Thiazole, oxadiazole, and carboxamide derivatives of artemisinin are highly selective and potent inhibitors of toxoplasma gondii

Christopher P. Hencken, Lorraine V Brando, Claudia Bordón, Remo Stohler, Bryan T. Mott, Robert H Yolken, Gary H. Posner, Lauren E. Woodard

Research output: Contribution to journalArticle

Abstract

We have prepared 23 new dehydroartemisinin (DART) trioxane derivatives (11 thiazoles, 2 oxadiazoles, and 10 carboxamides) and have screened them for in vitro activity in the Toxoplasma lytic cycle. Fifteen (65%) of the derivatives were noncytotoxic to host cells (TD50-320 μM). Eight thiazole derivatives and two carboxamide derivatives displayed effective inhibition of Toxoplasma growth (IC50 = 0.25-0.42 μM), comparable in potency to artemether (IC50 = 0.31 μM) and >100 times more inhibitory than the currently employed front-line drug trimethoprim (IC50 = 46 μM). The thiazoles as a group were more effective than the other derivatives at inhibiting growth of extracellular as well as intracellular parasites. Unexpectedly, two thiazole trioxanes (5 and 6) were parasiticidal; both inhibited parasite replication irreversibly after parasite exposure to 10 μM of drug for 24 h, whereas the standard trioxane drugs artemisinin and artemether were not parasiticidal. Some of the new derivatives of artemisinin described here represent effective anti-Toxoplasma trioxanes as well as molecular probes for elucidating the mechanism of action of the DART class of artemisinin derivatives.

Original languageEnglish (US)
Pages (from-to)3594-3601
Number of pages8
JournalJournal of Medicinal Chemistry
Volume53
Issue number9
DOIs
StatePublished - May 13 2010

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Oxadiazoles
Thiazoles
Toxoplasma
Inhibitory Concentration 50
Parasites
Pharmaceutical Preparations
Molecular Probes
Trimethoprim
Growth
artemisinine
artemether

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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Thiazole, oxadiazole, and carboxamide derivatives of artemisinin are highly selective and potent inhibitors of toxoplasma gondii. / Hencken, Christopher P.; Brando, Lorraine V; Bordón, Claudia; Stohler, Remo; Mott, Bryan T.; Yolken, Robert H; Posner, Gary H.; Woodard, Lauren E.

In: Journal of Medicinal Chemistry, Vol. 53, No. 9, 13.05.2010, p. 3594-3601.

Research output: Contribution to journalArticle

Hencken, Christopher P. ; Brando, Lorraine V ; Bordón, Claudia ; Stohler, Remo ; Mott, Bryan T. ; Yolken, Robert H ; Posner, Gary H. ; Woodard, Lauren E. / Thiazole, oxadiazole, and carboxamide derivatives of artemisinin are highly selective and potent inhibitors of toxoplasma gondii. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 9. pp. 3594-3601.
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