3 years ago

Optimization and Evaluation of Antiparasitic Benzamidobenzoic Acids as Inhibitors of Kinetoplastid Hexokinase 1

Jeffrey Aube, Elizabeth R. Sharlow, Stephen Patrick, Elizabeth Kahney, Daniel P Flaherty, Jennifer E. Golden, Warren S. Weiner, Haaris Khan, James C. Morris, Chad E. Schroeder, Amber Hackler, Michael T Harris
Kinetoplastid-based infections are neglected diseases that represent a significant human health issue. Chemotherapeutic options are limited due to toxicity, parasite susceptibility, and poor patient compliance. In response, we studied a molecular target-directed approach involving intervention of hexokinase activity - a pivotal enzyme in parasite metabolism. A benzamidobenzoic acid hit with modest biochemical inhibition of Trypanosoma brucei hexokinase 1 (TbHK1, IC₅₀ = 9.1 μM), low mammalian cytotoxicity (IMR90, EC₅₀ > 25 μM), and no appreciable activity on whole BSF parasites was optimized to afford a probe with improved TbHK1 potency and, significantly, efficacy against whole BSF parasites (TbHK1, IC₅₀ = 0.28 μM, BSF ED₅₀ = 1.9 μM). Compounds in this series also inhibited the hexokinase enzyme from Leishmania major (LmHK1), albeit with less potency compared to TbHK1, suggesting that inhibition of the glycolytic pathway may be a promising opportunity to target multiple, disease-causing trypanosomatid protozoa.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/cmdc.201700592

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