Abstract:
As part of a programme aimed at identifying rational new triple drug combinations for treatment of
malaria, tuberculosis and toxoplasmosis, we have selected quinolones as one component, given that
selected examples exhibit exceptionally good activities against the causative pathogens of the foregoing
diseases. The quinolone decoquinate (DQ), an old and inexpensive coccidiostat, displays anti-malarial
activity in vitro against Plasmodium falciparum (Pf). However, because of its exceedingly poor solubility
in water or organic solvents, development of DQ as a drug is problematical. We have therefore converted
DQ in straightforward fashion into tractable new derivatives that display good activities in vitro against
chloroquine-sensitive NF54 and multidrug-resistant K1 and W2 Pf, and relatively low toxicities against
human fibroblast cells. The most active compound, the N-acetyl derivative 30, is 5-fold more active than
DQ against NF54 and K1 and equipotent with DQ against W2. It possesses an activity profile against all
strains comparable with that of the artemisinin derivative artesunate. Overall, this compound and the
other accessible and active derivatives serve as an attractive template for development of new and economic
lead quinolones.
