Exploring Heteroaromatic Rings as a Replacement for the Labile Amide of Antiplasmodial Pantothenamides

Malaria-causing Plasmodium parasites are developing
resistance to antimalarial drugs, providing the impetus for new antiplasmodials.
Although pantothenamides show potent antiplasmodial activity, hydrolysis
by pantetheinases/vanins present in blood rapidly inactivates them.
We herein report the facile synthesis and biological activity of a
small library of pantothenamide analogues in which the labile amide
group is replaced with a heteroaromatic ring. Several of these analogues
display nanomolar antiplasmodial activity against Plasmodium
falciparum and/or Plasmodium knowlesi, and are stable in the presence of pantetheinase. Both a known triazole
and a novel isoxazole derivative were further characterized and found
to possess high selectivity indices, medium or high Caco-2 permeability,
and medium or low microsomal clearance in vitro.
Although they fail to suppress Plasmodium berghei proliferation in vivo, the pharmacokinetic and
contact time data presented provide a benchmark for the compound profile
likely required to achieve antiplasmodial activity in mice and should
facilitate lead optimization.