PDF(Pubmed)
Abstract：
The incorporation of bromine, iodine or fluorine into the tricyclic core structure of thiaplakortone A (1), a potent antimalarial marine natural product, is reported. Although yields were low, it was possible to synthesise a small nine-membered library using the previously synthesised Boc-protected thiaplakortone A (2) as a scaffold for late-stage functionalisation. The new thiaplakortone A analogues (3-11) were generated using N-bromosuccinimide, N-iodosuccinimide or a Diversinate™ reagent. The chemical structures of all new analogues were fully characterised by 1D/2D NMR, UV, IR and MS data analyses. All compounds were evaluated for their antimalarial activity against Plasmodium falciparum 3D7 (drug-sensitive) and Dd2 (drug-resistant) strains. Incorporation of halogens at positions 2 and 7 of the thiaplakortone A scaffold was shown to reduce antimalarial activity compared to the natural product. Of the new compounds, the mono-brominated analogue (compound 5) displayed the best antimalarial activity with IC50 values of 0.559 and 0.058 μM against P. falciparum 3D7 and Dd2, respectively, with minimal toxicity against a human cell line (HEK293) observed at 80 μM. Of note, the majority of the halogenated compounds showed greater efficacy against the P. falciparum drug-resistant strain.
摘要：
溴的掺入，碘或氟进入ThiaplakortoneA（1）的三环核结构，一种有效的抗疟疾海洋天然产品，据报道。尽管收益率很低，使用先前合成的Boc保护的thiaplakortoneA（2）作为后期官能化的支架，可以合成一个小型的九元文库。新的thiaplakortoneA类似物（3-11）是使用N-溴琥珀酰亚胺生成的，N-碘代琥珀酰亚胺或Diversinate™试剂。所有新类似物的化学结构均通过1D/2DNMR充分表征，UV,IR和MS数据分析。评估所有化合物对恶性疟原虫3D7（药物敏感）和Dd2（耐药）菌株的抗疟活性。与天然产物相比，在thiaplakortoneA支架的2和7位掺入卤素显示出降低抗疟疾活性。在新化合物中，单溴化类似物（化合物5）对恶性疟原虫3D7和Dd2的IC50值分别为0.559和0.058μM，显示出最佳的抗疟活性。在80μM时观察到对人细胞系(HEK293)的最小毒性。值得注意的是，大多数卤代化合物对恶性疟原虫耐药菌株显示出更大的效力。
