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

Published version

Published version
Repository DOI

Change log
Chan, Alex HY 
Ho, Terence CS 
Pope, Rebecca 

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.

thiamine diphosphate, enzyme inhibition, metal-binding group, malaria
Is Part Of
K.M. Medhealth (NA)