Atovaquone | CAS#95233-18-4 | Hydroxynaphthoquinone

MedKoo Cat#: 317258 | Name: Atovaquone

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Atovaquone is a synthetic hydroxynaphthoquinone with antiprotozoal activity that has antimicrobial activity and is being used in antimalarial protocols. Atovoquone blocks the mitochondrial electron transport at complex III of the respiratory chain of protozoa, thereby inhibiting pyrimidine synthesis, preventing DNA synthesis and leading to protozoal death. 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.

Chemical Structure

Atovaquone

CAS#95233-18-4

Theoretical Analysis

MedKoo Cat#: 317258

Name: Atovaquone

CAS#: 95233-18-4

Chemical Formula: C22H19ClO3

Exact Mass: 366.1023

Molecular Weight: 366.84

Elemental Analysis: C, 72.03; H, 5.22; Cl, 9.66; O, 13.08

Price and Availability

Size	Price	Availability
100mg	USD 90.00	Ready to ship
200mg	USD 150.00	Ready to ship
500mg	USD 250.00	Ready to ship
1g	USD 450.00	Ready to ship
2g	USD 750.00	Ready to ship
5g	USD 1,650.00	Ready to ship

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No Data

Synonym

566C; 566C80; 566C80 hydroxynaphthoquinone; 566C80, hydroxynaphthoquinone; Atovaquone; atovaquone GlaxoSmithKline brand; compound 566; Glaxo Wellcome brand of atovaquone; GlaxoSmithKline brand of atovaquone; hydroxynaphthoquinone 566C80; hydroxynaphthoquinone, 566C80; Mepron; Wellvone

IUPAC/Chemical Name

trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione

InChi Key

KUCQYCKVKVOKAY-CTYIDZIISA-N

InChi Code

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-

SMILES Code

O=C1C([C@H]2CC[C@H](C3=CC=C(Cl)C=C3)CC2)=C(O)C(C4=C1C=CC=C4)=O

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#C9R09B03

QC Data

View QC data: current batch, Lot# C9R09B03

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Atovaquone (Atavaquone) is a potent and selective inhibitor of the parasite’s mitochondrial cytochrome bc1 complex and has activity against human and P. falciparum cytochrome bc1 activity with IC50 values of 460 nM and 2.0 nM, respectively.

In vitro activity:

Atovaquone was recently shown to inhibit mitochondrial respiration at complex 3,3 which in turn has been reported to induce the phospho-eIF2α/ATF4 pathway in a GCN2-dependent manner.25-27 Therefore, the effect of atovaquone on the OCR of AML cells was tested. It was found that atovaquone induced dose-dependent reductions in OCR for multiple AML cell lines and primary samples (Figure 6D; supplemental Figures 15 and 16) and dose- and time-dependent effects on MV4-11 cells (supplemental Figure 15). In comparison, normal bone marrow demonstrated lower basal and maximal OCRs and little atovaquone-induced effect. Thus, atovaquone acts as a potent inhibitor of mitochondrial respiration in AML cells at clinically achievable doses. The data show that atovaquone induces apoptosis of AML samples but has negligible activity in normal healthy bone marrow. Reference: Blood Adv. 2019 Dec 23; 3(24): 4215–4227. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929386/

In vivo activity:

To test atovaquone in a PDX model, 18 NSG mice (female, n = 10; male, n = 8; supplemental Table 2) were injected with 1.2 × 106 patient-derived pheresis products (90% blasts; AML3) by tail vein and treated with atovaquone or vehicle as in the THP-1.ffluc in vivo model. Four mice were censored because of deaths unrelated to disease or treatment. Evidence of peripheral human CD45+/CD33+ AML cell engraftment was first noted on day 55 after cell injection. Atovaquone-treated mice again demonstrated decreased disease burden compared with control as shown in representative flow cytometry plots (Figure 4A). The peripheral blast percentages for atovaquone-treated and control mice were significantly different at each time point beginning on day 72 (Figure 4B; supplemental Figure 5A). Mice continued on treatment until they showed signs of clinical illness. Female mice became ill sooner than male mice, with an average time to morbidity of 119 days for female vs 133 days for male vehicle-treated mice. For atovaquonetreated mice, the average time to clinical illness was 159 days for female vs 163 days for male mice. Survival was significantly improved in mice exposed to atovaquone compared with control (log-rank P = .0004; Figure 4C; supplemental Figure 5B). In total, The results provide evidence for further clinical investigation into the use of atovaquone for the treatment of pediatric and adult AML. Reference: Blood Adv. 2019 Dec 23; 3(24): 4215–4227. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929386/

