Synthesis, biological evaluation and molecular modeling of 2-Hydroxyisoquinoline-1,3-dione analogues as inhibitors of HIV reverse transcriptase associated ribonuclease H and polymerase

Jing Tang; Sanjeev Kumar V. Vernekar; Yue Lei Chen; Lena Miller; Andrew D. Huber; Nataliya Myshakina; Stefan G. Sarafianos; Michael A. Parniak; Zhengqiang Wang

doi:10.1016/j.ejmech.2017.03.059

Synthesis, biological evaluation and molecular modeling of 2-Hydroxyisoquinoline-1,3-dione analogues as inhibitors of HIV reverse transcriptase associated ribonuclease H and polymerase

Jing Tang, Sanjeev Kumar V. Vernekar, Yue Lei Chen, Lena Miller, Andrew D. Huber, Nataliya Myshakina, Stefan G. Sarafianos, Michael A. Parniak, Zhengqiang Wang

Center for Drug Design

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not clinically validated as an antiviral target. 2-Hydroxyisoquinoline-1,3-dione (HID) is known to confer active site directed inhibition of divalent metal-dependent enzymatic functions, such as HIV RNase H, integrase (IN) and hepatitis C virus (HCV) NS5B polymerase. We report herein the synthesis and biochemical evaluation of a few C-5, C-6 or C-7 substituted HID subtypes as HIV RNase H inhibitors. Our data indicate that while some of these subtypes inhibited both the RNase H and polymerase (pol) functions of RT, potent and selective RNase H inhibition was achieved with subtypes 8–9 as exemplified with compounds 8c and 9c.

Original language	English (US)
Pages (from-to)	85-96
Number of pages	12
Journal	European Journal of Medicinal Chemistry
Volume	133
DOIs	https://doi.org/10.1016/j.ejmech.2017.03.059
State	Published - 2017

Bibliographical note

Funding Information:
This research was supported in part by the National Institutes of Health (AI100890 to SGS, MAP and ZW), and by the Research Development and Seed Grant Program of the Center for Drug Design, University of Minnesota.

Publisher Copyright:
© 2017 Elsevier Masson SAS

Keywords

2-hydroxyisoquinoline-1,3-diones
HIV
Inhibitor
RNase H
Reverse transcriptase

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejmech.2017.03.059

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539924

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Tang, J., Vernekar, S. K. V., Chen, Y. L., Miller, L., Huber, A. D., Myshakina, N., Sarafianos, S. G., Parniak, M. A., & Wang, Z. (2017). Synthesis, biological evaluation and molecular modeling of 2-Hydroxyisoquinoline-1,3-dione analogues as inhibitors of HIV reverse transcriptase associated ribonuclease H and polymerase. European Journal of Medicinal Chemistry, 133, 85-96. https://doi.org/10.1016/j.ejmech.2017.03.059

Synthesis, biological evaluation and molecular modeling of 2-Hydroxyisoquinoline-1,3-dione analogues as inhibitors of HIV reverse transcriptase associated ribonuclease H and polymerase. / Tang, Jing; Vernekar, Sanjeev Kumar V.; Chen, Yue Lei et al.

In: European Journal of Medicinal Chemistry, Vol. 133, 2017, p. 85-96.

Research output: Contribution to journal › Article › peer-review

Tang, J, Vernekar, SKV, Chen, YL, Miller, L, Huber, AD, Myshakina, N, Sarafianos, SG, Parniak, MA & Wang, Z 2017, 'Synthesis, biological evaluation and molecular modeling of 2-Hydroxyisoquinoline-1,3-dione analogues as inhibitors of HIV reverse transcriptase associated ribonuclease H and polymerase', European Journal of Medicinal Chemistry, vol. 133, pp. 85-96. https://doi.org/10.1016/j.ejmech.2017.03.059

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AU - Myshakina, Nataliya

AU - Sarafianos, Stefan G.

AU - Parniak, Michael A.

AU - Wang, Zhengqiang

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AB - Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not clinically validated as an antiviral target. 2-Hydroxyisoquinoline-1,3-dione (HID) is known to confer active site directed inhibition of divalent metal-dependent enzymatic functions, such as HIV RNase H, integrase (IN) and hepatitis C virus (HCV) NS5B polymerase. We report herein the synthesis and biochemical evaluation of a few C-5, C-6 or C-7 substituted HID subtypes as HIV RNase H inhibitors. Our data indicate that while some of these subtypes inhibited both the RNase H and polymerase (pol) functions of RT, potent and selective RNase H inhibition was achieved with subtypes 8–9 as exemplified with compounds 8c and 9c.

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Synthesis, biological evaluation and molecular modeling of 2-Hydroxyisoquinoline-1,3-dione analogues as inhibitors of HIV reverse transcriptase associated ribonuclease H and polymerase

Abstract

Bibliographical note

Keywords

UN SDGs

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