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

Journal of Medicinal Chemistry
Sanjeev Kumar V VernekarZhengqiang Wang

Abstract

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.

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Citations

Jul 4, 2018·ChemMedChem·Jayakanth KankanalaZhengqiang Wang
Aug 2, 2017·Antimicrobial Agents and Chemotherapy·Karen A KirbyStefan G Sarafianos
Oct 27, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Serena MassariOriana Tabarrini
Dec 2, 2018·Future Medicinal Chemistry·Shaoyong KeYanhong Wei
Apr 20, 2019·Medicinal Research Reviews·Xiangyi JiangPeng Zhan
Mar 11, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jenny DesantisOriana Tabarrini
Jan 29, 2021·Chemical Reviews·Maria E CilentoStefan G Sarafianos

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