title: Potent, Plasmodium-selective farnesyltransferase inhibitors that arrest the growth of malaria parasites: structure-activity relationships of ethylenediamine-analogue scaffolds and homology model validation.
abstract: New chemotherapeutics are urgently needed to combat malaria. We previously reported on a novel series of antimalarial, ethylenediamine-based inhibitors of protein farnesyltransferase (PFT). In the current study, we designed and synthesized a series of second generation inhibitors, wherein the core ethylenediamine scaffold was varied in order to examine both the homology model of Plasmodium falciparum PFT (PfPFT) and our predicted inhibitor binding mode. We identified several PfPFT inhibitors (PfPFTIs) that are selective for PfPFT versus the mammalian isoform of the enzyme (up to 136-fold selectivity), that inhibit the malarial enzyme with IC50 values down to 1 nM, and that block the growth of P. falciparum in infected whole cells (erythrocytes) with ED50 values down to 55 nM. The structure-activity data for these second generation, ethylenediamine-inspired PFT inhibitors were rationalized by consideration of the X-ray crystal structure of mammalian PFT and the homology model of the malarial enzyme.
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06511, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Cummings
authors.forename: Kasey
authors.initials: K
authors.lastname: Rivas
authors.forename: William P
authors.initials: WP
authors.lastname: Katt
authors.forename: Carrie
authors.initials: C
authors.lastname: Hornéy
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.forename: Debopam
authors.initials: D
authors.lastname: Chakrabarti
authors.forename: Saïd M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Michael H
authors.initials: MH
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: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005029:Ethylenediamines / Q000737:chemistry* / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D010961:Plasmodium / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D005029:Ethylenediamines; D051231:Farnesyltranstransferase