title: A novel influenza virus neuraminidase inhibitor AV5027.
abstract: A medium-sized focused library of novel Oseltamivir structural analogues with promising antiviral activity was successfully synthesized using a combinatorial approach. The synthesized compounds were then thoroughly evaluated in neuraminidase- and cell-based assays. As a result, (3R,4R,5S)-4-(2,2-difluoroacetylamino)-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid (AV5027) was identified as novel Hit-compound with picomolar potency. QSAR analysis was carried out based on the obtained biological data. Computational modeling was performed using a 3D-molecular docking approach and classical regression analysis. The developed integral model demonstrated a sufficient prediction accuracy and tolerance to evaluate compounds based on their potential activity against neuraminidase (NA) at least within the scaffold. Several compounds from the series can be reasonably regarded as promising anti-influenza drug-candidates.
authors.forename: Alexandre V
authors.initials: AV
authors.lastname: Ivachtchenko
authors.forename: Yan A
authors.initials: YA
authors.lastname: Ivanenkov
authors.forename: Oleg D
authors.initials: OD
authors.lastname: Mitkin
authors.forename: Pavel M
authors.initials: PM
authors.lastname: Yamanushkin
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Bichko
authors.forename: Irina A
authors.initials: IA
authors.lastname: Leneva
authors.forename: Olga V
authors.initials: OV
authors.lastname: Borisova
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D020650:Combinatorial Chemistry Techniques; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004285:Dogs; D015195:Drug Design; D005463:Fluoroacetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D009980:Influenza A virus / Q000187:drug effects / Q000201:enzymology; D009981:Influenza B virus / Q000187:drug effects / Q000201:enzymology; D061985:Madin Darby Canine Kidney Cells; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D021281:Quantitative Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
chemical_list: C587711:4-(2,2-difluoroacetylamino)-5-amino-3-(1-ethylpropoxy)cyclohex-1-enecarboxylic acid; D000998:Antiviral Agents; D003509:Cyclohexanecarboxylic Acids; D005463:Fluoroacetates; D014764:Viral Proteins; C487630:NA protein, influenza A virus; C541223:NA protein, influenza B virus; D009439:Neuraminidase