Über kausalprophylaktisch bei Vogelmalaria wirksame Substanzen

Kikuth, Walter; Mudrow-Reichenow, L

doi:10.1007/bf02184020

Cited by 14 publications

(12 citation statements)

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“…Further, cytochrome bc 1 expression is markedly increased in encysted EGS bradyzoites suggesting cytochrome bc 1 might be a viable drug target for this life stage. This mitochondrial membrane bound protein complex cytochome bc 1 , part of the electron transport chain responsible for generating ubiquinone for pyrimidine biosynthesis in Plasmodium , is the molecular target of the naphthoquinone, atovaquone 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 . Partial efficacy, rapid emergence of drug resistance in malaria and toxoplasmosis limit clinical usefulness of atovaquone.…”

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confidence: 99%

New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections

McPhillie

Zhou

Bissati

et al. 2016

Sci Rep

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Toxoplasma gondii, the most common parasitic infection of human brain and eye, persists across lifetimes, can progressively damage sight, and is currently incurable. New, curative medicines are needed urgently. Herein, we develop novel models to facilitate drug development: EGS strain T. gondii forms cysts in vitro that induce oocysts in cats, the gold standard criterion for cysts. These cysts highly express cytochrome b. Using these models, we envisioned, and then created, novel 4-(1H)-quinolone scaffolds that target the cytochrome bc1 complex Qi site, of which, a substituted 5,6,7,8-tetrahydroquinolin-4-one inhibits active infection (IC50, 30 nM) and cysts (IC50, 4 μM) in vitro, and in vivo (25 mg/kg), and drug resistant Plasmodium falciparum (IC50, <30 nM), with clinically relevant synergy. Mutant yeast and co-crystallographic studies demonstrate binding to the bc1 complex Qi site. Our results have direct impact on improving outcomes for those with toxoplasmosis, malaria, and ~2 billion persons chronically infected with encysted bradyzoites.

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confidence: 99%

New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections

McPhillie

Zhou

Bissati

et al. 2016

Sci Rep

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“…Discovered nearly 70 years ago, "Endochin" (3-nheptyl-7-methoxy-2-methyl-4(1H)-quinolone) (Casey, 1974,Salzer, et al, 1948 was considered a very promising lead with excellent therapeutic activity in an avian model of malaria but it failed in clinical trials (Kikuth and Mudrow-Reichenow, 1947). [The term endochin derives from its action upon the endothelial forms of avian malaria.]…”

Section: Discussionmentioning

confidence: 99%

Antimalarial quinolones: Synthesis, potency, and mechanistic studies

Winter

Kelly

Smilkstein

et al. 2008

Experimental Parasitology

138

102

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In the present article we examine the antiplasmodial activities of novel quinolone derivatives bearing extended alkyl or alkoxy side chains terminated by a trifluoromethyl group. In the series under investigation, the IC 50 values ranged from 1.2 to ≈ 30 nM against chloroquine-sensitive and multidrug-resistant Plasmodium falciparum strains. Modest to significant cross-resistance was noted in evaluation of these haloalkyl-and haloalkoxy-quinolones for activity against the atovaquoneresistant clinical isolate Tm90-C2B, indicating that a primary target for some of these compounds is the parasite cytochrome bc 1 complex. Additional evidence to support this biochemical mechanism includes the use of oxygen biosensor plate technology to show that the quinolone derivatives block oxygen consumption by parasitized red blood cells in a fashion similar to atovaquone in side-by-side experiments. Atovaquone is extremely potent and is the only drug in clinical use that targets the Plasmodium bc 1 complex, but rapid emergence of resistance to it in both mono-and combination therapy is evident and therefore additional drugs are needed to target the cytochrome bc 1 complex which are active against atovaquone-resistant parasites. Our study of a number of halogenated alkyl and alkoxy 4(1H)-quinolones highlights the potential for development of "endochin-like quinolones" (ELQ) bearing an extended trifluoroalkyl moiety at the 3-position that exhibit selective antiplasmodial effects in the low nanomolar range and inhibitory activity against chloroquine and atovaquone resistant parasites. Further studies of halogenated alkyl and alkoxy quinolones may lead to the development of safe and effective therapeutics for use in treatment or prevention of malaria and other parasitic diseases.

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“…In 1948, Salzer and co-workers presented a new drug molecule, endochin (1), 56 that was active against sporozoiteinduced malaria (P. cathemerium) in canaries; however, this drug was inactive against human malaria. 57 Endochin was identified as targeting mitochondrial processes of the malaria parasite. 58 Subsequently, attempts were made to improve the activity profile of 1 by generating derivatives of this molecule.…”

Section: Quinolonesmentioning

confidence: 99%

Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication

Poonam

Gupta

et al. 2018

Medicinal Research Reviews

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Over time, several exciting advances have been made in the treatment and prevention of malaria; however, this devastating disease continues to be a major global health problem and affects millions of people every year. Notably, the paucity of new efficient drug molecules and the inevitable drug resistance of the malaria parasite, Plasmodium falciparum, against frontline therapeutics are the foremost struggles facing malaria eradication initiatives. According to the malaria eradication agenda, the discovery of new chemical entities that can destroy the parasite at the liver stage, the asexual blood stage, the gametocyte stage, and the insect ookinete stage of the parasite life cycle (i.e., compounds exhibiting multistage activity) are in high demand, preferably with novel and multiple modes of action. Phenotypic screening of chemical libraries against the malaria parasite is certainly a crucial step toward overcoming these crises. In the last few years, various research groups, including industrial research laboratories, have performed large-scale phenotypic screenings that have identified a wealth of chemical entities active against multiple life stages of the malaria parasite. Vital scientific and technological developments have led to the discovery of multistage inhibitors of the malaria parasite; these compounds, considered highly valuable starting points for subsequent drug discovery and eradication of malaria, are reviewed.

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Über kausalprophylaktisch bei Vogelmalaria wirksame Substanzen

Cited by 14 publications

References 1 publication

New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections

New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections

Antimalarial quinolones: Synthesis, potency, and mechanistic studies

Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication

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