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Orally bioavailable 6-chloro-7-methoxy-4(1H)-quinolones efficacious against multiple stages of Plasmodium.

Cross RM, Flanigan DL, Monastyrskyi A, LaCrue AN, Sáenz FE, Maignan JR, Mutka TS, White KL, Shackleford DM, Bathurst I, Fronczek FR, Wojtas L, Guida WC, Charman SA, Burrows JN, Kyle DE, Manetsch R - J. Med. Chem. (2014)

Bottom Line: Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology.Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability.Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99% after 6 days.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of South Florida , CHE 205, 4202 East Fowler Avenue, Tampa, Florida 33620, United States.

ABSTRACT
The continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. Unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology. Structure-activity and structure-property relationship studies were conducted to generate a set of compounds with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with a variety of phenyl moieties possessing various properties. Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability. Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99% after 6 days.

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Plasma concentration versus time profiles for compound 7 in Sprague–Dawley rats (average of n = 2):(●) concentrations following IV administration at 0.15 mg/kgand (○) concentrations following oral administration of a PEG400suspension at 10 mg/kg.
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fig6: Plasma concentration versus time profiles for compound 7 in Sprague–Dawley rats (average of n = 2):(●) concentrations following IV administration at 0.15 mg/kgand (○) concentrations following oral administration of a PEG400suspension at 10 mg/kg.

Mentions: Compound 7 was furtherexamined for its pharmacokineticproperties in rats (Figure 6). Compound 7 exhibited a long in vivo half-life (32–42 h), lowplasma clearance (0.3 mL/(min·kg)), and low volume of distribution(0.7 L/kg) following intravenous administration. These propertiesare likely to be influenced by the extensive binding to plasma proteins(>99%). The apparent oral bioavailability of 7 afterdosing in PEG400 was approximately 14%. It is unlikely that bioavailabilitywas limited by extensive first-pass metabolism or poor intestinalpermeability, given that in vitro studies indicated that both of thesewere within acceptable ranges. Rather, the low aqueous solubilityof 7, as described above, would suggest that absorptionis likely to be limited by a combination of precipitation from theco-solvent vehicle and incomplete dissolution within the gastrointestinaltract.


Orally bioavailable 6-chloro-7-methoxy-4(1H)-quinolones efficacious against multiple stages of Plasmodium.

Cross RM, Flanigan DL, Monastyrskyi A, LaCrue AN, Sáenz FE, Maignan JR, Mutka TS, White KL, Shackleford DM, Bathurst I, Fronczek FR, Wojtas L, Guida WC, Charman SA, Burrows JN, Kyle DE, Manetsch R - J. Med. Chem. (2014)

Plasma concentration versus time profiles for compound 7 in Sprague–Dawley rats (average of n = 2):(●) concentrations following IV administration at 0.15 mg/kgand (○) concentrations following oral administration of a PEG400suspension at 10 mg/kg.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4234439&req=5

fig6: Plasma concentration versus time profiles for compound 7 in Sprague–Dawley rats (average of n = 2):(●) concentrations following IV administration at 0.15 mg/kgand (○) concentrations following oral administration of a PEG400suspension at 10 mg/kg.
Mentions: Compound 7 was furtherexamined for its pharmacokineticproperties in rats (Figure 6). Compound 7 exhibited a long in vivo half-life (32–42 h), lowplasma clearance (0.3 mL/(min·kg)), and low volume of distribution(0.7 L/kg) following intravenous administration. These propertiesare likely to be influenced by the extensive binding to plasma proteins(>99%). The apparent oral bioavailability of 7 afterdosing in PEG400 was approximately 14%. It is unlikely that bioavailabilitywas limited by extensive first-pass metabolism or poor intestinalpermeability, given that in vitro studies indicated that both of thesewere within acceptable ranges. Rather, the low aqueous solubilityof 7, as described above, would suggest that absorptionis likely to be limited by a combination of precipitation from theco-solvent vehicle and incomplete dissolution within the gastrointestinaltract.

Bottom Line: Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology.Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability.Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99% after 6 days.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of South Florida , CHE 205, 4202 East Fowler Avenue, Tampa, Florida 33620, United States.

ABSTRACT
The continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. Unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology. Structure-activity and structure-property relationship studies were conducted to generate a set of compounds with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with a variety of phenyl moieties possessing various properties. Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability. Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99% after 6 days.

Show MeSH
Related in: MedlinePlus