The antiviral thiazolides Nitazoxanide and RM5038

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Nitazoxanide (NTZ), 2-(acetyloxy)-N-(5-nitro-2-thiazolyl) benzamide, is an antiparasitic agent active against several protozoa and helminths, initially used for treating diarrhoea caused by giardia intestinalis and cryptosporidium. It also shows promising activity against several RNA and DNA viruses, including SARS-CoV-2 (EC₅₀ = 2.12 µM), therefore a potential treatment for COVID-19. NTZ’s antiprotozoal and antibacterial activity is believed to stem from the inhibition of pyruvate:ferredoxin oxidoreductase(PFOR), an essential enzyme for anaerobic energy metabolism. Tizoxanide, the active metabolite of NTZ, is highly protein bound however, its poor solubility remains as an issue.
Amino acid ester prodrugs (AAEPs) improved the solubility by adding bulky substituents and forming HCl salts. However, these salts were unstable at pH 5 and formed highly potent peptide end-products that are active against viruses.

A. V. Stachulski, J. Taujanskas, S. L. Pate, R. K. R. Rajoli, G. Aljayyoussi, S. H. Pennington, S. A. Ward, W. D. Hong, G. A. Biagini, A. Owen, G. L. Nixon, S. C. Leung and P. M. O’Neill, ACS Infectious Diseases, 2021, 7, 1317-1331.

A. V. Stachulski, J.-F. Rossignol, S. Pate, J. Taujanskas, J. A. Iggo, R. Aerts, E. Pascal, S. Piacentini, S. La Frazia, M. G. Santoro, L. van Vooren, L. Sintubin, M. Cooper, K. Swift and P. M. O’Neill, ACS Bio & Med Chem Au, 2023, 3, 327-334.