We report the discovery of novel uracil-based acyclic compounds as inhibitors of deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), an enzyme involved in nucleotide metabolism that has been identified as a promising target for the development of antimalarial drugs. Compounds were assayed against both P.falciparum dUTPase and intact parasites. A good correlation was observed between enzyme inhibition and cellular assays. Acyclic uracil derivatives were identified that showed greater or similar potency and in general increased selectivity compared to previously reported inhibitors. The most active compound reported here against the P. falciparum enzyme had a K(i) of 0.2 microM. Molecular modeling studies provided a good rationale for the observed activities. Preliminary ADME studies indicated that some of the lead compounds are drug-like molecules. These compounds are useful tools for further investigating P. falciparum dUTPase for the development of much-needed novel antimalarial drugs.