Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 141, Issue -, Pages 149-161Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.09.054
Keywords
N-Hydroxy thienopyrimidine-2,4-diones; Human immunodeficiency virus (HIV); RNase H; Integrase strand transfer; RT-Polymerase; Molecular modeling and crystallography
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Funding
- National Institutes of Health [AI100890]
- Center for Drug Design, University of Minnesota
- U.S. DOE [DE-AC02-06CH11357]
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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 mu M) with decent antiviral potency (EC50 = 7.4 mu M) and no cytotoxicity (CC50 > 100 mu M). In extended biochemical assays compound lid did not inhibit RT polymerase (pol) while inhibiting integrase strand transfer (INST) with 53 fold lower potency (IC50 = 2.1 mu M) than RNase H inhibition. Crystallographic and molecular modeling studies confirmed the RNase H active site binding mode. (C) 2017 Elsevier Masson SAS. All rights reserved.
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