A unified synthetic approach was developed that enabled the synthesis of diverse tropane-related scaffolds. The key intermediates that were exploited were cycloadducts formed by reaction between 3-hydroxy-pyridinium salts and vinyl sulfones or sulfonamides. The diverse tropane-related scaffolds were formed by addition of substituents to, cyclisation reactions of, and fusion of additional ring(s) to the key bicyclic intermediates. A set of 53 screening compounds was designed, synthesised and evaluated in order to determine the biological relevance of the scaffolds accessible using the synthetic approach. Two inhibitors of Hedgehog signalling, and four compounds with weak activity against the parasite P. falciparum, were discovered. Three of the active compounds may be considered to be indotropane or pyrrotropane pseudo natural products in which a tropane is fused with a fragment from another natural product class. It was concluded that the unified synthetic approach had yielded diverse scaffolds suitable for the design of performance-diverse screening libraries.

开发了一种统一的合成方法，可以合成多种与托烷相关的支架。开发的关键中间体是3-羟基吡啶鎓盐与乙烯基砜或磺酰胺之间反应形成的环加合物。通过将取代基添加到关键的双环中间体上，进行环化反应以及将额外的环与所述稠合的双环中间体融合，从而形成了多种与托烷相关的支架。设计，合成和评估了一组53种筛选化合物，以确定使用合成方法可接近的支架的生物学相关性。两种刺猬信号抑制剂和四种对恶性疟原虫的活性较弱的化合物，被发现。可以将其中的三种活性化合物视为吲哚环烷或吡咯烷假的天然产物，其中的托烷与另一种天然产物的片段融合在一起。结论是，统一的合成方法产生了适用于性能多样化筛选文库设计的多种支架。