Design, synthesis and biological evaluations of N-Hydroxy thienopyrimidine-2,4-diones as inhibitors of HIV reverse transcriptase-associated RNase H

Kankanala, Jayakanth; Kirby, Karen A.; Huber, Andrew D.; Casey, Mary C.; Wilson, Daniel J.; Sarafianos, Stefan G.; Wang, Zhengqiang

doi:10.1016/j.ejmech.2017.09.054

Title: Design, synthesis and biological evaluations of N-Hydroxy thienopyrimidine-2,4-diones as inhibitors of HIV reverse transcriptase-associated RNase H

Journal Article · Thu Sep 28 00:00:00 EDT 2017 · European Journal of Medicinal Chemistry

DOI:https://doi.org/10.1016/j.ejmech.2017.09.054· OSTI ID:1497210

Kankanala, Jayakanth ^[1]; Kirby, Karen A. ^[2]; Huber, Andrew D. ^[2]; Casey, Mary C. ^[2]; Wilson, Daniel J. ^[1]; Sarafianos, Stefan G. ^[2];

^[1]

Univ. of Minnesota, Minneapolis, MN (United States)
Univ. of Missouri, Columbia, MO (United States)

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only HIV enzymatic function not targeted by current antiviral drugs. Although various chemotypes have been reported to inhibit HIV RNase H, few have shown significant antiviral activities. We report herein the design, synthesis and biological evaluation of a novel N-hydroxy thienopyrimidine-2,3-dione chemotype (11) which potently and selectively inhibited RNase H with considerable potency against HIV-1 in cell culture. Current structure-activity-relationship (SAR) identified analogue 11d as a nanomolar inhibitor of RNase H (IC₅₀ = 0.04 μM) with decent antiviral potency (EC₅₀ = 7.4 μM) and no cytotoxicity (CC₅₀ > 100 μM). In extended biochemical assays compound 11d did not inhibit RT polymerase (pol) while inhibiting integrase strand transfer (INST) with 53 fold lower potency (IC₅₀ = 2.1 μM) than RNase H inhibition. Furthermore, crystallographic and molecular modeling studies confirmed the RNase H active site binding mode.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Inst. of Health

Grant/Contract Number:: AC02-06CH11357; AI100890

OSTI ID:: 1497210

Alternate ID(s):: OSTI ID: 1549288

Journal Information:: European Journal of Medicinal Chemistry, Vol. 141, Issue C; ISSN 0223-5234

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 34 works

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59 BASIC BIOLOGICAL SCIENCES
N-Hydroxy thienopyrimidine-2
4-diones
human immunodeficiency virus (HIV)
RNase H
integrase strand transfer
RT-Polymerase
molecular modeling and crystallography

Title: Design, synthesis and biological evaluations of N-Hydroxy thienopyrimidine-2,4-diones as inhibitors of HIV reverse transcriptase-associated RNase H

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