Abstract Malaria parasite has developed resistance to the available and affordable drugs. The world health organization has recommended the use of artemisinin and artemisinin based combination therapy (ACT) for the treatment of chloroquine resistant uncomplicated malaria. The use of the artemisinins is challenged by short half life of the drugs due to the presence of endogenous superoxide dismutase which attacks the peroxide bond and a high rate of recrudescence. These research was aimed at isosteric structural modification of dihydroartemisinin by replacing the peroxide bond with disulphide, assessing the characteristics of the products formed and the in vivo antiplasmodial efficacy using mice. Pure dihydroartemisinin solution was chemically reduced using hydrogen generated in situ from zine pellet and dilute hydrochloric acid. Chloroform was used to extract the organic phase. The reduced product was dissolved in dimethylsulphoxide and oxidized using hydrogen sulphide gas. The melting point, boiling point as well as GC-MS properties of the original starting material dihydroartemisinin, the deoxy and disulphide derivatives were analyzed. They were also tested for their antiplasmodial efficacy using Plasmodium berghei berghei. The stability of the products was accessed by incubating them respectively in susperoxide dismutase dissolved in phosphate buffer. Thin layer chromatographic analysis on the three compound gave Rf values of 0.71 for pure dihydroartemisinin (DHA), 0.59 for deoxydihyroartemisinin (RDHA) and 0.61 for the disulphide-dihydroartemisinin (DDHA) respectively indicating they were different compound. The GC-MS molecular ion fragment was 284, 254 and 316 for pure DHA, RDHA and DDHA respectively. Stability tests showed that RDHA was most stable followed by DDHA while pure DHA was least stable. Acute toxicity study LD50 was 547.70mg/kg, 273.86mg/kg and 346.41mg/kg for DHA, RDHA and DDHA respectively. The sulphide derivative had antimalaria activity close to the reference DHA, but is more stable since it is not susceptible to the endogenous enzyme superoxide dismutase.