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Inhibition of Thiamine Diphosphate-Dependent Enzymes by Triazole-Based Thiamine Analogues.

Published version
Peer-reviewed

Repository DOI


Type

Article

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Authors

Chan, Alex HY 
Ho, Terence CS 
Pope, Rebecca 

Abstract

Thiamine is metabolized into the coenzyme thiamine diphosphate (ThDP). Interrupting thiamine utilization leads to disease states. Oxythiamine, a thiamine analogue, is metabolized into oxythiamine diphosphate (OxThDP), which inhibits ThDP-dependent enzymes. Oxythiamine has been used to validate thiamine utilization as an anti-malarial drug target. However, high oxythiamine doses are needed in vivo because of its rapid clearance, and its potency decreases dramatically with thiamine levels. We report herein cell-permeable thiamine analogues possessing a triazole ring and a hydroxamate tail replacing the thiazolium ring and diphosphate groups of ThDP. We characterize their broad-spectrum competitive inhibition of ThDP-dependent enzymes and of Plasmodium falciparum proliferation. We demonstrate how the cellular thiamine-utilization pathway can be probed by using our compounds and oxythiamine in parallel.

Description

Funder: K.M. Medhealth

Keywords

thiamine diphosphate, enzyme inhibition, metal-binding group, malaria

Journal Title

ACS Med Chem Lett

Conference Name

Journal ISSN

1948-5875
1948-5875

Volume Title

14

Publisher

American Chemical Society (ACS)