Department of Chemistry and Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
Department of Medicinal Chemistry, University of Kansas, Lawrence, 66045 KS, USA.
Bioorg Med Chem. 2020 Oct 1;28(19):115678. doi: 10.1016/j.bmc.2020.115678. Epub 2020 Aug 1.
Malaria is a prevalent and deadly disease. The fast emergence of drug-resistant malaria parasites makes the situation even worse. Thus, developing new chemical entities, preferably with novel mechanisms of action, is urgent and important. Inspired by the complex and scarce isonitrile-containing terpene natural products, we evaluated a collection of easily prepared synthetic mono- and bis-isonitrile compounds, most of which feature a simple, but rigid stilbene backbone. From this collection, potent antimalarial lead compounds with EC value ranging from 27 to 88 nM against the Dd2 strain using a blood stage proliferation assay were identified. Preliminary SAR information showed that the isonitrile group is essential for the observed activity against the Dd2 strain and the bis-isonitrile compounds in general perform better than the corresponding mono-isonitrile compounds.
疟疾是一种流行且致命的疾病。疟原虫对抗疟药物的快速耐药性使得情况更加恶化。因此，开发新的化学实体，最好具有新颖的作用机制，是紧迫和重要的。受复杂且稀缺的含异腈萜类天然产物的启发，我们评估了一系列易于制备的合成单异腈和双异腈化合物，其中大多数化合物具有简单但刚性的二苯乙烯骨架。从该化合物库中，我们使用血液阶段增殖测定法鉴定出对 Dd2 株具有 EC 值范围为 27 至 88 nM 的有效抗疟先导化合物。初步 SAR 信息表明，异腈基团对观察到的 Dd2 株活性至关重要，并且双异腈化合物通常比相应的单异腈化合物表现更好。
