Second generation tetrahydroquinoline-based protein farnesyltransferase inhibitors as antimalarials.
Substituted tetrahydroquinolines (THQs) have been previously identified as inhibitors of mammalian protein farnesyltransferase (PFT). Previously we showed that blocking PFT in the malaria parasite led to cell death and that THQ-based inhibitors are the most potent among several structural classes of PFT inhibitors (PFTIs). We have prepared 266 THQ-based PFTIs and discovered several compounds that inhibit the malarial enzyme in the sub- to low-nanomolar range and that block the growth of the parasite (P. falciparum) in the low-nanomolar range. This body of structure-activity data can be rationalized in most cases by consideration of the X-ray structure of one of the THQs bound to mammalian PFT together with a homology structural model of the malarial enzyme. The results of this study provide the basis for selection of antimalarial PFTIs for further evaluation in preclinical drug discovery assays.
Bendale
Pravin
P
Department of Chemistry, University of Washington, Seattle, Washington 98195, USA.
Olepu
Srinivas
S
Suryadevara
Praveen Kumar
PK
Bulbule
Vivek
V
Rivas
Kasey
K
Nallan
Laxman
L
Smart
Brian
B
Yokoyama
Kohei
K
Ankala
Sudha
S
Pendyala
Prakash Rao
PR
Floyd
David
D
Lombardo
Louis J
LJ
Williams
David K
DK
Buckner
Frederick S
FS
Chakrabarti
Debopam
D
Verlinde
Christophe L M J
CL
Van Voorhis
Wesley C
WC
Gelb
Michael H
MH
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000962:Antimalarials; D011804:Quinolines; D051231:Farnesyltranstransferase