Exploration of a New Type of Pharmacologically Active Compounds Based on Quinazoline-type Alkaloid, Febrifugine

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Malaria, which is caused by a protozoan parasite of the genus Plasmodium, is a major parasitic infection in many tropical and subtropical regions. Malaria affects 300-500 million patients worldwide and leads to more than 2 million deaths each year. Although malaria has been widely eradicated in many parts of the world, the number of patients continues to rise mainly due to the emergence of chloroquine-resistant and multiple-drug-resistant strains of malaria parasites. Thus, the discovery of new and effective antimalarial drugs is urgently needed.Febrifugine, a quinazoline alkaloid, isolated from Dichroa febrifuga roots, shows powerful antimalarial activity against Plasmodium falciparum. The use of febrifugine as an antimalarial drug has been precluded due to side effects such as diarrhea, vomiting, and liver toxicity. However, the potent antimalarial activity of febrifugine has stimulated medicinal chemists to pursue compounds derived from febrifugine, which may be valuable leads for novel drugs. In this study, we synthesized a new series of febrifugine derivatives formed by structural modifications at either (i) the quinazoline ring, (ii) the linker, or (iii) the piperidine ring. Then we evaluated their antimalarial activities. As a result, a few of the compounds such as thienopyrimidine analog exhibited a potent antimalarial activity and a high therapeutic selectivity both in vitro and in vivo, suggesting that they are good antimalarial candidates.