3-Hydroxypyrimidine-2,4-dione-5-N-benzylcarboxamides Potently Inhibit HIV-1 Integrase and RNase H.
Resistance selection by human immunodeficiency virus (HIV) toward known drug regimens necessitates the discovery of structurally novel antivirals with a distinct resistance profile. On the basis of our previously reported 3-hydroxypyrimidine-2,4-dione (HPD) core, we have designed and synthesized a new integrase strand transfer (INST) inhibitor type featuring a 5-N-benzylcarboxamide moiety. Significantly, the 6-alkylamino variant of this new chemotype consistently conferred low nanomolar inhibitory activity against HIV-1. Extended antiviral testing against a few raltegravir-resistant HIV-1 clones revealed a resistance profile similar to that of the second generation INST inhibitor (INSTI) dolutegravir. Although biochemical testing and molecular modeling also strongly corroborate the inhibition of INST as the antiviral mechanism of action, selected antiviral analogues also potently inhibited reverse transcriptase (RT) associated RNase H, implying potential dual target inhibition. In vitro ADME assays demonstrated that this novel chemotype possesses largely favorable physicochemical properties suitable for further development.
Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Bulan
B
Wu
Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Jing
J
Tang
Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Daniel J
DJ
Wilson
Department of Molecular Microbiology and Immunology and Department of Biochemistry, Christopher S. Bond Life Sciences Center, University of Missouri , Columbia, Missouri 65211, United States.
Andrew D
AD
Huber
Department of Molecular Microbiology and Immunology and Department of Biochemistry, Christopher S. Bond Life Sciences Center, University of Missouri , Columbia, Missouri 65211, United States.
Mary C
MC
Casey
Department of Molecular Microbiology and Immunology and Department of Biochemistry, Christopher S. Bond Life Sciences Center, University of Missouri , Columbia, Missouri 65211, United States.
Juan
J
Ji
Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Jayakanth
J
Kankanala
Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Jiashu
J
Xie
Department of Molecular Microbiology and Immunology and Department of Biochemistry, Christopher S. Bond Life Sciences Center, University of Missouri , Columbia, Missouri 65211, United States.
Stefan G
SG
Sarafianos
Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Zhengqiang
Z
Wang
D002460:Cell Line; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000502:physiology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D000068898:Raltegravir Potassium / Q000494:pharmacology; D016914:Ribonuclease H / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099226:Dolutegravir
D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011744:Pyrimidinones; D000068898:Raltegravir Potassium; D016914:Ribonuclease H; D000099226:Dolutegravir; C514801:p31 integrase protein, Human immunodeficiency virus 1