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 chains that retain activity against chloroquine-resistant isolates of Plasmodium falciparum malaria (W. Hofheinz, C. Jaquet, and S. Jolidon, European patent 94116281.0, June 1995). We report here an assessment of the activities of four selected compounds containing ethyl, propyl, and isopropyl side chains. Reasonable in vitro activity (50% inhibitory concentration, < 100 nM) against chloroquine-resistant P. falciparum strains was consistently observed, and the compounds performed well in a variety of plasmodium berghei animal models. However, some potential drawbacks of these compounds became evident upon in-depth testing. In vitro analysis of more than 70 isolates of P. falciparum and studies with a mouse in vivo model suggested a degree of cross-resistance with chloroquine. In addition, pharmacokinetic analysis demonstrated the formation of N-dealkylated metabolites of these compounds. These metabolites are similarly active against chloroquine-susceptible strains but are much less active against chloroquine-resistant strains. Thus, the clinical dosing required for these compounds would probably be greater for chloroquine-resistant strains than for chloroquine-susceptible strains. The clinical potential of these compounds is discussed within the context of chloroquine's low therapeutic ratio and toxicity.

Ro 42-1611 (arteflene), a new effective antimalarial: chemical structure and biological activity.

The discovery of the natural peroxides qinghaosu (arteannuin A, artemisinin) (1) and yingzhaosu A (3) from traditional Chinese herbal medicines was a major advance in the search for new antimalarials (Fig. 1). Whereas qinghaosu can be produced from natural sources and has been well studied, yingzhaosu A has never been available for full evaluation as anti-malarial. We have designed a synthesis of the novel ring system present in yingzhaosu A, the 2,3-dioxabicyclo[3.3.1]nonane and prepared a series of yingzhaosu A analogues which were tested against Plasmodium berghei in mice. Structure-activity rules could be established and used for lead optimization. The best anti-malarial activity was observed for analogues having a keto group within the ring system and an aliphatic or aromatic lipophilic tail as ring substituent. The optimized analogues possessed activity comparable to qinghaosu. In spite of the presence of a peroxide ring, the new compounds were chemically stable against common reagents. In contrast to qinghaosu and its derivatives, they were also stable against hydrolytic decomposition and could therefore be expected to show improved pharmacokinetic properties. As one of the best compounds, Ro 42-1611 (arteflene) (26n, Fig. 2) was selected for detailed preclinical evaluation. Ro 42-1611 (arteflene) was found negative in a battery of mutagenicity tests. It had low acute toxicity after oral or subcutaneous administration. In a 4-week oral tolerance study in rats, doses of up to 400 mg/kg/day were well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)