Potent, Plasmodium-selective farnesyltransferase inhibitors that arrest the growth of malaria parasites: structure-activity relationships of ethylenediamine-analogue scaffolds and homology model validation.
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.
Fletcher
Steven
S
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06511, USA.
Cummings
Christopher G
CG
Rivas
Kasey
K
Katt
William P
WP
Hornéy
Carrie
C
Buckner
Frederick S
FS
Chakrabarti
Debopam
D
Sebti
Saïd M
SM
Gelb
Michael H
MH
Van Voorhis
Wesley C
WC
Hamilton
Andrew D
AD
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
D000962:Antimalarials; D004791:Enzyme Inhibitors; D005029:Ethylenediamines; D051231:Farnesyltranstransferase