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

Brett D Schwartz; Mark J Coster; Tina S Skinner-Adams; Katherine T Andrews; Jonathan M White; Rohan A Davis

doi:10.3390/md13095784

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

Mar Drugs. 2015 Sep 15;13(9):5784-95. doi: 10.3390/md13095784.

Authors

Brett D Schwartz¹, Mark J Coster², Tina S Skinner-Adams³, Katherine T Andrews⁴, Jonathan M White⁵, Rohan A Davis⁶

Affiliations

¹ Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia. b.schwartz@griffith.edu.au.
² Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia. m.coster@griffith.edu.au.
³ Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia. t.skinner-adams@griffith.edu.au.
⁴ Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia. k.andrews@griffith.edu.au.
⁵ School of Chemistry and Bio21 Institute, University of Melbourne, Parkville, Vic 3052, Australia. whitejm@unimelb.edu.au.
⁶ Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia. r.davis@griffith.edu.au.

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.

Keywords: Plasmodium falciparum; X-ray; antiplasmodial; crystal; cytotoxicity; natural product scaffold; regioisomer; synthesis; thiaplakortone; tricyclic.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimalarials / chemical synthesis*
Antimalarials / pharmacology*
Models, Molecular
Molecular Structure
Plasmodium falciparum / drug effects*
Structure-Activity Relationship
Triazines / chemical synthesis*
Triazines / pharmacology*

Substances

Antimalarials
Triazines