Kikuchi Haruhisa, Yamamoto Keisuke, Horoiwa Seiko, Hirai Shingo, Kasahara Ryota, Hariguchi Norimitsu, Matsumoto Makoto, Oshima Yoshiteru
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama, Sendai 980-8578, Japan.
J Med Chem. 2006 Jul 27;49(15):4698-706. doi: 10.1021/jm0601809.
Febrifugine (1), a quinazoline alkaloid, isolated from Dichroa febrifuga roots, shows powerful antimalarial activity against Plasmodium falciparum. The use of 1 as an antimalarial drug has been precluded because of side effects, such as diarrhea, vomiting, and liver toxicity. However, the potent antimalarial activity of 1 has stimulated medicinal chemists to pursue compounds derived from 1, which may be valuable leads for novel drugs. In this study, we synthesized a new series of febrifugine derivatives formed by structural modifications at (i) the quinazoline ring, (ii) the linker, or (iii) the piperidine ring. Then, we evaluated their antimalarial activities. Thienopyrimidine analogue 15 exhibited a potent antimalarial activity and a high therapeutic selectivity both in vitro and in vivo, suggesting that 15 is a good antimalarial candidate.
常山碱（1）是一种从常山根中分离出的喹唑啉生物碱，对恶性疟原虫显示出强大的抗疟活性。由于腹泻、呕吐和肝毒性等副作用，1作为抗疟药物的使用已被排除。然而，1的强效抗疟活性促使药物化学家研究从1衍生而来的化合物，这些化合物可能是新型药物的有价值先导物。在本研究中，我们合成了一系列新的常山碱衍生物，这些衍生物是通过对（i）喹唑啉环、（ii）连接基或（iii）哌啶环进行结构修饰而形成的。然后，我们评估了它们的抗疟活性。噻吩并嘧啶类似物15在体外和体内均表现出强效抗疟活性和高治疗选择性，表明15是一个良好的抗疟候选物。
