Peptidomimetic inhibitors of protein farnesyltransferase show potent antimalarial activity.
Malaria continues to represent a very serious health problem in the tropics. The current methods of clinical treatment are showing deficiencies due to the increased incidence of resistance in the parasite. In the present paper we report the design, synthesis, and evaluation of potential antimalarial agents against a novel target, protein farnesyltransferase. We show that the most potent compounds are active against Plasmodium falciparum in vitro at submicromolar concentrations.
Department of Chemistry, Yale University, New Haven, CT 06520, USA.
J
J
Ohkanda
J W
JW
Lockman
K
K
Yokoyama
M H
MH
Gelb
S L
SL
Croft
H
H
Kendrick
M I
MI
Harrell
J E
JE
Feagin
M A
MA
Blaskovich
S M
SM
Sebti
A D
AD
Hamilton
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D004791:Enzyme Inhibitors; C429403:FTI-2277; D007093:Imidazoles; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase