4(1H)-Quinolones and 1,2,3,4-tetrahydroacridones (THAs) are known to possess causal prophylactic activity and potent erythrocytic stage inhibition in avian malaria models, but not against malaria parasites in mammals. Recently, the Manetsch laboratory has synthesized and identified 4(1H)-quinolones and THAs displaying excellent in vitro activity against P. falciparum and adequate in vivo activity in P. berghei infected mice. Subsequent pharmacokinetic studies with lead quinolone compounds suggests the aqueous solubility is the major reason for poor bioavailability and moderate in vivo activity. Herein, we describe the development of a prodrug approach to circumvent the observed bioavailability issues. 4(1H)-quinolones have been derivatized via esterification, alkylation, alkyloxycarbonyloxymethylation or phosphorylation. Prepared prodrugs have then been tested for chemical stability at different pHs, aqueous solubility as well as regeneration of active parent compound in vitro. A selected set of prodrugs has been shown to possess improved in vivo antimalarial efficacy in a P. berghei infected mouse model.

Synthesis and evaluation of 4(1<i>H</i>)-quinolone prodrugs targeting multi-drug resistance <i>P. falciparum</i> malaria

245th National Meeting (2013)

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Synthesis and evaluation of 4(1H)-quinolone prodrugs targeting multi-drug resistance P. falciparum malaria