Development of Novel Antimalarial Drugs Based on Plant Alkaloids

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Although febrifugine and isofebrifugine, alkaloids isolated from Dichroa febrifuga roots, show powerful antimalarial activities against Plasmodium falciparum, their strong side effects such as emetic effect precluded their clinical use in malaria. However, their antimalarial potency makes them attractive substances as leads for developing new types of chemotherapeutic antimalarial drugs. We have thus evaluated the in vitro antimalarial activity of analogues of febrifugine and isofebrifugine. The activities of analogues derived from Df-1 and Df-2, condensation products of febrifugine and isofebrifugine with acetone, respectively, were also obtained. The oxidation and reduction derivatives of febrifugine were found to exhibit potential antimalarial activities with high selectivities against P. falciparum in vitro. Additionally, the Dess-Martin oxidation product of Df-1 was found to be strongly active with high selectivity against P. falciparum. A structure-activity relationship study demonstrates the essential role played by the 4-quinazolinone ring in the appearance of activity, and that the presence of a 1"-amino group and C-2', C-3" 0-functionalities are crucial in the activity of febrifugine.