6-Cyclohexylmethyl-3-hydroxypyrimidine-2,4-dione as an inhibitor scaffold of HIV reverase transcriptase: Impacts of the 3-OH on inhibiting RNase H and polymerase

Jing Tang, Karen A. Kirby, Andrew D. Huber, Mary C. Casey, Juan Ji, Daniel J. Wilson, Stefan G. Sarafianos, Zhengqiang Wang

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


3-Hydroxypyrimidine-2,4-dione (HPD) represents a versatile chemical core in the design of inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H and integrase strand transfer (INST). We report herein the design, synthesis and biological evaluation of an HPD subtype (4) featuring a cyclohexylmethyl group at the C-6 position. Antiviral testing showed that most analogues of 4 inhibited HIV-1 in the low nanomolar to submicromolar range, without cytotoxicity at concentrations up to 100 μM. Biochemically, these analogues dually inhibited both the polymerase (pol) and the RNase H functions of RT, but not INST. Co-crystal structure of 4a with RT revealed a nonnucleoside RT inhibitor (NNRTI) binding mode. Interestingly, chemotype 11, the synthetic precursor of 4 lacking the 3-OH group, did not inhibit RNase H while potently inhibiting pol. By virtue of the potent antiviral activity and biochemical RNase H inhibition, HPD subtype 4 could provide a viable platform for eventually achieving potent and selective RNase H inhibition through further medicinal chemistry.

Original languageEnglish (US)
Pages (from-to)168-179
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
StatePublished - 2017

Bibliographical note

Funding Information:
This research was supported by the National Institutes of Health (AI100890) and partially by 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.

Publisher Copyright:
© 2017 Elsevier Masson SAS


  • 3-Hydroxypyrimidine-2,4-dione (HPD)
  • Human immunodeficiency virus (HIV)
  • Inhibitors
  • Polymerase
  • RNase H


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