Development of Novel Antimalarial Drugs Based on Plant Alkaloids

虽然从白桦根中分离的生物碱白桦碱和异白桦碱对恶性疟原虫具有很强的抗疟活性，但其强烈的副作用（如催吐作用）阻碍了其在疟疾中的临床应用。然而，它们的抗疟效力使它们成为开发新型化疗抗疟药物的有吸引力的先导物质。因此，我们评估了热弗弗碱和异布弗碱类似物的体外抗疟活性。测定了Df-1和Df-2与丙酮的缩合产物和异异亮氨酸的活性。在体外实验中发现，热弗金的氧化和还原衍生物对恶性疟原虫具有高选择性，具有潜在的抗疟活性。此外，Df-1的dss - martin氧化产物对恶性疟原虫具有很强的活性和高选择性。一项结构-活性关系研究表明，4-喹唑啉酮环在活性的表现中起着至关重要的作用，并且1 ' -氨基和C-2', C-3 ' 0官能团的存在对热嘌呤的活性至关重要。

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.