tox. gondii. Pn. jirovecii is sensitive invitro at 0.1–3.0 mg/L and high doses are effective in the rat. |
| Acquired resistance | Point mutations on parasite cytochrome b, in particularat codon 268, cause resistance and readily occur when thedrug is used alone. The rapid selection of resistance led tothe development of the synergistic combination with proguanil.Failure of Pn. jirovecii prophylaxis has also been associatedwith cytochrome b mutations. |
| General Description | Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards. Atovaquone belongs to the class of naphthoquinones with a broad-spectrum activity against parasitic infections including malaria, toxoplasmosis and Pneumocystis pneumonia. It is a potent antiprotozoal compound which aids in collapsing the mitochondrial membrane potential in a malaria parasite. |
| Pharmaceutical Applications | A hydroxynaphthoquinone. Available as the trans isomer(which is more active than the cis form) for oral use. It is insolublein water. |
| 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. |
| Mechanism of action | Atovaquone is thought to produce its antiparasitic action by virtue of its ability toinhibit the mitochondrial respiratory chain. More specifically, atovaquone is a ubiquinonereductase inhibitor, inhibiting at the cytochrome bc1 complex. This action leads to a collapseof the mitochondrial membrane potential. The compound shows stereospecific inhibition, with thetrans isomer being more active than the cisisomer. |
| Pharmacokinetics | Oral absorption: Poor Cmax 750 mg oral: 27 mg/L (steady state) Plasma half-life: 70 h Plasma protein binding: >99% It is highly lipophilic and is poorly absorbed from the gastrointestinaltract following oral administration. Bioavailability isimproved when administered with meals, particularly thosewith a high fat content. Steady-state plasma concentrationsare up to 50% lower in AIDS patients than in asymptomaticHIV-positive cases and the elimination half-life is lower (55 h)in patients with AIDS. The concentration in CSF is <1% ofthe plasma level. Unlike some other naphthoquinones it is notmetabolized by human liver microsomes. Combinations withco-trimoxazole (in HIV patients) and with proguanil plusartesunate in healthy adults did not produce any changes inatovaquone pharmacokinetics. |
| Clinical Use | 3-[4-(4-Chlorophenyl)-cyclohexyl]-2-hydroxy-1,4-naphthoquinone(Mepron) is a highly lipophilic, water-insolubleanalog of ubiquinone 6, an essential component of the mitochondrialelectron transport chain in microorganisms. Thestructural similarity between atovaquone and ubiquinonesuggests that the former may act as an antimetabolite for thelatter and thereby interfere with the function of electrontransport enzymes. Atovaquone was originally developed as an antimalarialdrug, but Plasmodium falciparum was found to developa rapid tolerance to its action. More recently, the effectivenessof atovaquone against P. carinii was discovered. Itis a currently recommended alternative to trimethoprimsulfamethoxazole(TMP-SMX) for the treatment and prophylaxisof PCP in patients intolerant to this combination.Atovaquone was also shown to be effective in eradicatingT. gondii in preclinical animal studies. The oral absorption of atovaquone is slow and incomplete,in part because of the low water solubility of the drug.Aqueous suspensions provide significantly better absorptionthan do tablets. Food, especially if it has a high fat content,increases atovaquone absorption. Significant enterohepaticrecycling of atovaquone occurs, and most (nearly 95%) ofthe drug is excreted unchanged in the feces. In vivo, atovaquoneis largely confined to the plasma, where it is extensivelyprotein bound ( 99.9%). The half-life of the drugranges from 62 to 80 hours. The primary side effect is gastrointestinalintolerance. |
| Clinical Use | Pn. jirovecii pneumonia; alternative therapy for mild to moderate illness(prophylaxis and treatment) Prophylaxis and treatment of malaria in combination with proguanil It has also been used in cerebral toxoplasmosis in AIDSpatients and in a few cases of human babesiosis. |
| Side effects | Most clinical trials of atovaquone alone have involved patientswith AIDS in whom adverse effects are often difficult todetect; however, more than 20% reported fever, nausea, diarrheaand rashes. There were limited changes in hepatocellularfunction. In malaria, in combination with proguanil, there arefew reported side effects. |
| Veterinary Drugs and Treatments | Atovaquone (with azithromycin) appears effective in treating dogswith Babesia gibsoni (Asian genotype) infections, particularly indogs not immunosuppressed or splenectomized. Atovaquone maybe of benefit for treating pneumocystosis in dogs, but it is consideredsecond line therapy after potentiated sulfonamides.Atovaquone (with azithromycin) may be of benefit in treatingCytauxzoon felis infections in cats (research is in progress at the timeof writing). |
| Drug interactions | Potentially hazardous interactions with other drugs Antibacterials: avoid with rifabutin, concentration of both drugs reduced; avoid with rifampicin, concentration reduced and rifampicin concentration increased; concentration reduced by tetracycline. Antivirals: concentration reduced by efavirenz - avoid; concentration of indinavir possibly reduced; concentration of zidovudine increased. Metoclopramide: significant reduction in plasma atovaquone levels. |
| Metabolism | Atovaquone is poorly absorbed from the GI tract because of its poor water solubility and high fatsolubility, but the absorption can be significantly increased if taken with a fat-rich meal. The drugis highly bound to plasma protein (94%) and does not enter the CNS in significant quantities. It isnot significantly metabolized in humans and is exclusively eliminated in feces via the bile. |
| References | [1] Patent: WO2010/1378, 2010, A1. Location in patent: Page/Page column 11 [2] Patent: WO2012/153162, 2012, A1. Location in patent: Page/Page column 32-33 |
Atovaquone Preparation Products And Raw materials
| Raw materials | Aluminum chloride-->Cyclohexane-->Cyclohexene-->3-METHOXYPROPIONIC ACID-->1,4-Naphthoquinone-->1-Cyclohexylethan-1-one-->Ammonium persulfate-->Carbon disulfide-->Sodium bisulfite-->Acetyl chloride-->2-Chloro-1,4-naphthoquinone-->Silver nitrate |
