Potent 4-aminopiperidine based antimalarial agents.
A series of compounds with potent activity against a multi-drug-resistant strain of Plasmodium falciparum, the causative agent of the deadliest strain of malaria, is described. These compounds were also tested for cytotoxicity in human foreskin fibroblast assays, evaluated to determine their logD, and assayed for metabolism by human and murine hepatocytes. This work resulted in the development of compounds 9e and 10d, which showed good potency (IC(50)=75 nM and <60 nM, respectively, against Dd2), acceptable logD values, and reasonable metabolic stability.
Brinner
Kristin M
KM
Center for New Directions in Organic Synthesis, Chemistry Department, University of California, Berkeley, CA 94720, USA.
Powles
Mary Ann
MA
Schmatz
Dennis M
DM
Ellman
Jonathan A
JA
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001681:Biological Assay; D005347:Fibroblasts / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
C481395:4-aminopiperidine; D000962:Antimalarials; D010880:Piperidines