Newer series of trioxane derivatives as potent antimalarial agents.

Among synthesized 1,2,4-trioxane derivatives, six compounds were found to be considerably potent, with better activity against resistant strain of <italic>P. falciparum</italic> than the sensitive strain. The IC₅₀ values of the best compound with 4-hydroxyphenyl substitution were found to be 0.391 and 0.837 µg/mL against sensitive and resistant strain of <italic>P. falciparum</italic>, respectively. Results of the tested compounds were comparable with that of the standard drug, chloroquine (IC₅₀ = 0.044 and 0.205 µg/mL against sensitive and resistant strain of <italic>P. falciparum</italic>, respectively). Docking simulation, in silico drug-likeness and ADMET studies further validated the results of in vitro antimalarial activity. Trioxane derivatives exhibited good binding affinity for the <italic>P. falciparum</italic> cysteine protease falcipain 2 receptor (PDB id: 3BPF) with well defined drug-like and pharmacokinetic properties based on Lipinski’s rule of five with additional physicochemical and ADMET parameters. In view of having antimalarial potential, newly reported 1,2,4-trioxane derivative(s) may be useful as novel antimalarial lead(s) in the discovery and development of future antimalarial drug candidates as <italic>P. falciparum</italic> falcipain 2 inhibitors against resistant malaria. [ABSTRACT FROM AUTHOR]