Abstract
Six regioisomers associated with the tricyclic core of thiaplakortones A–D have been synthesized. Reaction of 1H-indole-4,7-dione and 1-tosyl-1H-indole-4,7-dione with 2-aminoethanesulfinic acid afforded a regioisomeric series, which was subsequently deprotected and oxidized to yield the tricyclic core scaffolds present in the thiaplakortones. All compounds were fully characterized using NMR and MS data. A single crystal X-ray structure was obtained on one of the N-tosyl derivatives. All compounds were screened for in vitro antiplasmodial activity against chloroquine-sensitive (3D7) and multidrug-resistant (Dd2) Plasmodium falciparum parasite lines. Several analogues displayed potent inhibition of P. falciparum growth (IC50 < 500 nM) but only moderate selectivity for P. falciparum versus human neonatal foreskin fibroblast cells.
Highlights
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]
While it is clear that the ethylamine side-chain present in thiaplakortones A and B translates to more potent and selective antiplasmodial agents, the current study shows that the tricyclic core motif present in 11–16 represents a minimum antiplasmodial pharmacophore for the thiaplakortone chemotype
Six analogues associated with the tricyclic core of thiaplakortones were synthesized from readily accessible and known 1H-indole-4,7-dione derivatives, and isolated in low to moderate yields
Summary
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. 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
