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.
Graphical Abstract 1Under a programme designed to develop new triple drug combinations for the treatment of malaria, tuberculosis, and toxoplasmosis, 1 we are preparing and evaluating efficacies of compound sets based on combinations of oxidant and redox drugs 2 coupled with a third partner with a different mode of action. In the case of malaria, the need to develop new drug combinations is particularly pressing. 3 Chemotherapy coupled with vector control and inculcation of public awareness has reduced mortality due to malaria by over 66% since 2000. 4 However, the emergence of malaria parasites resistant to the current clinically-used artemisinin derivatives 5 mandates the urgent development of newer artemisinin derivatives. Such derivatives must be incapable of providing the active metabolite dihydroartemisinin (DHA) common to the current clinical artemisinins, and should be rationally combined with the redox drug and a third combination partner to counter resistance and inhibit spread of resistant phenotypes by blocking transmission. 6 The third partner is logically constructed about the 4(1H)-quinolone scaffold. In addition to being used clinically against a variety of infectious diseases including tuberculosis, 7 certain quinolones have acquired lead status for development of drugs for treatment of toxoplasmosis 8,9 and malaria 10,11,12 respectively.Our attention is drawn to decoquinate (DQ, 1) that has been used for many years in veterinary medicine largely coadministered with poultry feed for treatment of coccidiosis wherein it displays negligible toxicity. 13,14 It is also used against other apicomplexan infections in animals 15 and is highly active in a murine model against Toxoplasma gondii. 16 Activity of DQ against malaria including P. berghei 17 in mic...