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Human cytomegalovirus terminase complex cleaves the concatemeric genomic viral DNA into unit lengths during genome packaging and particle assembly. Terminase complex ATPase and endonuclease activity is provided by the viral protein pUL89. pUL89 is an attractive drug target because its activities are required for infectious virus production. A domain located in the C-terminus of pUL89 has an RNase H/integrase-like fold and endonuclease activity that can be inhibited by compounds featuring a chelating triad motif. Previously, we developed a novel ELISA approach to screen for pUL89 inhibitors. In this report, we used the ELISA to identify 3-hydroxypyrimidine-2,4-dione as a promising scaffold for pUL89 inhibitor development. Several potent pUL89 inhibitors yielded low micromolar IC50 values in the enzymatic assay and low micromolar EC50 values for inhibition of HCMV replication. Two representative compounds inhibitory effects depended upon metal ions and occurred late in virus replication consistent with pUL89 inhibitors in infected cells.Metal chelating 3-Hydroxypyrimidine-2,4-diones inhibited HCMV pUL89 endonuclease activity in a biochemical assay.A subset of the enzyme inhibitors also inhibited HCMV replication.Select inhibitors acted late in HCMV replication and inhibited viral genome cleavage, characteristics of pUL89 inhibitors.The 3-Hydroxypyrimidine-2,4-diones are a promising scaffold for pUL89 and HCMV inhibitor discovery and development.