New Class of Uridine- and Adenosine-Based Morpholino Nucleosides as Potential Anti-SARS-CoV-2 Agents: Synthesis, Antiviral Evaluation, Molecular Modeling, and In Silico ADMET Properties

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Abstract Morpholino nucleosides play an important role in medicine as building blocks for antisense oligonucleotide drugs (PMOs), but their therapeutic applications as nucleosides are still unexplored. A novel library of 38 fused bicyclic morpholino-uridine and -adenosine derivatives was constructed through an innovative, single-step strategy based on a reductive aminocyclization reaction between readily prepared nucleoside secodialdehydes and bifunctional amines. By fine-tuning the reaction conditions, a diverse array of morpholino bicycles was obtained with high/complete stereoselectivity. With aminothiols and diamines, the NaCNBH3–AcOH reducing agent resulted in 3′-fused or 5′-fused ring systems, depending on the amine reactant, while the NaCNBH3–ZnCl2-mediated reduction gave predominantly 5′-fused bicycles due to intramolecular 3′-hydride donation by the reducing agent coordinated to the nucleobase. All new compounds were evaluated for their antiviral activity against SARS-CoV-2. Three analogues demonstrated significant efficacy, exhibiting single-digit micromolar EC50 values. Mechanistic investigations revealed that these compounds inhibit the viral life cycle at a postentry stage, with one compound potentially affecting later stages of the viral replication cycle. Furthermore, molecular docking, enzymatic inhibition studies, and in silico ADMET analyses were conducted. The findings emphasize the potential of this fused bicyclic system as an attractive scaffold in nucleoside chemistry and advocate for its further optimization as a promising class of SARS-CoV-2 inhibitors.

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