Synthesis and structure-activity relationships of 4-pyridones as potential antimalarials.
A series of diaryl ether substituted 4-pyridones have been identified as having potent antimalarial activity superior to that of chloroquine against Plasmodium falciparum in vitro and murine Plasmodium yoelii in vivo. These were derived from the anticoccidial drug clopidol through a systematic study of the effects of varying the side chain on activity. Relative to clopidol the most active compounds show >500-fold improvement in IC50 for inhibition of P. falciparum in vitro and about 100-fold improvement with respect to ED50 against P. yoelii in mice. These compounds have been shown elsewhere to act selectively by inhibition of mitochondrial electron transport at the cytochrome bc1 complex.
Yeates
Clive L
CL
Wellcome Research Laboratories, Langley Court, Beckenham, Kent, U.K.
Batchelor
John F
JF
Capon
Edward C
EC
Cheesman
Neil J
NJ
Fry
Mitch
M
Hudson
Alan T
AT
Pudney
Mary
M
Trimming
Helen
H
Woolven
James
J
Bueno
José M
JM
Chicharro
Jesús
J
Fernández
Esther
E
Fiandor
José M
JM
Gargallo-Viola
Domingo
D
Gómez de las Heras
Federico
F
Herreros
Esperanza
E
León
María L
ML
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D010967:Plasmodium yoelii; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000962:Antimalarials; D011728:Pyridones