Double-Winged 3‑Hydroxypyrimidine-2,4-diones: Potent and Selective Inhibition against HIV‑1 RNase H with Significant Antiviral Activity

Human immunodeficiency virus (HIV)
reverse transcriptase (RT)-associated
ribonuclease H (RNase H) remains the only virally encoded enzymatic
function yet to be exploited as an antiviral target. One of the possible
challenges may be that targeting HIV RNase H is confronted with a
steep substrate barrier. We have previously reported a 3-hydroxypyrimidine-2,4-dione
(HPD) subtype that potently and selectively inhibited RNase H without
inhibiting HIV in cell culture. We report herein a critical redesign
of the HPD chemotype featuring an additional wing at the C5 position
that led to drastically improved RNase H inhibition and significant
antiviral activity. Structure–activity relationship (SAR) concerning
primarily the length and flexibility of the two wings revealed important
structural features that dictate the potency and selectivity of RNase
H inhibition as well as the observed antiviral activity. Our current
medicinal chemistry data also revealed that the RNase H biochemical
inhibition largely correlated the antiviral activity.