To achieve malaria eradication, new preventative agents that act differently to front-line treatment drugs are needed. To identify potential chemoprevention starting points we screened a sub-set of the CSIRO Australia Compound Collection for compounds with slow-action in vitro activity against Plasmodium falciparum. This work identified N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines as a new antiplasmodial chemotype (e.g., 1 96 h IC50 550 nM) with a different action to delayed-death slow-action drugs. Structure activity relationship analysis of analogues identified multiple compounds with potent and selective in vitro activity against drug-sensitive and multi-drug resistant Plasmodium parasites (e.g., 31 and 32 96 h IC50 <40 nM; SI >2,500). However subsequent studies in mice with lead compound 1, which had the best microsomal stability of the compounds assessed, demonstrated rapid clearance (T1/2 <1.6 h) and poor oral in vivo efficacy. This indicates that improvements in the pharma-cokinetic profile of N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines would be needed for the development of this chemotype for malaria chemoprophylaxis.