title: In vitro and in vivo antimalarial activity of peptidomimetic protein farnesyltransferase inhibitors with improved membrane permeability.
abstract: A series of protein farnesyltransferase inhibitor ester prodrugs of FTI-2148 (17) were synthesized in order to evaluate the effects of ester structure modification on antimalarial activity and for further development of a farnesyltransferase inhibitor with in vivo activity. Evaluation against P. falciparum in red blood cells showed that all the investigated esters exhibited significant antimalarial activity, with the benzyl ester 16 showing the best inhibition (ED50=150 nM). Additionally, compound 16 displayed in vivo activity and was found to suppress parasitemia by 46.1% at a dose of 50 mg kg(-1) day(-1) against Plasmodium berghei in mice. The enhanced inhibition potency of the esters is consistent with improved cell membrane permeability compared to that of the free acid. The results of this study suggest that protein farnesyltransferase is a valid antimalarial drug target and that the antimalarial activity of these compounds derives from a balance between the hydrophobic character and the size and conformation of the ester moiety.
authors.affiliation: Department of Chemistry, Yale University, PO Box 208107, New Haven, CT 06520, USA.
authors.forename: Dora
authors.initials: D
authors.lastname: Carrico
authors.forename: Junko
authors.initials: J
authors.lastname: Ohkanda
authors.forename: Howard
authors.initials: H
authors.lastname: Kendrick
authors.forename: Kohei
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Blaskovich
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Bucher
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.forename: Debopam
authors.initials: D
authors.lastname: Chakrabarti
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.forename: Saïd M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D002463:Cell Membrane Permeability; D004912:Erythrocytes / Q000469:parasitology; D004952:Esters / Q000737:chemistry; D051231:Farnesyltranstransferase; D057927:Hydrophobic and Hydrophilic Interactions; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D018716:Molecular Mimicry; D041681:NIH 3T3 Cells; D010455:Peptides / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004952:Esters; D010455:Peptides; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase