Disclosed herein is a pharmacophore model for antimalarial activity and methods of making and using thereof. The pharmacophore comprises two hydrogen bond acceptor (lipid) functions and two hydrophobic (aromatic) functions. The pharmacophore model was made using a test set of tryptanthrin compounds which exhibit antimalarial activity. Also disclosed are tryptanthrin compounds having greater solubility and bioactivity as compared to prior art tryptanthrin compounds and methods of making and using thereof. Also disclosed are methods of treating malaria in a subject.