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

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

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

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. Crystallographic and molecular modeling studies confirmed the RNase H active site binding mode.

Original languageEnglish (US)
Pages (from-to)149-161
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume141
DOIs
StatePublished - Dec 1 2017

Bibliographical note

Funding Information:
This research was supported in part by the National Institutes of Health ( AI100890 to SGS and ZW), and by the Research Development and Seed Grant Program of the Center for Drug Design, University of Minnesota . Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy ( DOE ) Office of Science by Argonne National Laboratory , was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357 . We also thank Drs. Michail Isupov and Ronan Keegan of BioMEX Solutions, Inc. for assistance with structure solution and refinement. Appendix A

Publisher Copyright:
© 2017 Elsevier Masson SAS

Keywords

  • Human immunodeficiency virus (HIV)
  • Integrase strand transfer
  • Molecular modeling and crystallography
  • N-Hydroxy thienopyrimidine-2,4-diones
  • RNase H
  • RT-Polymerase

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