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

• Published in: ACS medicinal chemistry letters Vol. 14; no. 5; pp. 621 - 628
• Main Authors: Chan, Alex H. Y., Ho, Terence C. S., Fathoni, Imam, Pope, Rebecca, Saliba, Kevin J., Leeper, Finian J.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.05.2023; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; thiamine diphosphate; metal-binding group; enzyme inhibition; malaria; DESIGN; MECHANISM
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.3c00047

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.