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

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

doi:10.1016/j.ejmech.2017.01.041

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

Journal Article · Mon Jan 30 00:00:00 EST 2017 · European Journal of Medicinal Chemistry

DOI:https://doi.org/10.1016/j.ejmech.2017.01.041· OSTI ID:1349118

Tang, Jing ^[1]; Kirby, Karen A. ^[2]; Huber, Andrew D. ^[2]; Casey, Mary C. ^[2]; Ji, Juan ^[2]; Wilson, Daniel J. ^[1]; Sarafianos, Stefan G. ^[2]; Wang, Zhengqiang ^[1]

Univ. of Minnesota, Minneapolis, MN (United States)
Univ. of Missouri School of Medicine, Columbia, MO (United States)

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. Here, 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.

View Accepted Manuscript (DOE)

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:: 1349118

Alternate ID(s):: OSTI ID: 1419352

Journal Information:: European Journal of Medicinal Chemistry, Journal Name: European Journal of Medicinal Chemistry Journal Issue: C Vol. 128; ISSN 0223-5234

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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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

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