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 journalArticle

8 Scopus citations

Abstract

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
Volume128
DOIs
StatePublished - 2017

Keywords

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

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