title: In search of Flavivirus inhibitors part 2: tritylated, diphenylmethylated and other alkylated nucleoside analogues.
abstract: Several flaviviruses, such as the yellow fever virus and the dengue virus cause severe and potentially lethal infection in man. Following up on our initial hit 3',5'-bistritylated uridine 1, a series of alkylated nucleoside analogues were synthesized and evaluated for their in vitro antiviral activities against dengue fever virus and yellow fever virus. Hereto, alkyl and aryl groups were attached at various positions of the sugar ring combined with subtle variation of the heterocyclic base. Among the new series of derivatives, 3',5'-di-O-trityl-5-fluoro-2'-deoxyuridine (39) was the most efficient in this series and inhibited both yellow fever virus and dengue virus replication with a 50% effective concentration (EC₅₀) of ∼1 μg/mL without considerable cytotoxicity. The other fluorinated derivatives proved more toxic. Almost all diphenylmethylated pyrimidine nucleosides with 3',5'-di-O-benzhydryl-2'-deoxyuridine (50) as the example were endowed with strong cytotoxic effects down to 1 μg/mL.
authors.affiliation: Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, BE-3000 Leuven, Belgium.
authors.forename: Milind
authors.initials: M
authors.lastname: Saudi
authors.affiliation: Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, BE-3000 Leuven, Belgium.
authors.forename: Joanna
authors.initials: J
authors.lastname: Zmurko
authors.affiliation: Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, BE-3000 Leuven, Belgium.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kaptein
authors.affiliation: Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, BE-3000 Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Rozenski
authors.affiliation: Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, BE-3000 Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, BE-3000 Leuven, Belgium. Electronic address: arthur.vanaerschot@rega.kuleuven.be.
authors.forename: Arthur
authors.initials: A
authors.lastname: Van Aerschot
mesh_terms: D000478:Alkylation; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005416:Flavivirus / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides
keywords: 3′,5′-Di-O-benzhydryl-2′-deoxyuridine; Alkylated nucleosides; Dengue virus; Flavivirus inhibitors; Yellow fever virus