Toxoplasma gondii is the leading cause of food-borne illness in the United States and affects an estimated 60% of the worldwide population, with acute and chronic stages of human infection caused by the tachyzoite and bradyzoite forms, respectively. Chronic infection carries significant risk of resurgence and fatal complications in immunocompromised patients. Current treatments against T. gondii are ineffective against bradyzoites, which are differentiated from tachyzoites in part by reduced metabolic activity and reliance on glycolysis over the TCA cycle. Repurposing of a glycolytic inhibitor library recently led to discovery of a potent and selective benzoic acid-derived inhibitor of both T. gondii stages (T. gondii EC50 &lt; 1 µM, HFF CC50 &gt; 50 µM) in a tissue culture model of infection. Structural refinement in a series of 35 analogs resulted in derivatives with improved physicochemical properties, including solubility and microsomal stability. Efficacy studies necessitated improvements to the synthetic route for an advanced hit compound. A refined synthesis furnished the desired compound at 100-fold scale with a 95% material cost reduction and obviated the use of TMS-diazomethane using only one net additional step from the discovery route. Advancements in the in vitro profile, in vivo efficacy, and synthetic accessibility of these parasitic growth inhibitors will be discussed.

Development of benzoic acid derivatives as multistage inhibitors of Toxoplasma gondii

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.