Analogues of N3-Pyridyl Thiamine: Biochemical Evaluation, Computational Analysis, and Anti-plasmodial Activity

Thiamine is metabolized into the coenzyme thiamine pyrophosphate (TPP). Interruption of thiamine utilization results in disease states. Oxythiamine is an anti-thiamine which enters cells through transporters, undergoes enzymatic phosphorylation, and then inhibits TPP-dependent enzymes. In 2013, oxythiamine was used as a chemical tool to establish the thiamine utilization pathway as a drug target for the development of anti-malarial agents. More recently, we discovered another anti-thiamine compound, N3-pyridyl thiamine (N3PT), which shares a similar mode of action against Plasmodium with oxythiamine, while exhibiting greater potency and lower toxicity. Given its promising potential as an anti-malarial agent, we designed and synthesised analogues of N3PT in this study and then profiled their inhibition of TPP-dependent enzymes and of P. falciparum proliferation.