	Solvent	mg/mL	mM
Solubility
	DMSO	5.0	13.63

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 366.84 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Stevens AM, Xiang M, Heppler LN, Tošić I, Jiang K, Munoz JO, Gaikwad AS, Horton TM, Long X, Narayanan P, Seashore EL, Terrell MC, Rashid R, Krueger MJ, Mangubat-Medina AE, Ball ZT, Sumazin P, Walker SR, Hamada Y, Oyadomari S, Redell MS, Frank DA. Atovaquone is active against AML by upregulating the integrated stress pathway and suppressing oxidative phosphorylation. Blood Adv. 2019 Dec 23;3(24):4215-4227. doi: 10.1182/bloodadvances.2019000499. PMID: 31856268; PMCID: PMC6929386. 2. Gupta N, Srivastava SK. Atovaquone: An Antiprotozoal Drug Suppresses Primary and Resistant Breast Tumor Growth by Inhibiting HER2/β-Catenin Signaling. Mol Cancer Ther. 2019 Oct;18(10):1708-1720. doi: 10.1158/1535-7163.MCT-18-1286. Epub 2019 Jul 3. PMID: 31270151; PMCID: PMC6905100.

In vitro protocol:

In vivo protocol:

1: Nuralitha S, Siregar JE, Syafruddin D, Roelands J, Verhoef J, Hoepelman AI, Marzuki S. Within-Host Selection of Drug Resistance in a Mouse Model of Repeated Incomplete Malaria Treatment: Comparison between Atovaquone and Pyrimethamine. Antimicrob Agents Chemother. 2015 Oct 26. pii: AAC.00538-15. [Epub ahead of print] PubMed PMID: 26503662. 2: Teo BH, Lansdell P, Smith V, Blaze M, Nolder D, Beshir KB, Chiodini PL, Cao J, Färnert A, Sutherland CJ. Delayed Onset of Symptoms and Atovaquone-Proguanil Chemoprophylaxis Breakthrough by Plasmodium malariae in the Absence of Mutation at Codon 268 of pmcytb. PLoS Negl Trop Dis. 2015 Oct 20;9(10):e0004068. doi: 10.1371/journal.pntd.0004068. eCollection 2015 Oct. PubMed PMID: 26485258; PubMed Central PMCID: PMC4618945. 3: Dinter D, Gajski G, Domijan AM, Garaj-Vrhovac V. Cytogenetic and oxidative status of human lymphocytes after exposure to clinically relevant concentrations of antimalarial drugs atovaquone and proguanil hydrochloride in vitro. Fundam Clin Pharmacol. 2015 Sep 10. doi: 10.1111/fcp.12153. [Epub ahead of print] PubMed PMID: 26434663. 4: de Oliveira Silva E, Dos Santos Gonçalves N, Alves Dos Santos R, Jacometti Cardoso Furtado NA. Microbial Metabolism of Atovaquone and Cytotoxicity of the Produced Phase I Metabolite. Eur J Drug Metab Pharmacokinet. 2015 Aug 8. [Epub ahead of print] PubMed PMID: 26253156. 5: de Lima LP, Seabra SH, Carneiro H, Barbosa HS. Effect of 3-bromopyruvate and atovaquone on infection during in vitro interaction of Toxoplasma gondii and LLC-MK2 cells. Antimicrob Agents Chemother. 2015 Sep;59(9):5239-49. doi: 10.1128/AAC.00337-15. Epub 2015 Jun 15. PubMed PMID: 26077255; PubMed Central PMCID: PMC4538506. 6: Mendorf A, Klyuchnikov E, Langebrake C, Rohde H, Ayuk F, Regier M, Christopeit M, Zabelina T, Bacher A, Stübig T, Wolschke C, Bacher U, Kröger N. Atovaquone for Prophylaxis of Toxoplasmosis after Allogeneic Hematopoietic Stem Cell Transplantation. Acta Haematol. 2015;134(3):146-54. doi: 10.1159/000380757. Epub 2015 May 5. PubMed PMID: 25968483. 7: Song Z, Clain J, Iorga BI, Yi Z, Fisher N, Meunier B. Saccharomyces cerevisiae-based mutational analysis of the bc1 complex Qo site residue 279 to study the trade-off between atovaquone resistance and function. Antimicrob Agents Chemother. 2015 Jul;59(7):4053-8. doi: 10.1128/AAC.00710-15. Epub 2015 Apr 27. PubMed PMID: 25918152; PubMed Central PMCID: PMC4468654. 8: Plucinski MM, Huber CS, Akinyi S, Dalton W, Eschete M, Grady K, Silva-Flannery L, Mathison BA, Udhayakumar V, Arguin PM, Barnwell JW. Novel Mutation in Cytochrome B of Plasmodium falciparum in One of Two Atovaquone-Proguanil Treatment Failures in Travelers Returning From Same Site in Nigeria. Open Forum Infect Dis. 2014 Aug 5;1(2):ofu059. doi: 10.1093/ofid/ofu059. eCollection 2014 Sep. PubMed PMID: 25734129; PubMed Central PMCID: PMC4281801. 