J Parasitol. 2008 Oct 6:1. [Epub ahead of print]
Inhibition of Toxoplasma gondii and Plasmodium falciparum infections in vitro by NSC3852, a redox active anti-proliferative and tumor cell differentiation agent
Strobl JS, Seibert CW, Li Y, Nagarkatti R, Mitchell SM, Rosypal AC, Rathore D, Lindsay DS.
We searched the National Cancer Institute (NCI) compound library for structures related to the anti-tumor quinoline NSC3852 (5-nitroso-8-quinolinol) and used a computer algorithm to predict the anti-protozoan activity of each of 13 structures. Half of these compounds inhibited T. gondii tachyzoite propagation in human fibroblasts at = 1microM. The active compounds comprise a series of low molecular weight quinolines bearing nitrogen substituents in the ring-5 position. NSC3852 (EC50 80 nM) and NSC74949 (EC50 646 nM) were the most potent. NSC3852 also inhibited P. falciparum growth in human red blood cells (EC50 1.3 micro M). To investigate the mechanism for NSC3852's anti-T. gondii actvity, 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.
PMID: 18837587 [PubMed - as supplied by publisher]