Design and Discovery of 3,6-Substituted 1,2,4,5-Tetraoxanes as New Class of Falcipain-2 Inhibitors for Antimalarial Action

Abstract

A new series of tetraoxanes were developed and screened for in vitro antimalarial activity against chloroquine sensitive strains of Plasmodium falciparum (3D7 and RKL-2) and chloroquine resistant strain of P. falciparum (RKL-9). Among the synthesized derivatives, few compounds showed mild to moderate activity against the parasites as compared to a standard drug. The test results revealed two compounds, 5a (3,3,6-trimethyl-1,2,4,5-tetraoxane) and 5k (3,3-dimethyl-6,6-diphenyl-1,2,4,5-tetraoxane) possessing significant activity against chloroquine sensitive 3D7 strain (IC₅₀ = 1.953 ± 0.020 μg/mL) and RKL-2 strain (IC₅₀ = 3.906 ± 0.010 μg/mL). At the same time, only compound 5j (3-methyl-3,6,6-triphenyl-1,2,4,5-tetraoxane) showed superior activity against chloroquine resistant RKL-9 strain (IC₅₀ = 3.906 ± 0.006 μg/mL) in in contrast to all other derivatives of the set studied. In order to elucidate the vital drug interaction with falcipain-2 (FP-2), docking studies of potent ligands were performed.