Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly pathogenic positive-sense RNA virus responsible for the novel viral pandemic COVID-19. Beside the different vaccines and the only antiviral drug Paxlovid approved in the world, there is an urgent need for small molecules able to inhibit its viral replication. The viral RNA-dependent RNA polymerase (RdRp), which is involved in viral transcription and replication, has been identified as the most optimal target for an antiviral drug. Nucleoside (-tide) analogs are at the forefront of antiviral therapies and could be repositioned against SARS-CoV-2 such as Remdesivir and Molnupiravir or developed against SARS-CoV-2. Herein, we report the design and synthesis of various <i>hitherto unknown</i> C6-alkynyl-2,4-quinazolinedione <i>N-</i>1-ribonucleoside phosphoramidates. The synthesis pathway involves three key-steps: (1) the introduction of the nucleobase under Vorbrüggen conditions, (2) the modification at C6 position of the quinazolinedione moiety through a microwave-assisted Sonogashira Pd(0) cross-coupling reaction, and (3) the introduction of the phosphoramidate moiety at 5’-position in order to reach the prodrug form. As some of these analogs have shown activity against SARS-CoV-2, modifications on both the sugar and base moiety were performed. All synthesized compounds have been evaluated to determine their activity against SARS-CoV-2. Chemical synthesis and biological data will be presented.

Synthesis of nucleosi(-ti)de analogs targeting the inhibition of SARS-CoV-2

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