4-AMINOQUINOLINE ANALOGS OF CHLOROQUINE WITH SHORTENED SIDE-CHAINS RETAIN ACTIVITY AGAINST CHLOROQUINE-RESISTANT PLASMODIUM-FALCIPARUM

We have synthesized several 4-aminoquinolines with shortened side chai ns that retain activity against chloroquine-resistant isolates of Plas modium falciparum malaria (W. Hofheinz, C. Jaquet, and S. Jolidon, Eur opean patent 94116281.0, June 1995), We report here an assessment of t he activities of four selected compounds containing ethyl, propyl, and isopropyl side chains, Reasonable in vitro activity (50% inhibitory c oncentration, <100 nM) against chloroquine-resistant P. falciparum str ains was consistently observed, and the compounds performed well in a variety of Plasmodium berghei animal models, However, some potential d rawbacks of these compounds became evident upon in-depth testing, In v itro analysis of more than 70 isolates of P. falciparum and studies wi th a mouse in vivo model suggested a degree of cross-resistance with c hloroquine, In addition, pharmacokinetic analysis demonstrated the for mation of N-dealkylated metabolites of these compounds, These metaboli tes are similarly active against chloroquine-susceptible strains but a re much less active against chloroquine-resistant strains. Thus, the c linical dosing required for these compounds would probably be greater for chloroquine-resistant strains than for chloroquine-susceptible str ains. The clinical potential of these compounds is discussed within th e context of chloroquine's low therapeutic ratio and toxicity.