2-Oxo-tetrahydro-1,8-naphthyridines as selective inhibitors of malarial protein farnesyltransferase and as anti-malarials.
A new class of 2-oxo-tetrahydro-1,8-naphthyridine-based protein farnesyltransferase inhibitors were synthesized and found to inhibit protein farnesyltransferase from the malaria parasite with potencies in the low nanomolar range. The compounds were much less potent on mammalian protein prenyltransferases. Two of the compounds block the growth of malaria in culture with potencies in the sub-micromolar range. Some of the compounds were found to be much more metabolically stable than previously described tetrahydroquinoline-based protein farnesyltransferase inhibitors.
Olepu
Srinivas
S
Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
Suryadevara
Praveen Kumar
PK
Rivas
Kasey
K
Yokoyama
Kohei
K
Verlinde
Christophe L M J
CL
Chakrabarti
Debopam
D
Van Voorhis
Wesley C
WC
Gelb
Michael H
MH
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D009287:Naphthyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects; D051381:Rats
D000962:Antimalarials; D004791:Enzyme Inhibitors; D009287:Naphthyridines; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase