Characterization of Di-Aryl Urea Compounds Against Acute and Chronic Toxoplasma Gondii

Toxoplasma gondii is an obligate intracellular parasite that has infected nearly 60 million individuals in the United States alone. Acute infection causes ill effects to the fetus in utero when mothers are primarily infected, and to immunocompromised individuals. Chronic infection consists of quiescent tissue cysts located primarily in brain tissue and is capable of reverting back to the acute stage causing severe toxoplasma encephalitis in immunocompromised individuals. Current treatments for acute infection are lacking while there are no approved treatments for the clearance of chronic infection. The aim of this research was to evaluate a family of di-aryl urea compounds that had previously been shown to be active against a panel of apicomplexan, kinetoplastid, and helminth parasites for activity against T. gondii acute and chronic infection. In vitro models were utilized to determine activity against both acute and chronic T. gondii infection as well as possible host cellular toxicity. Compounds that exhibited selectivity in our in vitro assays were selected for further analysis in an in vivo murine model for activity against lethal acute infection in mice. One of the four compounds tested, U21, was successful at achieving 100% survival with no apparent toxicity in mice. Tested compounds did not have any effect on chronic T. gondii in a murine model. In efforts to identify a possible mode of action of U21 random mutagenesis, electron microscopy imaging, and differential expression analysis of treated T. gondii was utilized. Through these assays, it was found that U21 treatment may be causing dysregulated T. gondii lipid synthesis. Further investigation into dysregulated lipid synthesis caused by U21 is currently underway to confirm if it is indeed a possible mechanism of action