Artemisinin derivatives inhibit Toxoplasma gondii in vitro at multiple steps in the lytic cycle.
OBJECTIVE
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 beta-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 microM); however, only three of these proved to be relatively non-cytotoxic (TD50>or=200 microM). 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.
D'Angelo
John G
JG
Department of Chemistry and The Malaria Research Institute, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA.
Bordón
Claudia
C
Posner
Gary H
GH
Yolken
Robert
R
Jones-Brando
Lorraine
L
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity*; D037621:Artemisinins / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000469:parasitology; D006801:Humans; D020128:Inhibitory Concentration 50; D014122:Toxoplasma / Q000187:drug effects* / Q000254:growth & development
D000981:Antiprotozoal Agents; D037621:Artemisinins; C031327:artemisinin