Evaluation of ferrocenyl-containing ?-hydroxy-?-lactam-derived tetramates as potential antiplasmodials

A series of ferrocenyl-containing gamma-hydroxy-gamma-lactam tetramates were prepared in 2-3 steps through ring opening-ring closure (RORC) process of gamma-ylidene-tetronate derivatives in the presence of ferrocenyl alkylamines. The compounds were screened in vitro for their antiplasmodial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) clones of P. falciparum, displaying activity in the range of 0.12-100 mu M, with generally good resistance index. The most active ferrocene in these series exhibited IC50 equal to 0.09 mu M (3D7) and 0.12 mu M (W2). The low cytotoxicity of the ferrocenyl-containing gamma-hydroxy-gamma-lactam tetramates against Human Umbilical Vein Endothelial (HUVEC) cell line demonstrated selective antiparasitic activity. The redox properties of these ferrocene-derived tetramates were studied and physico-biochemical studies evidenced that these derivatives can exert potent antimalarial activities via a mechanism distinct from ferroquine.

Automated summary

A series of ferrocenyl-containing gamma-hydroxy-gamma-lactam tetramates were prepared through a ring opening-ring closure process in the presence of ferrocenyl alkylamines. These compounds exhibited good antiplasmodial activity and selective antiparasitic activity.