Synthesis, biochemical, and biological evaluation of C2 linkage derivatives of amino sugars, inhibitors of glucokinase from Trypanosoma cruzi

Scott B Green; Robert J Lanier Jr; Shane M Carey; David R Morgan; Hanna Gracz; Julian Sherman; Ana Rodriguez; Edward L D'Antonio

doi:10.1016/j.bmcl.2021.128227

Synthesis, biochemical, and biological evaluation of C2 linkage derivatives of amino sugars, inhibitors of glucokinase from Trypanosoma cruzi

Bioorg Med Chem Lett. 2021 Sep 1:47:128227. doi: 10.1016/j.bmcl.2021.128227. Epub 2021 Jun 24.

Authors

Scott B Green¹, Robert J Lanier Jr¹, Shane M Carey¹, David R Morgan², Hanna Gracz³, Julian Sherman⁴, Ana Rodriguez⁴, Edward L D'Antonio⁵

Affiliations

¹ Department of Natural Sciences, University of South Carolina Beaufort, 1 University Boulevard, Bluffton, SC 29909, USA.
² NMRService LLC, Raleigh, NC 27612, USA.
³ NMRService LLC, Raleigh, NC 27612, USA; Department of Molecular and Structural Biochemistry, North Carolina State University, 128 Polk Hall, Raleigh, NC 27695, USA.
⁴ Department of Microbiology, New York University School of Medicine, 430 East 29(th) Street, New York, NY 10016, USA.
⁵ Department of Natural Sciences, University of South Carolina Beaufort, 1 University Boulevard, Bluffton, SC 29909, USA. Electronic address: edantonio@uscb.edu.

PMID: 34174398
DOI: 10.1016/j.bmcl.2021.128227

Abstract

Eighteen amino sugar analogues were screened against Trypanosoma cruzi glucokinase (TcGlcK), a potential drug-target of the protozoan parasite in order to assess for viable enzyme inhibition. The analogues were divided into three amino sugar scaffolds that included d-glucosamine (d-GlcN), d-mannosamine (d-ManN), and d-galactosamine (d-GalN); moreover, all but one of these compounds were novel. TcGlcK is an important metabolic enzyme that has a role in producing G6P for glycolysis and the pentose phosphate pathway (PPP). The inhibition of these pathways via glucose kinases (i.e., glucokinase and hexokinase) appears to be a strategic approach for drug discovery. Glucose kinases phosphorylate d-glucose with co-substrate ATP to yield G6P and the formed G6P enters both pathways for catabolism. The compound screen revealed five on-target confirmed inhibitors that were all from the d-GlcN series, such as compounds 1, 2, 4, 5, and 6. Four of these compounds were strong TcGlcK inhibitors (1, 2, 4, and 6) since they were found to have micromolar inhibitory constant (K_i) values around 20 μM. Three of the on-target confirmed inhibitors (1, 5, and 6) revealed notable in vitro anti-T. cruzi activity with IC₅₀ values being less than 50 μM. Compound 1 was benzoyl glucosamine (BENZ-GlcN), a known TcGlcK inhibitor that was the starting point for the design of the compounds in this study; in addition, TcGlcK - compound 1 inhibition properties were previously determined [D'Antonio, E. L. et al. (2015) Mol. Biochem. Parasitol. 204, 64-76]. As such, compounds 5 and 6 were further evaluated biochemically, where formal K_i values were determined as well as their mode of TcGlcK inhibition. The K_i values determined for compounds 5 and 6 were 107 ± 4 μM and 15.2 ± 3.3 μM, respectively, and both of these compounds exhibited the competitive inhibition mode.

Keywords: Amino sugars; Chagas’ disease; Glucokinase; Inhibitors; Neglected tropical diseases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Sugars / chemical synthesis
Amino Sugars / chemistry
Amino Sugars / pharmacology*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Glucokinase / antagonists & inhibitors*
Glucokinase / metabolism
Molecular Structure
Structure-Activity Relationship
Trypanosoma cruzi / enzymology*

Substances

Amino Sugars
Enzyme Inhibitors
Glucokinase