Quinolone-Based Drugs Against Toxoplasma gondii and Plasmodium spp

Anquetin, Guillaume; Greiner, Jacques; Vierling, Pierre

doi:10.2174/1568005054880172

Cited by 21 publications

(8 citation statements)

References 125 publications

(242 reference statements)

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“…1) 25 that are also active against transmissible malaria parasites. Quinolones also display activities against Tg 26 , and here too newer compounds, e.g. ELQ-271 ( Fig.…”

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confidence: 90%

Accessible and distinct decoquinate derivatives active against Mycobacterium tuberculosis and apicomplexan parasites

et al. 2018

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The quinolone decoquinate is coadministered with feed for treatment of parasites which cause coccidiosis in poultry. However, from a drug-development perspective, the biological activity is often not adequately exploited due to poor physicochemical properties. Here we convert decoquinate into N-alkyl quinolone amides that, in contrast to decoquinate, are active against the tuberculosis bacterium with MIC 90 values ranging from 1.4 to 3.64 µM, and quinoline O-carbamates active against apicomplexan parasites that cause malaria, toxoplasmosis, and neosporosis with IC 50 values of 0.32-1.5 nM for the best derivative. Uniquely for the TB-active amides, disruption of cell wall homoeostasis is identified as one target. With IC 50 values against fetal lung fibroblast cells of 40 to >100 μM, the derivatives are selective for the pathogens. Structures of the most active derivatives are determined by NMR spectroscopy and X-ray crystallography. Analogues lacking the decyl side chain of decoquinate are inactive.

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“…1) 25 that are also active against transmissible malaria parasites. Quinolones also display activities against Tg 26 , and here too newer compounds, e.g. ELQ-271 ( Fig.…”

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confidence: 90%

Accessible and distinct decoquinate derivatives active against Mycobacterium tuberculosis and apicomplexan parasites

et al. 2018

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“…A plausible explanation of the activity of this class of antibiotics on P. falciparum came from the sequencing of its entire genome, 7,8 and from the recent biochemical characterization of gyrases and topoisomerase IV which could be the main targets of (fluoro)quinolones. 9,10 Using a dual strategy combining a prodrug/ bioorganometallic approach, we recently improved the antimalarial activity of ciprofloxacin (CIPRO 1). 11 This strategy revealed that the prodrug approach resulted in a dramatic increase of the antimalarial activity.…”

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confidence: 99%

Esterprodrugs of ciprofloxacin as DNA-gyrase inhibitors: synthesis, antiparasitic evaluation and docking studies

et al. 2011

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“…The apparent absence of gyrases in humans and their presence in Plasmodium falciparum make it an excellent target for a range of antibacterial agents. In fact, various quinolone drugs and their deriv-atives that are very potent against bacteria have also been shown to disrupt P. falciparum parasites (2,3,10,15). However, efforts to use gyrase inhibitors to kill the parasites have been somewhat limited due to the nonavailability of recombinant enzymes from Plasmodium falciparum to study biochemical activity and screen inhibitors.…”

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confidence: 99%

Molecular Cloning of Apicoplast-Targeted Plasmodium falciparum DNA Gyrase Genes: Unique Intrinsic ATPase Activity and ATP-Independent Dimerization of PfGyrB Subunit

Dar¹,

Sharma²,

Mondal

et al. 2007

Eukaryot Cell

119

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DNA gyrase, a typical type II topoisomerase that can introduce negative supercoils in DNA, is essential for replication and transcription in prokaryotes. The apicomplexan parasite Plasmodium falciparum contains the genes for both gyrase A and gyrase B in its genome. Due to the large sizes of both proteins and the unusual codon usage of the highly AT-rich P. falciparum gyrA (PfgyrA) and PfgyrB genes, it has so far been impossible to characterize these proteins, which could be excellent drug targets. Here, we report the cloning, expression, and functional characterization of full-length PfGyrB and functional domains of PfGyrA. Unlike Escherichia coli GyrB, PfGyrB shows strong intrinsic ATPase activity and follows a linear pattern of ATP hydrolysis characteristic of dimer formation in the absence of ATP analogues. These unique features have not been reported for any known gyrase so far. The PfgyrB gene complemented the E. coli gyrase temperature-sensitive strain, and, together with the N-terminal domain of PfGyrA, it showed typical DNA cleavage activity. Furthermore, PfGyrA contains a unique leucine heptad repeat that might be responsible for dimerization. These results confirm the presence of DNA gyrase in eukaryotes and confer great potential for drug development and organelle DNA replication in the deadliest human malarial parasite, P. falciparum.DNA topoisomerases are a special class of enzymes that promote the interconversions of various topological forms of DNA that are generated during DNA replication, transcription, recombination, or related processes (8, 12). These enzymes are grouped mainly into two classes, namely, type I and type II, based on their ability to break one or both strands of DNA. Type II enzymes are further divided into A and B subclasses. The archaeon Sulfolobus shibatae contains structurally distinct type IIB topoisomerases (8). Eukaryotic type IIA topoisomerases form homodimers, whereas bacterial type IIA enzymes form heterotetramers comprised of two subunits of A and B polypeptides each (8).The DNA gyrase falls into the type IIA category, and it is responsible for catalyzing ATP-dependent DNA supercoiling activity in prokaryotes (22, 31). The best-studied gyrase so far is from Escherichia coli, which forms an A 2 B 2 complex. The GyrA N-terminal domain contains the DNA breakage and union domain, while the C-terminal domain shows DNA wrapping activity (41, 42). The GyrB N-terminal domain has an ATPase function, whereas the C-terminal domain binds to DNA and probably interacts with GyrA (6, 9, 21). These enzymes are excellent targets for various antibacterial agents including quinolones and coumarins (1,16,32,33).Although gyrase is commonly found in prokaryotes, there are a few recent reports of the existence of bacterium-type gyrases in plants that might be important for organellar DNA replication and transcription. It has been shown that Arabidopsis thaliana DNA gyrase is targeted to the chloroplast and mitochondria and that both subunits are essential for growth (51).Similar to Arabido...

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Quinolone-Based Drugs Against Toxoplasma gondii and Plasmodium spp

Cited by 21 publications

References 125 publications

Accessible and distinct decoquinate derivatives active against Mycobacterium tuberculosis and apicomplexan parasites

Accessible and distinct decoquinate derivatives active against Mycobacterium tuberculosis and apicomplexan parasites

Esterprodrugs of ciprofloxacin as DNA-gyrase inhibitors: synthesis, antiparasitic evaluation and docking studies

Molecular Cloning of Apicoplast-Targeted Plasmodium falciparum DNA Gyrase Genes: Unique Intrinsic ATPase Activity and ATP-Independent Dimerization of PfGyrB Subunit

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