Optimization and Evaluation of Antiparasitic Benzamidobenzoic Acids as Inhibitors of Kinetoplastid Hexokinase 1.
Daniel P FlahertyMichael T HarrisChad E SchroederHaaris KhanElizabeth W KahneyAmber L HacklerStephen L PatrickWarren S WeinerJeffrey AubéElizabeth R SharlowJames C MorrisJennifer E GoldenPublished in: ChemMedChem (2017)
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 cells, EC50 >25 μm), and no appreciable activity on whole bloodstream-form (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 than toward TbHK1, suggesting that inhibition of the glycolytic pathway may be a promising opportunity to target multiple disease-causing trypanosomatid protozoa.
Keyphrases
- plasmodium falciparum
- human health
- risk assessment
- induced apoptosis
- randomized controlled trial
- emergency department
- climate change
- toxoplasma gondii
- cell cycle arrest
- oxidative stress
- case report
- trypanosoma cruzi
- gram negative
- escherichia coli
- endoplasmic reticulum stress
- signaling pathway
- klebsiella pneumoniae
- multidrug resistant
- fluorescent probe