Hydrogen sulfide (H2S) is an endogenous gasotransmitter with cardioprotective and antiviral effects. In this work, new cysteine-selective nucleoside-H2S-donor hybrid molecules were prepared by conjugating nucleoside biomolecules with a thiol-activatable dithioacetyl group. 5'-Dithioacetate derivatives were synthesized from the canonical nucleosides (uridine, adenosine, cytidine, guanosine and thymidine), and the putative 5'-thio metabolites were also produced from uridine and adenosine. According to our measurements made with an H2S-specific sensor, nucleoside dithioacetates are moderately fast H2S donors, the guanosine derivative showed the fastest kinetics and the adenosine derivative the slowest. The antioxidant activity of 5'-thionucleosides is significantly higher than that of trolox, but lower than that of ascorbic acid, while intact dithioacetates have no remarkable antioxidant effect. In human Calu cells, the guanosine derivative showed a moderate anti-SARS-CoV-2 effect which was also confirmed by virus yield reduction assay. Dithioacetyl-adenosine and its metabolite showed similar acute cardiac effects as adenosine, however, it is noteworthy that both 5'-thio modified adenosines increased left ventricular ejection fraction or stroke volume, which was not observed with native adenosine.

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

Department of Pharmacodynamics Faculty of Pharmacy University of Debrecen Rex Ferenc u 1 Debrecen 4002 Hungary

Department of Pharmacology and Pharmacotherapy Faculty of Medicine University of Debrecen Nagyerdei krt 98 Debrecen 4032 Hungary

Department of Physical Chemistry Faculty of Science and Technology University of Debrecen Egyetem tér 1 Debrecen 4032 Hungary

Doctoral School of Pharmaceutical Sciences Faculty of Pharmacy University of Debrecen Nagyerdei krt 98 Debrecen 4032 Hungary

HUN REN UD Molecular Recognition and Interaction Research Group University of Debrecen Egyetem tér 1 Debrecen 4032 Hungary

HUN REN UD Pharmamodul Research Group University of Debrecen Nagyerdei krt 98 Debrecen 4032 Hungary

Institute of Healthcare Industry University of Debrecen Nagyerdei krt 98 Debrecen 4032 Hungary

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo nam 2 Prague 166 10 Czech Republic

National Laboratory of Virology University of Pécs Ifjúság útja 20 Pécs 7624 Hungary

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