Daub Mary Elisabeth, Prudhomme Jacques, Ben Mamoun Choukri, Le Roch Karine G, Vanderwal Christopher D
Department of Chemistry, University of California , 1102 Natural Sciences II, Irvine, California 92697, United States.
Department of Cell Biology & Neuroscience, University of California , 900 University Avenue, Riverside, California 92521, United States.
ACS Med Chem Lett. 2017 Feb 16;8(3):355-360. doi: 10.1021/acsmedchemlett.7b00013. eCollection 2017 Mar 9.
Several kalihinol natural products, members of the broader isocyanoterpene family of antimalarial agents, are potent inhibitors of , the agent of the most severe form of human malaria. Our previous total synthesis of kalihinol B provided a blueprint to generate many analogues within this family, some as complex as the natural product and some much simplified and easier to access. Each analogue was tested for blood-stage antimalarial activity using both drug-sensitive and -resistant strains. Many considerably simpler analogues of the kalihinols retained potent activity, as did a compound with a different decalin scaffold made in only three steps from sclareolide. Finally, one representative compound showed reasonable stability toward microsomal metabolism, suggesting that the isonitrile functional group that is critical for activity is not an inherent liability in these compounds.
几种卡里希诺醇天然产物，属于更广泛的抗疟异氰基萜类药物家族成员，是最严重形式的人类疟疾病原体恶性疟原虫的有效抑制剂。我们之前对卡里希诺醇B的全合成提供了一个蓝图，可在此家族中生成许多类似物，有些与天然产物一样复杂，有些则大大简化且更易于获取。使用药物敏感和耐药菌株对每个类似物进行了血液阶段抗疟活性测试。许多明显更简单的卡里希诺醇类似物保留了强效活性，一种仅通过三步从香紫苏内酯制备的具有不同十氢化萘骨架的化合物也是如此。最后，一种代表性化合物对微粒体代谢表现出合理的稳定性，这表明对活性至关重要的异腈官能团在这些化合物中并非固有缺陷。
