Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities.

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.

The mode of action of anticoccidial quinolones (6-decyloxy-4-hydroxyquinoline-3-carboxylates) in chickens.

The anticoccidial mode of action of quinolones (6-decyloxy-4-hydroxyquinoline-3-carboxylates) against Eimeria tenella and E. acervulina in chickens has been investigated, using decoquinate and M&B 15,584 as examples. The well known static effect on sporozoites of relatively high continuous drug concentrations in the food masked other components of the mode of action, newly described here. Lower concentrations of quinolones allowed sporozoites to continue their development. First-stage schizonts were susceptible to a secondary cidal effect, although later schizonts seemed to be rather refractory. Furthermore, the sporulation of oocysts produced by E. tenella that completed its life cycle in the presence of suboptimal concentrations of quinolones was inhibited: this probably reflects a drug effect on gametocytes. Quinolones were absorbed rapidly from the chicken intestine, probably in less than 1 h. Drug withdrawal experiments showed that quinolones persisted in chicken tissues at active concentrations for up to 48 h. Despite their static effect on sporozoites, they may nevertheless be expected to exert a therapeutic effect against drug-sensitive coccidia in interrupted regimes that allow the later cidal effect to come into play. This allows immunity to coccidiosis to develop in the presence of drug. These new results, with the previously available data have been combined in an updated account of the anticoccidial mode of action of quinolones in the chicken.