Synthesis and Structure-Activity Relationships of 4-Pyridones as Potential Antimalarials.
作者
Yeates, Clive L.;Batchelor, John F.;Capon, Edward C.;Cheesman, Neil J.;Fry, Mitch;Hudson, Alan T.;Pudney, Mary;Trimming, Helen;Woolven, James;Bueno, Jose M.;Chicharro, Jesus;Fernandez, Esther;Fiandor, Jose M.;Gargallo-Viola, Domingo;Gomez de las Heras, Fe
[摘要]：A series of diaryl ether substituted 4-pyridones, e.g. I (R1 = H, Br, Cl, OMe, NO2, etc.; R2 = Ph, 4-FC6H4, 3-F3CC6H4, 4-F3COC6H4, etc.), 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 compds. 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 compds. have been shown elsewhere to act selectively by inhibition of mitochondrial electron transport at the cytochrome bc1 complex.
