derivatives of 5 have been described in which the diethylamino moiety has been replaced by a tert-butylamino group, a modification which reduces cross-resistance (26). The 5-substituted analogues 6 and 7, proved to be the most effective antimalarials in vitro, with ICso values of 0.98 and 1.24 nM against P. falciparum, and favorable cross-resistance profiles. Other quinolines of interest include tafenoquine 8, which is a second generation agent related to primoquine, 9 and mefoquine, 10. Tafenoquine, also known as WR 238605, appears to be an effective prophylactic agent for the prevention of P. falciparum malaria (27). Newly synthesized short chain quinolines such as 11 have been described that retain good antimalarial activity against the K1 chloroquine resistant strain of p. falciparum (28).
Artemisinin and Its Analogues - Perhaps the most promising advance in the treatment of malaria is the discovery of artemisinin, 12, which is also known by the Chinese name qinghaosu, and the related compound arteether, 13. These analogues are 1,2,4-trioxosesquiterpenes that produce oxidative stress in P. falciparum, and they are reduced by the organism in an Fe(ll)-dependent process to produce cytotoxic radical intermediates (29). Artemisinin itself is a potent antimalarial, with an ICso of 7.3 nM against P. falciparum. In the 10-deoxyartemisinin series, replacement of the 3-methyl group with an n-propyl moiety, as in 14, produced a 7-fold increase in activity with respect to artemisinin, while substitution at the 9-position produced a 70-fold increase (compound 15) (30). Artemisinin and its derivatives have limited oral bioavailability, and are hydrolytically unstable, problems which have been addressed by the synthesis of analogues related to 16 and 17, in
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