6-Biphenylmethyl-3-hydroxypyrimidine-2,4-diones potently and selectively inhibited HIV reverse transcriptase-associated RNase H

Lei Wang; Jing Tang; Andrew D. Huber; Mary C. Casey; Karen A. Kirby; Daniel J. Wilson; Jayakanth Kankanala; Michael A. Parniak; Stefan G. Sarafianos; Zhengqiang Wang

doi:10.1016/j.ejmech.2018.07.035

6-Biphenylmethyl-3-hydroxypyrimidine-2,4-diones potently and selectively inhibited HIV reverse transcriptase-associated RNase H

Lei Wang, Jing Tang, Andrew D. Huber, Mary C. Casey, Karen A. Kirby, Daniel J. Wilson, Jayakanth Kankanala, Michael A. Parniak, Stefan G. Sarafianos, Zhengqiang Wang

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Abstract

Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains an unvalidated drug target. Reported HIV RNase H inhibitors generally lack significant antiviral activity. We report herein the design, synthesis, biochemical and antiviral evaluations of a new 6-biphenylmethyl subtype of the 3-hydroxypyrimidine-2,4-dione (HPD) chemotype. In biochemical assays, analogues of this new subtype potently inhibited RT RNase H in low nanomolar range without inhibiting RT polymerase (pol) or integrase strand transfer (INST) at the highest concentrations tested. In cell-based assays, a few analogues inhibited HIV in low micromolar range without cytotoxicity at concentrations up to 100 μM.

Original language	English (US)
Pages (from-to)	680-691
Number of pages	12
Journal	European Journal of Medicinal Chemistry
Volume	156
DOIs	https://doi.org/10.1016/j.ejmech.2018.07.035
State	Published - Aug 5 2018

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Masson SAS

Keywords

3-Hydroxypyrimidine-2,4-dione (HPD)
Human immunodeficiency virus (HIV)
Inhibitors
RNase H
Structure-activity-relationship (SAR)

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10.1016/j.ejmech.2018.07.035

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114935

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Wang, L., Tang, J., Huber, A. D., Casey, M. C., Kirby, K. A., Wilson, D. J., Kankanala, J., Parniak, M. A., Sarafianos, S. G., & Wang, Z. (2018). 6-Biphenylmethyl-3-hydroxypyrimidine-2,4-diones potently and selectively inhibited HIV reverse transcriptase-associated RNase H. European Journal of Medicinal Chemistry, 156, 680-691. https://doi.org/10.1016/j.ejmech.2018.07.035

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abstract = "Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains an unvalidated drug target. Reported HIV RNase H inhibitors generally lack significant antiviral activity. We report herein the design, synthesis, biochemical and antiviral evaluations of a new 6-biphenylmethyl subtype of the 3-hydroxypyrimidine-2,4-dione (HPD) chemotype. In biochemical assays, analogues of this new subtype potently inhibited RT RNase H in low nanomolar range without inhibiting RT polymerase (pol) or integrase strand transfer (INST) at the highest concentrations tested. In cell-based assays, a few analogues inhibited HIV in low micromolar range without cytotoxicity at concentrations up to 100 μM.",

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AU - Wang, Lei

AU - Tang, Jing

AU - Huber, Andrew D.

AU - Casey, Mary C.

AU - Kirby, Karen A.

AU - Wilson, Daniel J.

AU - Kankanala, Jayakanth

AU - Parniak, Michael A.

AU - Sarafianos, Stefan G.

AU - Wang, Zhengqiang

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AB - Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains an unvalidated drug target. Reported HIV RNase H inhibitors generally lack significant antiviral activity. We report herein the design, synthesis, biochemical and antiviral evaluations of a new 6-biphenylmethyl subtype of the 3-hydroxypyrimidine-2,4-dione (HPD) chemotype. In biochemical assays, analogues of this new subtype potently inhibited RT RNase H in low nanomolar range without inhibiting RT polymerase (pol) or integrase strand transfer (INST) at the highest concentrations tested. In cell-based assays, a few analogues inhibited HIV in low micromolar range without cytotoxicity at concentrations up to 100 μM.

KW - 3-Hydroxypyrimidine-2,4-dione (HPD)

KW - Human immunodeficiency virus (HIV)

KW - Inhibitors

KW - RNase H

KW - Structure-activity-relationship (SAR)

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ER -

6-Biphenylmethyl-3-hydroxypyrimidine-2,4-diones potently and selectively inhibited HIV reverse transcriptase-associated RNase H

Abstract

Bibliographical note

Keywords

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UN SDGs

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