In search of Flavivirus inhibitors part 2: Tritylated, diphenylmethylated and other alkylated nucleoside analogues

• A new series of alkylated nucleosides was evaluated for Flavivirus inhibition.
• Only some tritylated analogues showed clear antiviral properties.
• 3′,5′-di-O-trityl-5-fluoro-2′-deoxyuridine displayed selective inhibitory properties.
• Diphenylmethylated pyrimidine nucleosides were endowed with strong cytotoxic effects.

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.

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