Author:

Keywords:

SILVER - 260644;info:eu-repo/grantAgreement/EC/FP7/260644, Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, Flavivirus inhibitors, Dengue virus, Yellow fever virus, Alkylated nucleosides, 3 ',5 '-Di-O-benzhydryl-2 '-deoxyuridine, YELLOW-FEVER VACCINE, PROTECTING-GROUP, DENGUE, FLUORINE, DIAZOALKANES, 3′,5′-Di-O-benzhydryl-2′-deoxyuridine, Alkylation, Antiviral Agents, Drug Screening Assays, Antitumor, Flavivirus, Magnetic Resonance Spectroscopy, Nucleosides, Spectrometry, Mass, Electrospray Ionization, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

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.