title: Second generation tetrahydroquinoline-based protein farnesyltransferase inhibitors as antimalarials.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Pravin
authors.initials: P
authors.lastname: Bendale
authors.forename: Srinivas
authors.initials: S
authors.lastname: Olepu
authors.forename: Praveen Kumar
authors.initials: PK
authors.lastname: Suryadevara
authors.forename: Vivek
authors.initials: V
authors.lastname: Bulbule
authors.forename: Kasey
authors.initials: K
authors.lastname: Rivas
authors.forename: Laxman
authors.initials: L
authors.lastname: Nallan
authors.forename: Brian
authors.initials: B
authors.lastname: Smart
authors.forename: Kohei
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Sudha
authors.initials: S
authors.lastname: Ankala
authors.forename: Prakash Rao
authors.initials: PR
authors.lastname: Pendyala
authors.forename: David
authors.initials: D
authors.lastname: Floyd
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: David K
authors.initials: DK
authors.lastname: Williams
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.forename: Debopam
authors.initials: D
authors.lastname: Chakrabarti
authors.forename: Christophe L M J
authors.initials: CL
authors.lastname: Verlinde
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
mesh_terms: 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
chemical_list: D000962:Antimalarials; D011804:Quinolines; D051231:Farnesyltranstransferase