2004
DOI: 10.1073/pnas.0404037101
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Prodrugs of bisthiazolium salts are orally potent antimalarials

Abstract: We created neutral antimalarial prodrugs that deliver bisthiazolium compounds with antimalarial activity in the nanomolar range. These drugs primarily affect early intraerythrocytic stages through rapid, nonreversible cytotoxicity. The compounds are suitable for both parenteral and oral use and plasma promotes rapid conversion of the prodrug into the drug. We demonstrate that very low doses offer protection in a murine model of malaria. The drugs show great potential for curing high parasitemia with short-cour… Show more

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Cited by 105 publications
(158 citation statements)
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“…Lysobisphosphatidic acid and phosphoinositides regulate release of VSV nucleocapsid into cytoplasm [13] SigD/SopB is a type III bacterial derived phosphoinositide phosphatase [29,112] Molecular species of phosphatidylcholine and phosphatidylethanolamine are altered in host plasmamembrane after Plasmodium infection [116] GP Ethanolamine phospholipids required for Sindbis virus production [111] Intracellular mycobacteria release a heterogeneous mixture of lipids [27,113] Growth arrest of Plasmodium [117] and Toxoplasma [85] by disruption of phosphatidylcholine synthesis Semliki Forest virus mRNA capping enzyme requires association with anionic membrane phospholipids for activity [14] Phosphatidylinositol mannosides stimulate fusion of early endosomes with mycobacterial phagosomes [30] Glycosylated phosphatidylinositol causes phagosome maturation arrest [114] SapM, a mycobacterial derived phosphatase hydrolyses PI3P contributing to inhibition of phagolysosome maturation [115] Sphingosine 1-kinase is recruited to nascent phagosomes [118] Inhibition of sphingolipid biosynthesis in T. gondii blocks replication [119] SP Sphingomyelin metabolism important for P. falciparum development [120] Inhibition of cholesterol biosynthesis inhibits Hepatitis C virus RNA replication [15] Inhibition of cholesterol acquisition by the host lowers T. gondii replication [40] ST Cholesterol esterification essential for optimal T. gondii proliferation [121,122] Isopreonoid synthesis inhibitors with anti-malarial [123] and anti-T. gondii activity [124] PR Block of protein farnesylation as antiapicomplexan therapies [125] 5…”
Section: Glmentioning
confidence: 99%
“…Lysobisphosphatidic acid and phosphoinositides regulate release of VSV nucleocapsid into cytoplasm [13] SigD/SopB is a type III bacterial derived phosphoinositide phosphatase [29,112] Molecular species of phosphatidylcholine and phosphatidylethanolamine are altered in host plasmamembrane after Plasmodium infection [116] GP Ethanolamine phospholipids required for Sindbis virus production [111] Intracellular mycobacteria release a heterogeneous mixture of lipids [27,113] Growth arrest of Plasmodium [117] and Toxoplasma [85] by disruption of phosphatidylcholine synthesis Semliki Forest virus mRNA capping enzyme requires association with anionic membrane phospholipids for activity [14] Phosphatidylinositol mannosides stimulate fusion of early endosomes with mycobacterial phagosomes [30] Glycosylated phosphatidylinositol causes phagosome maturation arrest [114] SapM, a mycobacterial derived phosphatase hydrolyses PI3P contributing to inhibition of phagolysosome maturation [115] Sphingosine 1-kinase is recruited to nascent phagosomes [118] Inhibition of sphingolipid biosynthesis in T. gondii blocks replication [119] SP Sphingomyelin metabolism important for P. falciparum development [120] Inhibition of cholesterol biosynthesis inhibits Hepatitis C virus RNA replication [15] Inhibition of cholesterol acquisition by the host lowers T. gondii replication [40] ST Cholesterol esterification essential for optimal T. gondii proliferation [121,122] Isopreonoid synthesis inhibitors with anti-malarial [123] and anti-T. gondii activity [124] PR Block of protein farnesylation as antiapicomplexan therapies [125] 5…”
Section: Glmentioning
confidence: 99%
“…The biosynthesis of phosphatidylcholine (PC), the most abundant membrane phospholipid (PL) in P. falciparum , is a remarkable example of the level of parasitic adaptation and dependence toward its host and represents a promising target for novel chemotherapies ( 8,9 ).…”
Section: (Pathway Iii)mentioning
confidence: 99%
“…The lower limit of quantification (LLOQ) was defined as the lowest concentration that could be determined with an accuracy within 80 -120% and an imprecision Յ20% on a day-to-day basis (11)(12)(13)(14). To determine the analytical error in the LLOQ, we used QC samples containing the compounds of interest.…”
Section: Determination Of the Lower Limit Of Quantificationmentioning
confidence: 99%
“…The bisquaternary ammonium salts showed the highest activities. The third generation consists of neutral prodrugs that deliver bisthiazolium salts with antimalarial activity when present in nanomolar concentrations (11 ). In plasma, the prodrug is rapidly converted into the active drug, and the prodrugs have also been found to offer protection in a murine model of malaria as well as in P. cynomolgi-infected Rhesus monkeys (11 ).…”
mentioning
confidence: 99%
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