Design, Synthesis, and Biological Evaluations of Hydroxypyridonecarboxylic Acids as Inhibitors of HIV Reverse Transcriptase Associated RNase H.
Targeting the clinically unvalidated reverse transcriptase (RT) associated ribonuclease H (RNase H) for human immunodeficiency virus (HIV) drug discovery generally entails chemotypes capable of chelating two divalent metal ions in the RNase H active site. The hydroxypyridonecarboxylic acid scaffold has been implicated in inhibiting homologous HIV integrase (IN) and influenza endonuclease via metal chelation. We report herein the design, synthesis, and biological evaluations of a novel variant of the hydroxypyridonecarboxylic acid scaffold featuring a crucial N-1 benzyl or biarylmethyl moiety. Biochemical studies show that most analogues consistently inhibited HIV RT-associated RNase H in the low micromolar range in the absence of significant inhibition of RT polymerase or IN. One compound showed reasonable cell-based antiviral activity (EC50 = 10 μM). Docking and crystallographic studies corroborate favorable binding to the active site of HIV RNase H, providing a basis for the design of more potent analogues.
Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Jayakanth
J
Kankanala
Department of Molecular Microbiology and Immunology and Department of Biochemistry, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center , Columbia, Missouri 65211, United States.
Karen A
KA
Kirby
Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Feng
F
Liu
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania 15219, United States.
Lena
L
Miller
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania 15219, United States.
Eva
E
Nagy
Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Daniel J
DJ
Wilson
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania 15219, United States.
Michael A
MA
Parniak
Department of Molecular Microbiology and Immunology and Department of Biochemistry, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center , 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
D003503:Cyclobutanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054309:Ribonuclease H, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C000619432:3-(hydroxy(pyridin-2-yl)methyl)-1-methyl-3-(4-(trifluoromethyl)pyridin-2-yl)cyclobutanol; D003503:Cyclobutanes; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D054309:Ribonuclease H, Human Immunodeficiency Virus