ABSTRACT
4'-n-Butoxy-2,4-dimethoxy-chalcone (MBC) has been described as protecting mice from an otherwise lethal infection with Plasmodium yoelii when dosed orally at 50 mg/kg/dose, daily for 5 days. In contrast, we found that oral dosing of MBC at 640 mg/kg/dose, daily for 5 days, failed to extend the survivability of P. berghei-infected mice. The timing of compound administration and metabolic activation likely contribute to the outcome of efficacy testing in vivo. Microsomal digest of MBC yielded 4'-n-butoxy-4-hydroxy-2-methoxy-chalcone and 4'-(1-hydroxy-n-butoxy)-2,4-dimethoxy-chalcone. We propose that the latter will hydrolyze in vivo to 4'-hydroxy-2,4-dimethoxy-chalcone, which has greater efficacy than MBC in our P. berghei-infected mouse model and was detected in plasma following oral dosing of mice with MBC. Pharmacokinetic parameters suggest that poor absorption, distribution, metabolism and excretion properties contribute to the limited in vivo efficacy observed for MBC and its analogs.
Subject(s)
Antimalarials/pharmacokinetics , Chalcones/pharmacokinetics , Malaria/drug therapy , Microsomes, Liver/metabolism , Plasmodium berghei/drug effects , Animals , Antimalarials/blood , Antimalarials/pharmacology , Antimalarials/therapeutic use , Biotransformation , Chalcones/blood , Chalcones/pharmacology , Chalcones/therapeutic use , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Drug Resistance , Half-Life , Humans , Inhibitory Concentration 50 , Malaria/blood , Malaria/metabolism , Male , Mice , Mice, Inbred ICR , Molecular Structure , Spectrometry, Mass, Electrospray Ionization , Survival Analysis , Tandem Mass SpectrometryABSTRACT
Investigation of a series of 1-phenyl-3-aryl-2-propen-1-ones resulted in the identification of nine inhibitors with submicromolar efficacy against at least one Plasmodium falciparum strain in vitro. These inhibitors were inactive when given orally in a Plasmodium berghei infected mouse model. Significant compound degradation occurred upon their exposure to a liver microsome preparation, suggesting metabolic instability may be responsible for the lack of activity in vivo.
Subject(s)
Antimalarials/pharmacology , Antimalarials/pharmacokinetics , Ketones/pharmacology , Ketones/pharmacokinetics , Plasmodium falciparum/drug effects , Animals , Malaria, Falciparum/drug therapy , Mice , Microsomes, Liver/physiologyABSTRACT
The reported synthetic procedure of WR182393, a 2-guanidinoimidazolidinedione derivative with high prophylactic antimalarial activity, was found to be a mixture of three closely related products. Poor solubility of WR182393 in both water and organic solvents and its impractical synthetic method have made the purification and structure identification of the reaction mixture a highly challenging task. The problems were circumvented by prodrug approach involving carbamate formation of the mixture, which enhances the solubility of the mixture in common organic solvents and facilitates the separation and structure determination of the two products. The structures of the two components were determined by X-ray crystallography and NMR of their corresponding carbamates 3a and 4a. Additional alkyl carbamates were prepared according to the same approach and two new carbamates 3b and 4d were found to possess higher intramuscular (im) efficacy than the parent compound WR182393 against Plasmodium cynomolgi in Rhesus monkey.
