Previously we have shown that pentacycloundecylamine-chloroquinoline (PCU-CQ) conjugates possess significant chemosensitizing abilities and can circumvent the resistance associated with chloroquine (CQ) resistant plasmodia. In order to further explore structurally related polycyclic compounds as reversed CQ agents we synthesized a series of eight aza-adamantanol (1–4) and adamantane-imine (5–8) CQ conjugates. All conjugates showed limited cytotoxicity against CHO cells (IC₅₀ > 37 µM). Compounds 1, 2 and 5 were highly active (K1 IC₅₀ < 100 nM) exhibiting a 3–4-fold increase in antiplasmodial activity against CQ resistant strain K1 compared to CQ. Reduced cross-resistance (resistance index, RI: 2–4.3) relative to CQ (RI = 38) was also observed for these compounds. Compound 1 which showed an 18-fold enhancement at retaining its activity against the K1 strain compared to CQ is a promising candidate to substitute CQ in P. falciparum resistant malaria.

以前我们已经表明，五环十一烷基胺-氯喹啉（PCU-CQ）缀合物具有显着的化学增敏能力，并且可以规避与耐氯喹（CQ）的疟原虫相关的耐药性。为了进一步探索结构相关的多环化合物作为反向CQ剂我们合成了一系列8氮杂金刚烷醇（的1 - 4）和金刚烷亚胺（5 - 8）CQ缀合物。所有缀合物均显示出对CHO细胞有限的细胞毒性（IC ₅₀  > 37 µM）。化合物1，2和5是高度活性的（K1 IC ₅₀ <100 nM）与CQ相比，对CQ抗性菌株K1的抗疟原虫活性提高了3-4倍。这些化合物的交叉电阻（电阻指数，RI：2-4.3）相对于CQ（RI = 38）也有所降低。与CQ相比，在保留其对K1菌株的活性方面显示出18倍增强的化合物1是在恶性疟原虫抗性疟疾中替代CQ的有前途的候选物。