Dihydroartemisinin-stachyose conjugate (sDHA) improves the oral bioavailability of dihydroartemisinin and antiemphalitic malaria effects.

A dihydroartemisinin (DHA)-stachyose conjugate (sDHA) was synthesized via succinate ester linkage to enhance solubility and anti-cerebral malaria efficacy. Structural characterization (FT-IR, 1H NMR) confirmed a 1:1 M ratio. sDHA exhibited 55, 86, and 66 fold higher saturated solubility in water, simulated gastric fluid, and intestinal fluid (4.68 ± 0.36, 13.74 ± 1.07, and 10.62 ± 0.78 mg/mL) than free DHA, with a critical micelle concentration of 1.91 ± 0.32 mg/mL. In rats, oral sDHA achieved a 3.71-fold higher AUC0-12h(14.56 ± 1.23 vs. 3.93 ± 0.41 μg·h/mL) and 2.75-fold longer absorption half-life (t1/2α: 3.37 ± 0.28 vs. 1.22 ± 0.15 h) versus DHA. In Plasmodium-infected mice, high-dose sDHA reduced parasitemia by 60% versus controls, lowered mortality by 33%-40%, extended survival by 26%-50%, and alleviated neurobehavioral deficits. This excipient-free oligosaccharide conjugate offers a translatable strategy for improving BCS IV antimalarial drugs.