title: In search of flavivirus inhibitors: evaluation of different tritylated nucleoside analogues.
abstract: Following up on a hit that was identified in a large scale cell-based antiviral screening effort, a series of triphenylmethyl alkylated nucleoside analogues were synthesized and evaluated for their in vitro antiviral activities against the dengue virus (DENV) and the yellow fever virus (YFV). Hereto, trityl moieties were attached at various positions of the sugar ring combined with subtle variations of the heterocyclic base. Several triphenylmethyl modified nucleosides were uncovered being endowed with submicromolar in vitro antiviral activity against the YFV. The most selective inhibitor in this series was 3',5'-bis-O-tritylated-5-chlorouridine (1b) affording a selectivity index of over 90, whereas the 3',5'-bis-O-tritylated inosine congener (5b) displayed the highest activity, but proved more toxic. The finding of these lipophilic structures being endowed with high antiviral activity for flaviviruses, should stimulate the interest for further structure-activity research.
authors.affiliation: Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, BE-3000 Leuven, Belgium.
authors.forename: Grégory
authors.initials: G
authors.lastname: Chatelain
authors.forename: Yannick
authors.initials: Y
authors.lastname: Debing
authors.forename: Tine
authors.initials: T
authors.lastname: De Burghgraeve
authors.forename: Joanna
authors.initials: J
authors.lastname: Zmurko
authors.forename: Milind
authors.initials: M
authors.lastname: Saudi
authors.forename: Jef
authors.initials: J
authors.lastname: Rozenski
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Arthur
authors.initials: A
authors.lastname: Van Aerschot
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005416:Flavivirus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides
keywords: 3′,5′-di-O-Trityl-uridine; Bis-O-tritylated nucleosides; Dengue virus; Flavivirus inhibitors; MUGGLEKABKZTPD-KJQSMSQRSA-N; QJBAWUAFPJZOKV-HOCDMSHKSA-N; Yellow fever virus