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.
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.
Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
Jing
J
Tang
Department of Molecular Microbiology and Immunology and Department of Biochemistry, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center, Columbia, MO 65211, USA.
Karen A
KA
Kirby
Department of Molecular Microbiology and Immunology and Department of Biochemistry, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center, Columbia, MO 65211, USA.
Andrew D
AD
Huber
Department of Molecular Microbiology and Immunology and Department of Biochemistry, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center, Columbia, MO 65211, USA.
Mary C
MC
Casey
Department of Molecular Microbiology and Immunology and Department of Biochemistry, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center, Columbia, MO 65211, USA.
Juan
J
Ji
Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
Daniel J
DJ
Wilson
Department of Molecular Microbiology and Immunology and Department of Biochemistry, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center, Columbia, MO 65211, USA.
Stefan G
SG
Sarafianos
Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: wangx472@umn.edu.
Zhengqiang
Z
Wang
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D003460:Crystallization; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D016133:Polymerase Chain Reaction; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D054309:Ribonuclease H, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
C000617096:6-cyclohexylmethyl-3-hydroxypyrimidine-2,4-dione; D019380:Anti-HIV Agents; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil; D054303:HIV Reverse Transcriptase; D054309:Ribonuclease H, Human Immunodeficiency Virus
3-Hydroxypyrimidine-2,4-dione (HPD); Human immunodeficiency virus (HIV); Inhibitors; Polymerase; RNase H