Synthesis and Antiplasmodial Evaluation of Analogues Based on the Tricyclic Core of Thiaplakortones A–D

• Main Authors: Brett D. Schwartz, Mark J. Coster, Tina S. Skinner-Adams, Katherine T. Andrews, Jonathan M. White, Rohan A. Davis
• Format: Article
• Language: English
• Published: MDPI AG 2015-09-01
• Series: Marine Drugs
• Subjects: synthesis; thiaplakortone; regioisomer; tricyclic; natural product scaffold; X-ray; crystal; Plasmodium falciparum; antiplasmodial; cytotoxicity
• Online Access: http://www.mdpi.com/1660-3397/13/9/5784
• ISSN: 1660-3397

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.