title: Synthesis and Antiplasmodial Evaluation of Analogues Based on the Tricyclic Core of Thiaplakortones A-D.
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.
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia. b.schwartz@griffith.edu.au.
authors.forename: Brett D
authors.initials: BD
authors.lastname: Schwartz
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia. m.coster@griffith.edu.au.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Coster
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia. t.skinner-adams@griffith.edu.au.
authors.forename: Tina S
authors.initials: TS
authors.lastname: Skinner-Adams
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia. k.andrews@griffith.edu.au.
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Andrews
authors.affiliation: School of Chemistry and Bio21 Institute, University of Melbourne, Parkville, Vic 3052, Australia. whitejm@unimelb.edu.au.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: White
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia. r.davis@griffith.edu.au.
authors.forename: Rohan A
authors.initials: RA
authors.lastname: Davis
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D014227:Triazines
keywords: Plasmodium falciparum; X-ray; antiplasmodial; crystal; cytotoxicity; natural product scaffold; regioisomer; synthesis; thiaplakortone; tricyclic