Thiaplakortones A–D: Antimalarial Thiazine Alkaloids from the Australian Marine Sponge Plakortis lita

Abstract

A high-throughput screening campaign using a prefractionated natural product library and an in vitro antimalarial assay identified active fractions derived from the Australian marine sponge Plakortis lita. Bioassay-guided fractionation of the CH₂Cl₂/CH₃OH extract from P. lita resulted in the purification of four novel thiazine-derived alkaloids, thiaplakortones A–D (<b>1</b>–<b>4</b>). The chemical structures of <b>1</b>–<b>4</b> were determined following analysis of 1D/2D NMR and MS data. Comparison of the chiro-optical data for <b>3</b> and <b>4</b> with literature values of related <i>N</i>-methyltryptophan natural products was used to determine the absolute configuration for both thiaplakortones C and D as 11<i>S</i>. Compounds <b>1</b>–<b>4</b> displayed significant growth inhibition against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum (IC₅₀ values <651 nM) and only moderate cytotoxicity against HEK293 cells (IC₅₀ values >3.9 μM). Thiaplakortone A (<b>1</b>) was the most active natural product, with IC₅₀ values of 51 and 6.6 nM against 3D7 and Dd2 lines, respectively