Abstract
Third world nations require immediate access to inexpensive therapeutics to counter the high mortality inflicted by malaria. Here, we report a new class of antimalarial protein farnesyltransferase (PFT) inhibitors, designed with specific emphasis on simple molecular architecture, to facilitate easy access to therapies based on this recently validated antimalarial target. This novel series of compounds represents the first Plasmodium falciparum selective PFT inhibitors reported (up to 145-fold selectivity), with lead inhibitors displaying excellent in vitro activity (IC(50) < 1 nM) and toxicity to cultured parasites at low concentrations (ED(50) < 100 nM). Initial studies of absorption, metabolism, and oral bioavailability are reported.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Administration, Oral
-
Aniline Compounds / chemical synthesis*
-
Aniline Compounds / chemistry
-
Aniline Compounds / pharmacology
-
Animals
-
Antimalarials / chemical synthesis*
-
Antimalarials / chemistry
-
Antimalarials / pharmacology
-
Binding Sites
-
Biological Availability
-
Caco-2 Cells
-
Cell Membrane Permeability
-
Farnesyltranstransferase / antagonists & inhibitors*
-
Humans
-
Imidazoles / chemical synthesis*
-
Imidazoles / chemistry
-
Imidazoles / pharmacology
-
In Vitro Techniques
-
Male
-
Mice
-
Microsomes, Liver / metabolism
-
Models, Molecular
-
Nitriles / chemical synthesis
-
Nitriles / chemistry
-
Nitriles / pharmacology
-
Plasmodium falciparum / drug effects*
-
Plasmodium falciparum / enzymology*
-
Rats
-
Structure-Activity Relationship
-
Sulfonamides / chemical synthesis
-
Sulfonamides / chemistry
-
Sulfonamides / pharmacology
Substances
-
Aniline Compounds
-
Antimalarials
-
Imidazoles
-
Nitriles
-
Sulfonamides
-
Farnesyltranstransferase