title: Structurally simple, potent, Plasmodium selective farnesyltransferase inhibitors that arrest the growth of malaria parasites.
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.
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Glenn
authors.forename: Sung-Youn
authors.initials: SY
authors.lastname: Chang
authors.forename: Carrie
authors.initials: C
authors.lastname: Hornéy
authors.forename: Kasey
authors.initials: K
authors.lastname: Rivas
authors.forename: Kohei
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Erin E
authors.initials: EE
authors.lastname: Pusateri
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Cummings
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.forename: Prakash R
authors.initials: PR
authors.lastname: Pendyala
authors.forename: Debopam
authors.initials: D
authors.lastname: Chakrabarti
authors.forename: Saïd M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Michael
authors.initials: M
authors.lastname: Gelb
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D000962:Antimalarials; D007093:Imidazoles; D009570:Nitriles; D013449:Sulfonamides; D051231:Farnesyltranstransferase