Synthesis of novel pyridine and pyrimidine thioglycoside phosphoramidates for the treatment of COVID-19 and influenza A viruses

Abstract

A novel series of pyridine, cytosine, and uracil thioglycoside analogs (4a–i, 9a,b, and 13a,b, respectively) and their corresponding phosphoramidates (6a–I, 10a,b, and 14a,b, respectively) were synthesized and assessed for their antiviral inhibitory activities in a dual-pathogen screening protocol against SARS-CoV-2 and influenza A virus (IAV). MTT cytotoxicity (TC50) and plaque reduction assays were used to explore inhibition and cytotoxicity percentage values for H5N1 influenza virus strain and the half-maximal cytotoxic concentration (CC₅₀) and inhibitory concentration (IC₅₀) for SARS-CoV-2 virus. Most of the tested compounds demonstrated dose-dependent inhibition behavior. Both cytosine thioglycoside phosphoramidates 10a and 10b exhibited the most potent profiles with 83% and 86% inhibition at 0.25 µM concentration against H5N1 and IC₅₀ values of 12.16 µM, 14.9 µM against SARS-CoV-2, respectively. Moreover, compounds 10a and 10b have been shown to have the highest selectivity index (SI) among all the tested compounds against SARS-CoV-2 with 28.2 and 26.9 values, respectively.

Graphical abstract

Keywords:

• Antivirals
• carbohydrate methodology
• COVID-19 and Influenza A Viruses
• nucleotide sugars
• pyridine and pyrimidine thioglycosides
• SARS-CoV-2 virus
• Sofosbuvir

Acknowledgments

We would like to thank the Egyptian Academy of Scientific Research & Technology (ASRT) program of “Jessor” for awarding such a grant.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Egyptian Academy of Scientific Research & Technology (ASRT) program of “Jessor”.