Structurally Simple, Potent, Plasmodium Selective Farnesyltransferase Inhibitors That Arrest the Growth of Malaria Parasites
| Autor: | Matthew P. Glenn, Carrie Hornéy, Erin E. Pusateri, Andrew D. Hamilton, Frederick S. Buckner, Christopher G. Cummings, Sung Youn Chang, Prakash Rao Pendyala, Saïd M. Sebti, Michael H. Gelb, Wesley C. Van Voorhis, Kohei Yokoyama, Steven Fletcher, Kasey Rivas, Debopam Chakrabarti |
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| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Male
Models Molecular Cell Membrane Permeability Farnesyltransferase Plasmodium falciparum Administration Oral Biological Availability Pharmacology In Vitro Techniques Article Antimalarials Mice Structure-Activity Relationship Drug Discovery Nitriles medicine Structure–activity relationship Animals Farnesyltranstransferase Humans IC50 Farnesyl-diphosphate farnesyltransferase Sulfonamides Aniline Compounds Binding Sites biology Chemistry Imidazoles medicine.disease biology.organism_classification In vitro Rats biology.protein Microsomes Liver Molecular Medicine Caco-2 Cells Malaria |
| Popis: | 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 (IC50 < 1 nM) and toxicity to cultured parasites at low concentrations (ED50 < 100 nM). Initial studies of absorption, metabolism, and oral bioavailability are reported. |
| Databáze: | OpenAIRE |
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