ABSTRACT
Investigation of a series of 2,N-bisarylated 2-ethoxyacetamides resulted in the identification of four inhibitors 5, 20, 24, 29 with single-digit micromolar in vitro efficacy against two drug-resistant Plasmodium falciparum strains. These compounds are analogs of structurally-related 1,3-bisaryl-2-propen-1-ones (chalcones), the latter showing efficacy in vitro but not in a malaria-infected mouse. The 2,N-bisarylated 2-ethoxyacetamides (e.g., 2, 5, 20) were shown to possess significantly greater stability in the presence of metabolizing enzymes than the corresponding 1,3-bisaryl-2-propen-1-ones (e.g., 1, 3, 18).
Subject(s)
Acetamides/chemistry , Antimalarials/chemistry , Acetamides/metabolism , Acetamides/pharmacology , Animals , Antimalarials/metabolism , Antimalarials/pharmacology , Chalcone/chemistry , Chloroquine/pharmacology , Drug Resistance/drug effects , Half-Life , Mice , Microsomes, Liver/metabolism , Plasmodium falciparum/drug effects , Structure-Activity RelationshipABSTRACT
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
Diiodobutadiyne (1) and diiodohexatriyne (2) form cocrystals with bispyridyl oxalamides and ureas, based on the halogen bond between the alkynyl iodine and pyridine nitrogen. In each cocrystal, the oxalamide or urea host forms one-dimensional hydrogen-bonded networks, aligning the diiodopolyyne for potential topochemical polymerization with a repeat distance matching the host repeat.
