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Optimization and Evaluation of Antiparasitic Benzamidobenzoic Acids as Inhibitors of Kinetoplastid Hexokinase 1
Author(s) -
Flaherty Daniel P.,
Harris Michael T.,
Schroeder Chad E.,
Khan Haaris,
Kahney Elizabeth W.,
Hackler Amber L.,
Patrick Stephen L.,
Weiner Warren S.,
Aubé Jeffrey,
Sharlow Elizabeth R.,
Morris James C.,
Golden Jennifer E.
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700592
Subject(s) - hexokinase , antiparasitic , trypanosoma brucei , biology , enzyme , antiparasitic agent , potency , biochemistry , protozoa , pharmacology , trypanocidal agent , trypanosoma , leishmania , microbiology and biotechnology , glycolysis , cytotoxicity , kinetoplastida , parasite hosting , in vitro , malaria , virology , immunology , medicine , protozoal disease , pathology , gene , world wide web , computer science
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, IC 50 =9.1 μ m ), low mammalian cytotoxicity (IMR90 cells, EC 50 >25 μ m ), 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, IC 50 =0.28 μ m ; BSF, ED 50 =1.9 μ m ). 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.