Antimalarial quinolones: synthesis, potency, and mechanistic studies

Abstract

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.

Figure 1

Chemical structures of quinolones and acridones employed in this study.

Figure 2

Isobolar analysis of the antiplasmodial activity of 7-methoxy-2-methyl-3-(6,6,6-trifluorohexyl)-4(1H)-quinolone (7) and clopidol. Shown are the results from a single representative experiment which did not differ significantly from two other identical experiments conducted independently.

Figure 3

Comparison of the inhibitory of effect of atovaquone and chloroquine on oxygen consumption by P. yoelii infected erythrocytes. Note that the y-axis reflects relative fluorescence units and oxygen consumption is reported as an increase in fluorescence from the oxygen sensitive dye embedded in the matrix.

Figure 4

Comparison of the inhibitory effect of 7-methoxy-2-methyl-3-(6,6,6-trifluorohexyl)-4(1H)-quinolone (7) and atovaquone on oxygen consumption by P. yoelii infected erythrocytes. Note that the y-axis reflects relative fluorescence units and oxygen consumption is reported as an increase in fluorescence from the oxygen sensitive dye embedded in the matrix.

Figure 5

Chemical structures of selected alkyl- and alkoxy-quinolones and pyridones that have been evaluated as antimalarials in the past.