Inhibition of Toxoplasma gondii and Plasmodium falciparum infections in vitro by NSC3852, a redox active antiproliferative and tumor cell differentiation agent.
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.
Virginia College of Osteopathic Medicine, Virginia Tech Corporate Research Center, Blacksburg, Virginia 24060, USA. jstrobl@vcom.vt.edu
Jeannine S
JS
Strobl
Christopher W
CW
Seibert
Yunbo
Y
Li
Rana
R
Nagarkatti
Sheila M
SM
Mitchell
Alexa C
AC
Rosypal
Dharmendar
D
Rathore
David S
DS
Lindsay
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles; D002460:Cell Line; D002478:Cells, Cultured; D003959:Diamines; D004912:Erythrocytes / Q000469:parasitology; D005347:Fibroblasts / Q000469:parasitology; D005456:Fluorescent Dyes; D006801:Humans; D006912:Hydroxyquinolines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D009603:Nitroso Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009930:Organic Chemicals; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014122:Toxoplasma / Q000187:drug effects* / Q000254:growth & development
D000970:Antineoplastic Agents; D000975:Antioxidants; D000981:Antiprotozoal Agents; D052160:Benzothiazoles; D003959:Diamines; D005456:Fluorescent Dyes; D006912:Hydroxyquinolines; D009603:Nitroso Compounds; D009930:Organic Chemicals; D011804:Quinolines; D017382:Reactive Oxygen Species; C098022:SYBR Green I; D009569:Nitric Oxide; C510786:5-nitroso-8-quinolinol