We searched the National Cancer Institute (NCI) compound library for structures related to the antitumor
quinoline NSC3852 (5-nitroso-8-quinolinol) and used a computer algorithm to predict the antiprotozoan activity for each of 13 structures. Half of these compounds inhibited Toxoplasma gondii tachyzoite propagation in human fibroblasts at < or =1 microM. The active compounds comprise a series of low-molecular-weight
quinolines bearing
nitrogen substituents in the ring-5 position.
NSC3852 (EC(50) 80 nM) and NSC74949 (EC(50) 646 nM) were the most potent.
NSC3852 also inhibited Plasmodium falciparum growth in human red blood cells (EC(50) 1.3 microM). To investigate the mechanism for
NSC3852's
anti-T. gondii activity, we used chemiluminescence assays to detect
reactive oxygen species (ROS) formation in freshly isolated tachyzoites and in infected host cells; the absence of ROS generation by
NSC3852 in these assays indicated
NSC3852 does not redox cycle in T. gondii. Inhibitors of
enzyme sources of
free radicals such as
superoxide anion,
nitric oxide (NO), and their reaction product
peroxynitrite did not interfere with the
anti-T. gondii activity of
NSC3852. However, inhibition of T. gondii tachyzoite propagation by
NSC3852 involved redox reactions because tachyzoites were protected from
NSC3852 by inclusion of the cell permeant
superoxide dismutase mimetic,
MnTMPyP, or
N-acetylcysteine in the culture medium. We conclude that the Prediction of Activity Spectra for Substances (PASS) computer program is useful in finding new compounds that inhibit T. gondii tachyzoites in vitro and that
NSC3852 is a potent T. gondii inhibitor that acts by indirect generation of oxidative stress in T. gondii.