Synthesis and Evaluation of Novel Nucleotide Prodrugs Against SARS-CoV-2
Abstract
Positive sense RNA (ribonucleic acid) viruses (+ssRNA) are the known causative agents of diseases throughout history. These includes Hepatitis C Virus (HCV), SARS-CoV, and recently SARS-CoV-2. RNA dependent RNA polymerase (RdRp), a critical enzyme in the life cycle of the virus, can be targeted by using nucleotide antivirals thus causing inhibition. Novel ribonucleotides antiviral agents that possess nucleobase modifications and a 5′-phosphoramidate prodrug moiety, referred to as a ProTide, have been synthesized. The ribonucleoside analogues were constructed by CuI catalyzed azide-alkyne cycloaddition chemistry (CuAAC), also referred to as ‘click’ chemistry. The synthetic route utilized 5-ethynylpyrimidines and azidoribofuranoses as CuI ‘click’ chemistry substrates. Once the nucleosides were appropriately protected, they were phosphorylated with a synthesized phosphoramidate reagent. The final ProTides was screened against SARS-CoV-2 for their inhibition of RdRp along with the evaluation of cytotoxicity showing low inhibition and no cytotoxicity.