Lead optimization of antimalarial propafenone analogues.
Previously reported studies identified analogues of propafenone that had potent antimalarial activity, reduced cardiac ion channel activity, and properties that suggested the potential for clinical development for malaria. Careful examination of the bioavailability, pharmacokinetics, toxicology, and efficacy of this series of compounds using rodent models revealed orally bioavailable compounds that are nontoxic and suppress parasitemia in vivo. Although these compounds possess potential for further preclinical development, they also carry some significant challenges.
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
David
D
Lowes
Anupam
A
Pradhan
Lalitha V
LV
Iyer
Toufan
T
Parman
Jason
J
Gow
Fangyi
F
Zhu
Anna
A
Furimsky
Andrew
A
Lemoff
W Armand
WA
Guiguemde
Martina
M
Sigal
Julie A
JA
Clark
Emily
E
Wilson
Liang
L
Tang
Michele C
MC
Connelly
Joseph L
JL
Derisi
Dennis E
DE
Kyle
Jon
J
Mirsalis
R Kiplin
RK
Guy
D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D002738:Chloroquine / Q000494:pharmacology; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D005260:Female; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000378:metabolism; D018512:Parasitemia / Q000188:drug therapy; D010962:Plasmodium berghei / Q000187:drug effects*; D011405:Propafenone / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D011405:Propafenone; D002738:Chloroquine; D019389:Cytochrome P-450 CYP2D6