Antiviral amino acid ester prodrugs

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The low solubility of Nitazoxanide and RM5038 limits their effectiveness against respiratory viruses, as a sufficient circulating concentration is needed. To address this, amino acid ester prodrugs were developed to improve solubility. However, these prodrugs can be unstable and prone to hydrolysis.
The research group synthesised amino acid ester prodrugs of these drugs by adding bulky tert-leucine (purple), resulting in prodrugs 5a and 6. The bioavailability of these prodrugs was 20-25% when administered orally to rats. Among the two, 6 had better solubility and could be recrystallised, whereas 5a had lower solubility. NMR studies revealed that 5a decomposed steadily at temperatures 25-40°C, and a major product was formed without an added base. A reaction of 5a in THF with NEt₃ yielded pure pseudotripeptide 8, which had an insertion of amino acid unit into the amide bond (orange).
Under similar conditions, prodrug 6 formed tripeptide 20 through rearrangement. Both 8 and 20 showed decreased clearance rates in hepatocytes and followed the major glucuronidation metabolic pathway. However, 20 was inactive and toxic (IC₅₀ > 40.8 µM ), while 8 retained good antiviral activity and a high cell safety index.

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.