JAC Advance Access originally published online on November 6, 2008
Journal of Antimicrobial Chemotherapy 2009 63(1):146-150; doi:10.1093/jac/dkn451
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Original research |
Artemisinin derivatives inhibit Toxoplasma gondii in vitro at multiple steps in the lytic cycle
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1 Department of Chemistry and The Malaria Research Institute, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA 2 Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA
Received 7 May 2008; returned 14 June 2008; revised 12 August 2008; accepted 2 October 2008
* Corresponding author. Tel: +1-410-614-0730; Fax: +1-410-955-3723; E-mail: lbrando{at}jhmi.edu
Objectives: We sought to improve upon the usefulness of artemisinins as anti-Toxoplasma agents by synthesizing new unsaturated, carba derivatives and then testing them for in vitro efficacy against three steps of the lytic cycle of Toxoplasma gondii tachyzoites.
Methods: Novel derivatives of ART were synthesized and then tested for in vitro antiparasitic activity using T. gondii tachyzoites constitutively expressing β-galactosidase and human fibroblast host cells. Compounds were evaluated for parasite growth inhibition and cytotoxicity, inhibition of replication and inhibition of parasite invasion of host cells.
Results: Five of the seven new derivatives, 3a–c, 3e and 3f, effectively inhibited T. gondii growth (IC50 = 1.0–4.4 µM); however, only three of these proved to be relatively non-cytotoxic (TD50 
200 µM). The same five derivatives also inhibited tachyzoite replication, and attachment to and invasion of host cells as effectively as or better than the parent compound ART. In addition, one of the derivatives incapable of inhibiting growth, deoxy-3a, was found to inhibit parasite invasion.
Conclusions: These new artemisinin derivatives have the ability to inhibit multiple steps of T. gondii's lytic cycle. Synthetic unsaturated, carba derivatives of ART have potential as therapeutic agents for the prevention and treatment of toxoplasmosis in humans.
Keywords: parasite , toxoplasmosis , treatment , in vitro inhibition , antiparasitic drugs
Present address. Division of Chemistry, Alfred University, Meyers Hall 219, Alfred, NY 14802, USA. 
These authors contributed equally to this work.