4,5-Dihydroxypyrimidine Methyl Carboxylates, Carboxylic Acids, and Carboxamides as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease

Human cytomegalovirus (HCMV) terminase
complex entails a metal-dependent
endonuclease at the C-terminus of pUL89 (pUL89-C). We report herein
the design, synthesis, and characterization of dihydroxy­pyr­imidine
(DHP) acid (14), methyl ester (13), and
amide (15) subtypes as inhibitors of HCMV pUL89-C. All
analogs synthesized were tested in an endonuclease assay and a thermal
shift assay (TSA) and subjected to molecular docking to predict binding
affinity. Although analogs inhibiting pUL89-C in the sub-μM
range were identified from all three subtypes, acids (14) showed better overall potency, substantially larger thermal shift,
and considerably better docking scores than esters (13) and amides (15). In the cell-based antiviral assay,
six analogs inhibited HCMV with moderate activities (EC50 = 14.4–22.8 μM). The acid subtype (14)
showed good in vitro ADME properties, except for
poor permeability. Overall, our data support the DHP acid subtype
(14) as a valuable scaffold for developing antivirals
targeting HCMV pUL89-C.