title: Synthesis, biological evaluation and molecular modeling of 2-Hydroxyisoquinoline-1,3-dione analogues as inhibitors of HIV reverse transcriptase associated ribonuclease H and polymerase.
abstract: Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not clinically validated as an antiviral target. 2-Hydroxyisoquinoline-1,3-dione (HID) is known to confer active site directed inhibition of divalent metal-dependent enzymatic functions, such as HIV RNase H, integrase (IN) and hepatitis C virus (HCV) NS5B polymerase. We report herein the synthesis and biochemical evaluation of a few C-5, C-6 or C-7 substituted HID subtypes as HIV RNase H inhibitors. Our data indicate that while some of these subtypes inhibited both the RNase H and polymerase (pol) functions of RT, potent and selective RNase H inhibition was achieved with subtypes 8-9 as exemplified with compounds 8c and 9c.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Tang
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Sanjeev Kumar V
authors.initials: SKV
authors.lastname: Vernekar
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Yue-Lei
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Department of Microbiology & Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
authors.forename: Lena
authors.initials: L
authors.lastname: Miller
authors.affiliation: Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA; Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Huber
authors.affiliation: Department of Natural Science, Chatham University, 1 Woodland Road, Pittsburgh, PA 15232, USA.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Myshakina
authors.affiliation: Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA; Department of Molecular Microbiology & Immunology, University of Missouri School of Medicine, Columbia, MO 65211, USA; Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Sarafianos
authors.affiliation: Department of Microbiology & Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Parniak
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: wangx472@umn.edu.
authors.forename: Zhengqiang
authors.initials: Z
authors.lastname: Wang
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D016914:Ribonuclease H / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C558516:2-hydroxyisoquinoline-1,3(2H,4H)-dione; D019380:Anti-HIV Agents; D007546:Isoquinolines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H
keywords: 2-hydroxyisoquinoline-1,3-diones; HIV; Inhibitor; RNase H; Reverse transcriptase