title: Synthetic 1,4-pyran naphthoquinones are potent inhibitors of dengue virus replication.
abstract: Dengue virus infection is a serious public health problem in endemic areas of the world where 2.5 billion people live. Clinical manifestations of the Dengue infection range from a mild fever to fatal cases of hemorrhagic fever. Although being the most rapidly spreading mosquito-borne viral infection in the world, until now no strategies are available for effective prevention or control of Dengue infection. In this scenario, the development of compounds that specifically inhibit viral replication with minimal effects to the human hosts will have a substantial effect in minimizing the symptoms of the disease and help to prevent viral transmission in the affected population. The aim of this study was to screen compounds with potential activity against dengue virus from a library of synthetic naphthoquinones. Several 1,2- and 1,4-pyran naphthoquinones were synthesized by a three-component reaction of lawsone, aldehyde (formaldehyde or arylaldehydes) and different dienophiles adequately substituted. These compounds were tested for the ability to inhibit the ATPase activity of the viral NS3 enzyme in in vitro assays and the replication of dengue virus in cultured cells. We have identified two 1,4-pyran naphthoquinones, which inhibited dengue virus replication in mammal cells by 99.0% and three others that reduced the dengue virus ATPase activity of NS3 by two-fold in in vitro assays.
authors.affiliation: Laboratório de Genômica Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Emmerson C B
authors.initials: EC
authors.lastname: da Costa
authors.affiliation: Universidade Federal do Rio de Janeiro, Departamento de Virologia, Instituto de Microbiologia Paulo de Góes, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Raquel
authors.initials: R
authors.lastname: Amorim
authors.affiliation: Universidade Federal Fluminense, Departamento de Química Orgânica, Instituto de Química, Niterói, Rio de Janeiro, Brazil.
authors.forename: Fernando C
authors.initials: FC
authors.lastname: da Silva
authors.affiliation: Universidade Federal Fluminense, Departamento de Química Orgânica, Instituto de Química, Niterói, Rio de Janeiro, Brazil.
authors.forename: David R
authors.initials: DR
authors.lastname: Rocha
authors.affiliation: Universidade Federal do Rio de Janeiro, Departamento de Virologia, Instituto de Microbiologia Paulo de Góes, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Papa
authors.affiliation: Universidade Federal do Rio de Janeiro, Departamento de Virologia, Instituto de Microbiologia Paulo de Góes, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Luciana B
authors.initials: LB
authors.lastname: de Arruda
authors.affiliation: Laboratório de Genômica Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Ronaldo
authors.initials: R
authors.lastname: Mohana-Borges
authors.affiliation: Universidade Federal Fluminense, Departamento de Química Orgânica, Instituto de Química, Niterói, Rio de Janeiro, Brazil.
authors.forename: Vitor F
authors.initials: VF
authors.lastname: Ferreira
authors.affiliation: Universidade Federal do Rio de Janeiro, Departamento de Genética, Instituto de Biologia, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Amilcar
authors.initials: A
authors.lastname: Tanuri
authors.affiliation: Universidade Federal do Rio de Janeiro, Departamento de Virologia, Instituto de Microbiologia Paulo de Góes, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Luciana J
authors.initials: LJ
authors.lastname: da Costa
authors.affiliation: Universidade Federal do Rio de Janeiro, Departamento de Química Orgânica, Instituto de Química, Macaé, Rio de Janeiro, Brazil.
authors.forename: Sabrina B
authors.initials: SB
authors.lastname: Ferreira
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002522:Chlorocebus aethiops; D003716:Dengue Virus / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D056945:Hep G2 Cells; D006801:Humans; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D009285:Naphthoquinones; D011714:Pyrans; D017361:Viral Nonstructural Proteins; D000251:Adenosine Triphosphatases