title: Discovery and Synthesis of Heterocyclic Carboxamide Derivatives as Potent Anti-norovirus Agents.
abstract: There is an urgent need for structurally novel anti-norovirus agents. In this study, we describe the synthesis, anti-norovirus activity, and structure-activity relationship (SAR) of a series of heterocyclic carboxamide derivatives. Heterocyclic carboxamide 1 (50% effective concentration (EC50)=37 µM) was identified by our screening campaign using the cytopathic effect reduction assay. Initial SAR studies suggested the importance of halogen substituents on the heterocyclic scaffold and identified 3,5-di-boromo-thiophene derivative 2j (EC50=24 µM) and 4,6-di-fluoro-benzothiazole derivative 3j (EC50=5.6 µM) as more potent inhibitors than 1. Moreover, their hybrid compound, 3,5-di-bromo-thiophen-4,6-di-fluoro-benzothiazole 4b, showed the most potent anti-norovirus activity with a EC50 value of 0.53 µM (70-fold more potent than 1). Further investigation suggested that 4b might inhibit intracellular viral replication or the late stage of viral infection.
authors.affiliation: Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka.
authors.forename: Mai
authors.initials: M
authors.lastname: Ohba
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Oka
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ando
authors.forename: Saori
authors.initials: S
authors.lastname: Arahata
authors.forename: Asaka
authors.initials: A
authors.lastname: Ikegaya
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Takagi
authors.forename: Naohisa
authors.initials: N
authors.lastname: Ogo
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Owada
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Kawamori
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Wang
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Saif
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D029322:Norovirus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000577:Amides; D000998:Antiviral Agents; D006571:Heterocyclic Compounds