**4. Conclusions**

In summary, six analogues associated with the tricyclic core of thiaplakortones were synthesized from readily accessible and known 1*H*-indole-4,7-dione derivatives, and isolated in low to moderate yields. Regiochemistry was moderated by substitution of the indole nitrogen. All compounds were tested for *in vitro* antiplasmodial activity towards two *P. falciparum* parasite lines (3D7 and Dd2). Compound **16** showed the best antiparasitic activity with IC50 values of 252 and 127 nM towards 3D7 and Dd2 lines, respectively. The moderate toxicity (IC50 4600 nM) of compound **16** towards NFF cells equates to a selectivity index of 18.2–36.2. These studies have identified that while the ethylamine side-chain present in the marine natural products, thiaplakortones A and B, translates to more potent and selective antiplasmodial compounds, this functionality is by no means essential for activity. Furthermore, the truncated thiaplakortone molecules (**11**–**16**) synthesized during this work has allowed delineation of a minimum antiplasmodial pharmacophore for the thiaplakortone chemotype.

**Acknowledgments:** We thank the National Health and Medical Research Council (NHMRC) for financial support towards this research through a project grant (APP1024314). R.A.D. and K.T.A. acknowledge the Australian Research Council (ARC) for an ARC Linkage Grant (LP120200339) and an ARC Future Fellowship, respectively. We also thank the ARC for support toward NMR and MS equipment (Grant LE0668477 and LE0237908). G. MacFarlane (University of Queensland) and W. Loa (Griffith University) are acknowledged for HRESIMS measurements. We also acknowledge the Australian Red Cross Blood Service for the provision of human blood and sera.

**Author Contributions:** B.D.S. designed and conducted all synthetic experiments and analyzed the results. T.S.S. and K.T.A. designed and performed all the biological experiments, and contributed to data interpretation. M.J.C. assisted with synthetic experimental design, and SAR data analysis. J.M.W. obtained the X-ray diffraction data for compound **11**, and solved the crystal structure. R.A.D. was the project leader overseeing the design of the experiments, analysis of the results and the identification and characterization of all compounds. All authors contributed to manuscript preparation.

**Conflicts of Interest:** The authors declare no conflict of interest.
