Structurally simple, potent, Plasmodium selective farnesyltransferase inhibitors that arrest the growth of malaria parasites.
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.
Glenn
Matthew P
MP
Department of Chemistry, Yale University, New Haven, Connecticut 06511, USA.
Chang
Sung-Youn
SY
Hornéy
Carrie
C
Rivas
Kasey
K
Yokoyama
Kohei
K
Pusateri
Erin E
EE
Fletcher
Steven
S
Cummings
Christopher G
CG
Buckner
Frederick S
FS
Pendyala
Prakash R
PR
Chakrabarti
Debopam
D
Sebti
Saïd M
SM
Gelb
Michael
M
Van Voorhis
Wesley C
WC
Hamilton
Andrew D
AD
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
D000814:Aniline Compounds; D000962:Antimalarials; D007093:Imidazoles; D009570:Nitriles; D013449:Sulfonamides; D051231:Farnesyltranstransferase