In:
ChemMedChem, Wiley, Vol. 12, No. 23 ( 2017-12-07), p. 1994-2005
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201700592
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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