9: Ingasia LA, Akala HM, Imbuga MO, Opot BH, Eyase FL, Johnson JD, Bulimo WD, Kamau E. Molecular characterization of the cytochrome b gene and in vitro atovaquone susceptibility of Plasmodium falciparum isolates from Kenya. Antimicrob Agents Chemother. 2015 Mar;59(3):1818-21. doi: 10.1128/AAC.03956-14. Epub 2015 Jan 12. PubMed PMID: 25583715; PubMed Central PMCID: PMC4325819. 10: Boggild AK, Lau R, Reynaud D, Kain KC, Gerson M. Failure of atovaquone-proguanil malaria chemoprophylaxis in a traveler to Ghana. Travel Med Infect Dis. 2015 Jan-Feb;13(1):89-93. doi: 10.1016/j.tmaid.2014.12.010. Epub 2014 Dec 31. PubMed PMID: 25582377. 11: Sönmez N, Büyükbaba Boral O, Kaşali K, Tekeli F. [Effects of atovaquone and astragalus combination on the treatment and IL-2, IL-12, IFN-γ levels on mouse models of acute toxoplasmosis]. Mikrobiyol Bul. 2014 Oct;48(4):639-51. Turkish. PubMed PMID: 25492659. 12: Grynberg S, Lachish T, Kopel E, Meltzer E, Schwartz E. Artemether-lumefantrine compared to atovaquone-proguanil as a treatment for uncomplicated Plasmodium falciparum malaria in travelers. Am J Trop Med Hyg. 2015 Jan;92(1):13-7. doi: 10.4269/ajtmh.14-0249. Epub 2014 Nov 4. PubMed PMID: 25371188; PubMed Central PMCID: PMC4347368. 13: Akhoon BA, Singh KP, Varshney M, Gupta SK, Shukla Y, Gupta SK. Understanding the mechanism of atovaquone drug resistance in Plasmodium falciparum cytochrome b mutation Y268S using computational methods. PLoS One. 2014 Oct 15;9(10):e110041. doi: 10.1371/journal.pone.0110041. eCollection 2014. PubMed PMID: 25334024; PubMed Central PMCID: PMC4198183. 14: Guler JL, White J 3rd, Phillips MA, Rathod PK. Atovaquone tolerance in Plasmodium falciparum parasites selected for high-level resistance to a dihydroorotate dehydrogenase inhibitor. Antimicrob Agents Chemother. 2015 Jan;59(1):686-9. doi: 10.1128/AAC.02347-14. Epub 2014 Oct 20. PubMed PMID: 25331708; PubMed Central PMCID: PMC4291421. 15: Oz HS. Toxoplasmosis complications and novel therapeutic synergism combination of diclazuril plus atovaquone. Front Microbiol. 2014 Sep 15;5:484. doi: 10.3389/fmicb.2014.00484. eCollection 2014. PubMed PMID: 25309522; PubMed Central PMCID: PMC4164033. 16: Siregar JE, Kurisu G, Kobayashi T, Matsuzaki M, Sakamoto K, Mi-ichi F, Watanabe Y, Hirai M, Matsuoka H, Syafruddin D, Marzuki S, Kita K. Direct evidence for the atovaquone action on the Plasmodium cytochrome bc1 complex. Parasitol Int. 2015 Jun;64(3):295-300. doi: 10.1016/j.parint.2014.09.011. Epub 2014 Sep 28. PubMed PMID: 25264100. 17: Maude RJ, Nguon C, Dondorp AM, White LJ, White NJ. The diminishing returns of atovaquone-proguanil for elimination of Plasmodium falciparum malaria: modelling mass drug administration and treatment. Malar J. 2014 Sep 24;13:380. doi: 10.1186/1475-2875-13-380. PubMed PMID: 25249272; PubMed Central PMCID: PMC4192368. 18: Rijpma SR, van den Heuvel JJ, van der Velden M, Sauerwein RW, Russel FG, Koenderink JB. Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity. Malar J. 2014 Sep 13;13:359. doi: 10.1186/1475-2875-13-359. PubMed PMID: 25218605; PubMed Central PMCID: PMC4172838. 19: Oz HS. Novel Synergistic Protective Efficacy of Atovaquone and Diclazuril on Fetal-Maternal Toxoplasmosis. Int J Clin Med. 2014 Aug;5(15):921-932. PubMed PMID: 25210646; PubMed Central PMCID: PMC4157831. 20: Tahar R, Almelli T, Debue C, Foumane Ngane V, Djaman Allico J, Whegang Youdom S, Basco LK. Randomized trial of artesunate-amodiaquine, atovaquone-proguanil, and artesunate-atovaquone-proguanil for the treatment of uncomplicated falciparum malaria in children. J Infect Dis. 2014 Dec 15;210(12):1962-71. doi: 10.1093/infdis/jiu341. Epub 2014 Jun 18. PubMed PMID: 24943722.