Design and synthesis of novel 1,2,4,5-tetraoxane derivatives as a chemotherapeutic approach against malaria.

Malaria continues to be a profound global health problem, with escalating drug resistance in Plasmodium falciparum paving way for the necessity of affordable synthetic antimalarial agents. A virtual library of 300 tetraoxane derivatives was designed and subjected to in silico ADMET and molecular docking against falcipain-2 (PDB: 3BPF). Seven classified drug candidates (KD-1 to KD-7) were synthesised via two-step acid-catalyzed cyclic condensation of gem-dihydroperoxides. These compounds were evaluated in vitro against chloroquine-resistant (PfRKL-9) and chloroquine-sensitive (Pf3D7) strains. All derivatives exhibited inhibition dose-dependently, with KD-7 demonstrating the highest potency, followed by KD-1 and KD-2. Microscopic observation indicated effective inhibition of parasite development at the schizont stage. Although the synthesised scaffolds currently demonstrate promising foundational activity, this work unlocks an opportunity to scrutinise structural flexibility with synthetic approaches for further optimisation to combat the escalating trend of antimalarial resistance.