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

• Published in: Journal of organic chemistry 2013-10, Vol.78 (19), p.9608-9613
• Main Authors: Davis, Rohan A, Duffy, Sandra, Fletcher, Sabine, Avery, Vicky M, Quinn, Ronald J
• Format: Article
• Language: English
• Subjects: Alkaloids - chemistry; Alkaloids - pharmacology; Animals; Antimalarials - pharmacology; Australia; Biological Products; Humans; Inhibitory Concentration 50; Molecular Structure; Plakortis; Plasmodium falciparum - drug effects; Porifera - chemistry; Porifera - drug effects; Thiazines - chemistry; Triazines - chemistry; Triazines - pharmacology; Tryptophan - analogs & derivatives; Tryptophan - chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo400988y

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 (1–4). The chemical structures of 1–4 were determined following analysis of 1D/2D NMR and MS data. Comparison of the chiro-optical data for 3 and 4 with literature values of related N-methyltryptophan natural products was used to determine the absolute configuration for both thiaplakortones C and D as 11S. Compounds 1–4 displayed significant growth inhibition against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum (IC50 values 3.9 μM). Thiaplakortone A (1) was the most active natural product, with IC50 values of 51 and 6.6 nM against 3D7 and Dd2 lines, respectively.