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

Journal Article · · European Journal of Medicinal Chemistry
 [1];  [2];  [2];  [2];  [1];  [2];  [1]
  1. Univ. of Minnesota, Minneapolis, MN (United States)
  2. Univ. of Missouri, Columbia, MO (United States)
+ Show Author Affiliations
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.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Inst. of Health; USDOE Office of Science (SC)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1497210
Alternate ID(s):
OSTI ID: 1549288
Journal Information:
European Journal of Medicinal Chemistry, Journal Name: European Journal of Medicinal Chemistry Journal Issue: C Vol. 141; ISSN 0223-5234
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (4)

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Hydroxypyridonecarboxylic Acids as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease journal July 2018
Regioselective B–H/C–H activation and metal–metal bond formation induced by half-sandwich metals complexes at hydroxy-substituted o -carboranes journal January 2018
Design, synthesis, and biologic evaluation of novel galloyl derivatives as HIV ‐1 RN ase H inhibitors journal January 2019

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Related Subjects

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