Naphthoquinone Antimalarials. I. General Survey<sup>1,2</sup>

Fieser, Louis; Berliner, Ernst; Bondhus, Frances J.; Chang, Frederic C.; Dauben, William G.; Ettlinger, Martin G.; Fawaz, G.; Fields, Melvin; Fieser, Mary; Heidelberger, Charles; Heymann, H; Seligman, Arnold M.; Vaughan, Wyman R.; Wilson, Armin G.; Wilson, E. R.; Wu, Mao-i; Leffler, Marlin T.; Hamlin, K. E.; Hathaway, Robert J.; Matson, Edward J.; Moore, Elaine; Moore, M. B.; Rapala, Richard T.; Zaugg, Harold E.

doi:10.1021/ja01190a001

Cited by 95 publications

(28 citation statements)

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“…At pH 7.4, a pH value optimal for enzyme activity 28 , an IC 50 value of 45 nM was obtained, which agrees well with previously published data 25 . As hydroxynaphthoquinones ionize 37 and pH-dependent potency of inhibition has been reported for another ionizable cyt bc 1 inhibitor, 5-n-heptyl-6-hydroxy-4,7-dioxobenzothiazole 38 (HDBT), potency of atovaquone inhibition was monitored for a pH range between 6.5 and 7.4. In this pH range, the uninhibited enzyme activity is within B80% of the maximum turnover 28 .…”

Section: Resultsmentioning

confidence: 99%

“…Ionized and non-ionized form of hydroxynaphthoquinones show distinct ultraviolet/visible spectra 37 , which include for atovaquone a prominent absorption maximum at 277 nm on ionization and maxima at 253 and 285 nm for the non-ionized form (Fig. 2b).…”

Section: Resultsmentioning

confidence: 99%

“…In general, ionization of the hydroxyl group of hydroxynaphthoquinones is known and pK a values are described in the range of 4.7-6.8 (ref. 37). We determined a pK a of 6.9 for atovaquone in detergent solution.…”

Section: Discussionmentioning

confidence: 99%

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Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action

2014

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action

2014

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“…The biological activity of substituted-1,4-naphthoquinones was fi rst reported by Fieser et al ( 1948 ). Lapachol obtained from the wood extract of Tabebuia serratifolia (Bignoniaceae) showed antifungal activity (Velasquez et al 2004 ).…”

Section: Naphthoquinonesmentioning

confidence: 99%

Phytochemical Pesticides

Walia¹,

Saha²,

Rana³

2014

Advances in Plant Biopesticides

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Many phytochemical pesticides exhibiting broad spectrum of activity against pests and diseases have long been considered as attractive alternative to synthetic chemical pesticides as they are biodegradable, target specifi c, and pose no or less hazard to the environment or to human health. Although a large number of studies suggest that plant-based materials do affect arthropod pests, vectors, and other pathogens, yet only a handful of botanicals are currently used in agriculture, and there are few prospects for commercial development of new botanical products. Several factors appear to limit the success of botanicals, most notably regulatory barriers and the availability of competing products of microbial origin that are cost-effective and relatively safe compared with their predecessors. In the context of agricultural pest management, botanical pesticides are best suited for use in organic food production and can play a much greater role in the production and post-harvest protection of food and food products in developing countries. There is thus a need to organize natural sources, develop quality control, adopt standardization strategies, and modify regulatory mechanisms.

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“…Menoctone, also known as 2-hydroxy-3-(8-cyclohexyloctyl)-1,4-naphthoquinone, was first synthesized by Fieser et al in 1948 (3). Initial studies with menoctone and analogs thereof found that the drug reduced blood stage parasitemia but failed to prevent recrudescence at safe, nontoxic levels of drug administration (3). In 1965, Howland used rat liver mitochondrial preparations to model how menoctone and various naphthoquinones inhibited the respiratory chain between cytochromes b and c 1 (35).…”

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Menoctone Resistance in Malaria Parasites Is Conferred by M133I Mutations in Cytochrome b That Are Transmissible through Mosquitoes

Blake

Johnson

Siegel

et al. 2017

Antimicrob Agents Chemother

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Malaria-related mortality has slowly decreased over the past decade; however, eradication of malaria requires the development of new antimalarial chemotherapies that target liver stages of the parasite and combat the emergence of drug resistance. The diminishing arsenal of anti-liver-stage compounds sparked our interest in reviving the old and previously abandoned compound menoctone. In support of these studies, we developed a new convergent synthesis method that was facile, required fewer steps, produced better yields, and utilized less expensive reagents than the previously published method. Menoctone proved to be highly potent against liver stages of Plasmodium berghei (50 percent inhibitory concentration [IC 50 ] ϭ 0.41 nM) and erythrocytic stages of Plasmodium falciparum (113 nM). We selected for resistance to menoctone and found M133I mutations in cytochrome b of both P. falciparum and P. berghei. The same mutation has been observed previously in atovaquone resistance, and we confirmed cross-resistance between menoctone and atovaquone in vitro (for P. falciparum) and in vivo (for P. berghei). Finally, we assessed the transmission potential of menoctone-resistant P. berghei and found that the M133I mutant parasites were readily transmitted from mouse to mosquitoes and back to mice. In each step, the M133I mutation in cytochrome b, inducing menoctone resistance, was confirmed. In summary, this study is the first to show the mechanism of resistance to menoctone and that menoctone and atovaquone resistance is transmissible through mosquitoes.

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Naphthoquinone Antimalarials. I. General Survey^1,2

Cited by 95 publications

References 0 publications

Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action

Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action

Phytochemical Pesticides

Menoctone Resistance in Malaria Parasites Is Conferred by M133I Mutations in Cytochrome b That Are Transmissible through Mosquitoes

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Naphthoquinone Antimalarials. I. General Survey1,2

Cited by 95 publications

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Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action

Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action

Phytochemical Pesticides

Menoctone Resistance in Malaria Parasites Is Conferred by M133I Mutations in Cytochrome b That Are Transmissible through Mosquitoes

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Naphthoquinone Antimalarials. I. General Survey^1,2