In vitro activity of 2-alkyl-3-hydroxy-1,4-naphthoquinones against Theileria parva

Boehm, Peter; Cooper, Keith; Hudson, A. T.; Elphick, Jane P.; McHardy, N.

doi:10.1021/jm00135a011

Cited by 37 publications

(13 citation statements)

References 6 publications

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“…[292] Interestingly, activity against Theileria parva infections in cattle was observed which led to extensive structural variations, resulting in parvaquone (86), a highly efficient therapeutic of the Theileria parva infection. [293] Subsequently, the cyclohexyl residue of parvaquone was widely explored, leading to the compound BW58C80 (87), which has broad antiprotozoal activity. [294] In humans, the tert-butyl residue is rapidly hydroxylated to the 1000-fold less active metabolite.…”

Section: Development Of 2-hydroxynaphthoquinonesmentioning

confidence: 99%

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

2007

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Since ancient times, humankind has had to struggle against the persistent onslaught of pathogenic microorganisms. Nowadays, malaria is still the most important infectious disease worldwide. Considerable success in gaining control over malaria was achieved in the 1950s and 60s through landscaping measures, vector control with the insecticide DDT, and the widespread administration of chloroquine, the most important antimalarial agent ever. In the late 1960s, the final victory over malaria was believed to be within reach. However, the parasites could not be eradicated because they developed resistance against the most widely used and affordable drugs of that time. Today, cases of malaria infections are on the rise and have reached record numbers. This review gives a short description of the malaria disease, briefly addresses the history of antimalarial drug development, and focuses on drugs currently available for malaria therapy. The present knowledge regarding their mode of action and the mechanisms of resistance are explained, as are the attempts made by numerous research groups to overcome the resistance problem within classes of existing drugs and in some novel classes. Finally, this review covers all classes of antimalarials for which at least one drug candidate is in clinical development. Antimalarial agents that are solely in early development stages will be addressed in a separate review.

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Section: Development Of 2-hydroxynaphthoquinonesmentioning

confidence: 99%

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

2007

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“…The most efficacious vaccine approach for East Coast fever was developed many years ago and includes infection of cattle with T. parva sporozoites and immediate treatment with a drug that impairs the establishment of infection, such as oxytetracycline (6) or, alternatively, buparvaquone (BPQ), which is currently the only effective compound for the treatment of bovine theileriosis (7)(8)(9). BPQ is a hydroxynaphtoquinone related to parvaquone (10,11). To be effective, the compound must be administered during the early stage of infection, and the drug is not always affordable or available to farmers (12).…”

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confidence: 99%

In Vitro Screening of the Open-Source Medicines for Malaria Venture Malaria Box Reveals Novel Compounds with Profound Activities against Theileria annulata Schizonts

Hostettler

Müller

Hemphill

2016

Antimicrob Agents Chemother

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“…Atovaquone (2-[trans-4-(4Ј-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-hydroxynaphthoquinone) (2, 3) is an anti-protozoal compound that has broad-spectrum activity against apicomplexan parasites including Plasmodium (4), Toxoplasma (5), Theileria (6), and Babesia (7) and the fungus Pneumocystis carinii (8). The effects of the drug on cell respiration and the structural similarities of atovaquone and ubiquinol suggested that the bc 1 complex was the target (4).…”

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confidence: 99%

Molecular Basis for Atovaquone Binding to the Cytochrome bc 1 Complex

Kessl

Lange

Merbitz-Zahradnik

et al. 2003

Journal of Biological Chemistry

154

163

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Atovaquone is a substituted 2-hydroxynaphthoquinone that is used therapeutically to treat Plasmodium falciparum malaria, Pneumocystis carinii pneumonia, and Toxoplasma gondii toxoplasmosis. It is thought to act on these organisms by inhibiting the cytochrome bc 1 complex. We have examined the interaction of atovaquone with the bc 1 complex isolated from Saccharomyces cerevisiae, a surrogate, nonpathogenic fungus. Atovaquone inhibits the bc 1 complex competitively with apparent K i ‫؍‬ 9 nM, raises the midpoint potential of the Rieske iron-sulfur protein from 285 to 385 mV, and shifts the g values in the EPR spectrum of the Rieske center. These results indicate that atovaquone binds to the ubiquinol oxidation pocket of the bc 1 complex, where it interacts with the Rieske iron-sulfur protein. A computed energy-minimized structure for atovaquone liganded to the yeast bc 1 complex suggests that a phenylalanine at position 275 of cytochrome b in the bovine bc 1 complex, as opposed to leucine at the equivalent position in the yeast enzyme, is responsible for the decreased sensitivity of the bovine bc 1 complex (K i ‫؍‬ 80 nM) to atovaquone. When a L275F mutation was introduced into the yeast cytochrome b, the sensitivity of the yeast enzyme to atovaquone decreased (K i ‫؍‬ 100 nM) with no loss in activity, confirming that the L275F exchange contributes to the differential sensitivity of these two species to atovaquone. These results provide the first molecular description of how atovaquone binds to the bc 1 complex and explain the differential inhibition of the fungal versus mammalian enzymes.

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In vitro activity of 2-alkyl-3-hydroxy-1,4-naphthoquinones against Theileria parva

Cited by 37 publications

References 6 publications

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

In Vitro Screening of the Open-Source Medicines for Malaria Venture Malaria Box Reveals Novel Compounds with Profound Activities against Theileria annulata Schizonts

Molecular Basis for Atovaquone Binding to the Cytochrome bc 1 Complex

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