Synthesis and Antimalarial Evaluation of Halogenated Analogues of Thiaplakortone A.

The incorporation of bromine, iodine or fluorine into the tricyclic core structure of thiaplakortone A (), 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 () as a scaffold for late-stage functionalisation. The new thiaplakortone A analogues (-) were generated using -bromosuccinimide, -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 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 ) displayed the best antimalarial activity with IC values of 0.559 and 0.058 μM against 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 drug-resistant strain.