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 neededin
vivobecause 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 ofPlasmodium falciparumproliferation. We demonstrate
how the cellular thiamine-utilization pathway can be probed by using
our compounds and oxythiamine in parallel.