Recent advances in antimalarial drug development.
ABSTRACT Malaria caused by protozoa of the genus Plasmodium, because of its prevalence, virulence, and drug resistance, is the most serious and widespread parasitic disease encountered by mankind. The inadequate armory of drugs in widespread use for the treatment of malaria, development of strains resistant to commonly used drugs such as chloroquine, and the lack of affordable new drugs are the limiting factors in the fight against malaria. These factors underscore the continuing need of research for new classes of antimalarial agents, and a re-examination of the existing antimalarial drugs that may be effective against resistant strains. This review provides an in-depth look at the most significant progress made during the past 10 years in antimalarial drug development.
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ABSTRACT: A series of protein farnesyltransferase inhibitor ester prodrugs of FTI-2148 (17) were synthesized in order to evaluate the effects of ester structure modification on antimalarial activity and for further development of a farnesyltransferase inhibitor with in vivo activity. Evaluation against P. falciparum in red blood cells showed that all the investigated esters exhibited significant antimalarial activity, with the benzyl ester 16 showing the best inhibition (ED50=150 nM). Additionally, compound 16 displayed in vivo activity and was found to suppress parasitemia by 46.1% at a dose of 50 mg kg(-1) day(-1) against Plasmodium berghei in mice. The enhanced inhibition potency of the esters is consistent with improved cell membrane permeability compared to that of the free acid. The results of this study suggest that protein farnesyltransferase is a valid antimalarial drug target and that the antimalarial activity of these compounds derives from a balance between the hydrophobic character and the size and conformation of the ester moiety.Bioorganic & Medicinal Chemistry 01/2005; 12(24):6517-26. · 2.90 Impact Factor
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ABSTRACT: Thymidylate synthetase and dihydrofolate reductase exist as a bifunctional protein in a number of species of protozoa which span diverse groups of the subkingdom. The enzymes copurify upon gel filtration and on affinity chromatography columns specific for dihydrofolate reductase. The bifunctional protein has been found in species of Crithidia, Leishmania, Trypanosoma, Plasmodium, Eimeria, Tetrahymena and Euglena. For reasons unknown, neither enzyme could be detected in Entamoeba histolytica or E. invadens. Since neither enzyme has yet been found as a separate protein in protozoa, it is likely that the bifunctional protein is widespread among these primitive eukaryotes. In most cases, the apparent size of the native protein is approximately twice that of the subunit possessing thymidylate synthetase. Further, with one exception, the subunit sizes are close to the sum of the subunit sizes of the separate enzymes found in other sources.Molecular and Biochemical Parasitology 05/1984; 11:257-65. · 2.73 Impact Factor
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ABSTRACT: The in vitro antiplasmodial activity of some dihydrostilbenamides, phtalazinones, imidazo[2,1-a]isoindole and pyrimido[2,1-a]isoindole derivatives related to the natural dihydrostilbenoid isonotholaenic acid is reported. The evaluation was performed on cultures of F32 strain of Plasmodium falciparum and potent representative compounds were also evaluated in the ferriprotoporphyrin IX biomineralization inhibition test (FBIT). Compounds having the imidazo[2,1-a]isoindole skeleton were the most active and one compound of this group resulted to be as potent as chloroquine, but acting through a mechanism different that of the inhibition of heme biomineralization.Bioorganic & Medicinal Chemistry Letters 09/2003; 13(16):2769-72. · 2.34 Impact Factor