D-xylofuranosyl nucleoside analogues bearing alkylthio and glucosylthio substituents at the C3'-position were prepared by photoinitiated radical-mediated hydrothiolation reactions from the corresponding 2',5'-di-O-silyl-3'-exomethylene uridine. Sequential desilylation and 5'-O-butyrylation of the 3'-thiosubstituted molecules produced a 24-membered nucleoside series with diverse substitution patterns, and the compounds were evaluated for their in vitro antiviral activity against three dangerous human RNA viruses, SARS-CoV-2, SINV and CHIKV. Eight compounds exhibited SARS-CoV-2 activity with low micromolar EC50 values in Vero E6 cells, and two of them also inhibited virus growth in human Calu cells. The best anti-SARS-CoV-2 activity was exhibited by 2',5'-di-O-silylated 3'-C-alkylthio nucleosides. Twelve compounds showed in vitro antiviral activity against CHIKV and fourteen against SINV with low micromolar EC50 values, with the 5'-butyryl-2'-silyl-3'-alkylthio substitution pattern being the most favorable against both viruses. In the case of the tested nucleosides, removal of the 2'-O-silyl group completely abolished the antiviral activity of the compounds against all three viruses. Overall, the most potent antiviral agent was the disilylated 3'-glucosylthio xylonucleoside, which showed excellent and specific antiviral activity against SINV with an EC50 value of 3 μM and no toxic effect at the highest tested concentration of 120 μM.

Department of Pharmaceutical Chemistry Faculty of Pharmacy University of Debrecen Egyetem tér 1 Debrecen 4032 Hungary

Department of Pharmaceutical Chemistry Faculty of Pharmacy University of Debrecen Egyetem tér 1 Debrecen 4032 Hungary; National Laboratory of Virology Szentágothai Research Centre University of Pécs Ifjúság útja 20 Pecs 7624 Hungary

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo náměstí 2 16610 Prague 6 Czech Republic

National Laboratory of Virology Szentágothai Research Centre University of Pécs Ifjúság útja 20 Pecs 7624 Hungary; Institute of Biology Faculty of Sciences University of Pécs Ifjúság útja 6 Pécs 7624 Hungary

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