In the present article we examine the antiplasmodial activities of novel
quinolone derivatives bearing extended alkyl or
alkoxy side chains terminated by a trifluoromethyl group. In the series under investigation, the IC50 values ranged from 1.2 to approximately 30 nM against
chloroquine-sensitive and multidrug-resistant Plasmodium falciparum strains. Modest to significant cross-resistance was noted in evaluation of these haloalkyl- and haloalkoxyquinolones for activity against the
atovaquone-resistant clinical isolate Tm90-C2B, indicating that a primary target for some of these compounds is the parasite
cytochrome bc1 complex. Additional evidence to support this biochemical mechanism includes the use of
oxygen biosensor plate technology to show that the
quinolone derivatives block oxygen consumption by parasitized red blood cells in a fashion similar to
atovaquone in side-by-side experiments.
Atovaquone is extremely potent and is the only
drug in clinical use that targets the Plasmodium bc1 complex, but rapid emergence of resistance to it in both mono- and combination
therapy is evident and therefore additional drugs are needed to target the
cytochrome bc1 complex which are active against
atovaquone-resistant parasites. Our study of a number of halogenated alkyl and
alkoxy 4(1H)-quinolones highlights the potential for development of "endochin-like
quinolones" (ELQ), bearing an extended trifluoroalkyl moiety at the 3-position, that exhibit selective antiplasmodial effects in the low nanomolar range and inhibitory activity against
chloroquine and
atovaquone-resistant parasites. Further studies of halogenated alkyl- and
alkoxy-
quinolones may lead to the development of safe and effective
therapeutics for use in treatment or prevention of
malaria and other
parasitic diseases.