7-Chloro-4-aminoquinoline γ-hydroxy-γ-lactam derived-tetramates as a new family of antimalarial compounds

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

“…Ferrocenyl-containing -tetramates 20-28 and derivatized-lactams 31-33, 35-37 were evaluated against CQ-sensitive (3D7) and CQ-resistant (W2) clones of P. falciparum (Tables 2-4) (Table S1, ESI) [8,19]. All experiments were carried out twice in assays with drug concentrations in triplicate.…”

“…The current recommended first-line malaria treatment in most endemic areas are artemisinin-based combined therapies (ACTs) [7]. In our current research program directed towards the synthesis and biological evaluation of new antimalarials, we have previously reported on the synthesis of a set of hydroxy--lactam derived-tetramates bearing a 7-chloro-4-aminoquinoline skeleton of general structure 1 [8]. In vitro antimalarial activity of these new -lactams was measured using P. falciparum clones [9] of different sensitivities (3D7 and W2) and they were found to be active in the range of 14-827 nM with generally good resistance index.…”

“…While synthetic antimalarials having a -lactam or pyrrolone skeleton have been scarcely explored [10], one can argue that molecules of general structure 1 are chloroquine-like structures and they may in part act through inhibition of hemozoin formation [11] as CQ. Since these tetramates are obtained easily through ring opening-ring closure (RORC) process of readily available -ylidene-tetronates [12] in the presence of amines [8], our next goal was to screen synthetic or commercially available amines in an effort to identify new potent tetramates not bearing a 4-aminoquinoline skeleton. From these screening experiments, ferrocenylcontaining -hydroxy--lactam tetramates were discovered as the most potent molecules.…”