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The incorporation of bromine, iodine or fluorine into the tricyclic core structure of thiaplakortone A (<b>1</b>), 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 (<b>2</b>) as a scaffold for late-stage functionalisation. The new thiaplakortone A analogues (<b>3</b>–<b>11</b>) were generated using <i>N</i>-bromosuccinimide, <i>N</i>-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 <i>Plasmodium falciparum</i> 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 <b>5</b>) displayed the best antimalarial activity with IC₅₀ values of 0.559 and 0.058 μM against <i>P. falciparum</i> 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 <i>P. falciparum</i> drug-resistant strain.