Study of the naturally occurring lignan brachangobinan A as antiplasmodial agent: Synthesis, biological evaluation, and in silico prediction

This study focused on the synthesis, structural validation, and evaluation of the antiplasmodial efficacy of brachangobinan A (BA) and its enantiomers, (+)-BA and (-)-BA, as potential antimalarial agents. BA, (+)-BA, and (-)-BA were synthesized through chemical processes and validated via advanced spectroscopic techniques. In vitro studies were conducted to assess their efficacy against Plasmodium falciparum strains 3D7 and K1 by determining their half maximal inhibitory concentration (IC₅₀) values, cytotoxicity profiles, and selectivity indices. Additional evaluations examined the impacts of exposure to these compounds on stage-specific effects, parasite morphology, and parasitemia levels, as well as potential mechanisms of action through in silico drug target prediction and molecular docking simulations. In vivo efficacy was tested in a mouse model of malaria caused by P. yoelii 17XNL. The results revealed that BA, (+)-BA, and (-)-BA exhibited promising in vitro antiplasmodial activity and selectivity, inducing morphological changes and demonstrating cidal effects. Drug-likeness predictions indicated favorable safety profiles but challenges in terms of bioavailability. In silico analyses identified Pf HSP90, Pf CDK2H, and Pf MAPK as key targets of (+)-BA and (-)-BA. In vivo studies confirmed the efficacy of BA in reducing parasitemia levels (trial 1: 19.72 %; trial 2: 15.00 %) compared with the untreated group (trial 1: 29.95 %; trial 2: 28.27 %) without adverse effects. These findings suggest that BA and its enantiomers have potential as seed compounds for development of antimalarial agents.