title: Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses.
abstract: Herpes simplex virus 1 (HSV-1) and HSV-2 remain major human pathogens despite the development of anti-HSV therapeutics as some of the first antiviral drugs. Current therapies are incompletely effective and frequently drive the evolution of drug-resistant mutants. We recently determined that certain natural troponoid compounds such as β-thujaplicinol readily suppress HSV-1 and HSV-2 replication. Here, we screened 26 synthetic α-hydroxytropolones with the goals of determining a preliminary structure-activity relationship for the α-hydroxytropolone pharmacophore and providing a starting point for future optimization studies. Twenty-five compounds inhibited HSV-1 and HSV-2 replication at 50 μM, and 10 compounds inhibited HSV-1 and HSV-2 at 5 μM, with similar inhibition patterns and potencies against both viruses being observed. The two most powerful inhibitors shared a common biphenyl side chain, were capable of inhibiting HSV-1 and HSV-2 with a 50% effective concentration (EC50) of 81 to 210 nM, and also strongly inhibited acyclovir-resistant mutants. Moderate to low cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC50] of 50 to >100 μM). Therapeutic indexes ranged from >170 to >1,200. These data indicate that troponoids and specifically α-hydroxytropolones are a promising lead scaffold for development as anti-HSV drugs provided that toxicity can be further minimized. Troponoid drugs are envisioned to be employed alone or in combination with existing nucleos(t)ide analogs to suppress HSV replication far enough to prevent viral shedding and to limit the development of or treat nucleos(t)ide analog-resistant mutants.
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ireland
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Tavis
authors.affiliation: Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York, USA Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, New York, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: D'Erasmo
authors.affiliation: Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York, USA Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, New York, USA.
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Hirsch
authors.affiliation: Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York, USA Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, New York, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Murelli
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Cadiz
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Bindi S
authors.initials: BS
authors.lastname: Patel
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Ankit K
authors.initials: AK
authors.lastname: Gupta
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Tiffany C
authors.initials: TC
authors.lastname: Edwards
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Korom
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Eileen A
authors.initials: EA
authors.lastname: Moran
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA morrisla@slu.edu.
authors.forename: Lynda A
authors.initials: LA
authors.lastname: Morrison
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D024882:Drug Resistance, Viral / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000254:growth & development; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D020128:Inhibitory Concentration 50; D013329:Structure-Activity Relationship; D014334:Tropolone / Q000031:analogs & derivatives / Q000494:pharmacology*; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D014334:Tropolone