**1. Introduction**

The marine natural products, thiaplakortones A–D (**1**–**4**), were first reported in 2013 as part of a Medicines for Malaria Venture sponsored research project that aimed to discover new antiplasmodial agents from nature (Figure 1) [1]. These unique thiazine-derived secondary metabolites were obtained from the organic extract from the Great Barrier Reef sponge *Plakortis lita*, and all were shown to inhibit the *in vitro* growth of *Plasmodium falciparum*. Thiaplakortone A (**1**) was the most active with *in vitro* IC50 values of 6.6 and 51 nM against multidrug-resistant (Dd2) and chloroquine-sensitive (3D7) *P. falciparum* lines, respectively [1]*.* Due to supply issues initially curtailing *in vivo* malaria studies, total syntheses of thiaplakortones A and B were undertaken and the first total synthesis of **1** and **2**, along with a series of mono- and di-methyl analogues (**5**–**7**) was subsequently reported and some preliminary structure-activity relationships (SAR) ascertained (Figure 1) [2]. While *in vivo* toxicity effects for several of the synthetic compounds indicated potential liabilities associated with this structure class, the limited number of analogues investigated made it difficult to assess their true potential as antiplasmodial leads [2]. In order to more thoroughly explore this compound class a larger analogue library based on the thiaplakortone A scaffold was recently undertaken and reported [3]. This 38-membered library consisted of a series of amide and urea analogues based on the thiaplakortone A natural product scaffold. Several analogues showed potent *in vitro P. falciparum* growth inhibition (IC50 < 500 nM) and good selectivity for *P. falciparum* versus human neonatal foreskin fibroblast (NFF) cells (selectivity index >100) [3]. Furthermore, analogues **8** and **9** displayed good metabolic stability and solubility, and when administered subcutaneously to mice plasma concentrations remained >0.2 μM for 8 h. Analogues **8** and **9** were also well tolerated in mice after subcutaneous administration of 32 mg/kg twice daily for 4 d. In addition, using this dosing protocol blood stage *P. berghei* parasitemia was suppressed by 52% for **8** and 26% for **9**, relative to controls [3]. In order to further investigate the thiaplakortone core, we have recently undertaken synthetic studies that resulted in the removal of the ethylamine side-chain present in thiaplakortones A and B in order to determine the biological implications of the –CH2CH2NH2 moiety. Herein we report the total synthesis of several side-chain truncated regioisomers associated with the tricyclic core of thiaplakortones A–D, along with their *in vitro* antiplasmodial activity and mammalian cell toxicity.

**Figure 1.** Chemical structures of the natural products thiaplakortones A–D (**1**–**4**) and some of the previously synthesized thiaplakortone A analogues (**5**–**9**).
