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. 2023 Apr 11;3(4):327-334.
doi: 10.1021/acsbiomedchemau.2c00083. eCollection 2023 Aug 16.

Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity

Andrew V Stachulski  1 , Jean-Francois Rossignol  2 , Sophie Pate  1 , Joshua Taujanskas  1 , Jonathan A Iggo  1 , Rudi Aerts  3 , Etienne Pascal  3 , Sara Piacentini  4 , Simone La Frazia  4 , M Gabriella Santoro  4   5 , Lieven van Vooren  6 , Liesje Sintubin  6 , Mark Cooper  7 , Karl Swift  7 , Paul M O'Neill  1
Affiliations

Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity

Andrew V Stachulski et al. ACS Bio Med Chem Au. .

Abstract

Amino acid ester prodrugs of the thiazolides, introduced to improve the pharmacokinetic parameters of the parent drugs, proved to be stable as their salts but were unstable at pH > 5. Although some of the instability was due to simple hydrolysis, we have found that the main end products of the degradation were peptides formed by rearrangement. These peptides were stable solids: they maintained significant antiviral activity, and in general, they showed improved pharmacokinetics (better solubility and reduced clearance) compared to the parent thiazolides. We describe the preparation and evaluation of these peptides.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
1H NMR spectrum of pure 5a in d6-DMSO.
Figure 2
Figure 2
Time-course 1H NMR spectra of the aromatic region of 5a in d6-DMSO + 10%D2O. Evolution with time over an 18 day period at 298–313 K. The sample was held in an isothermal bath at a specified temperature between measurements. Spectra were recorded at the temperature stated in each case. (a) t = zero, 298 K; (b) t = 1 week, 308 K; (c) t = 8 days, 308 K; (d) t = 9 days, 308 K; (e) t = 11 days, 313 K; (f) t = 14 days, 313 K; (g) t = 18 days, 313 K.
Figure 3
Figure 3
Assignment and integration of the final time-point spectrum. The figure shows the Ar region protons corresponding to: (a) tizoxanide 3, (b) prodrug ester 5a, (c) rearranged product 8, and (d) the final time-point spectrum showing by integration a virtually 50% loss of 5a.
Scheme 1
Scheme 1. General Synthesis of Aminothiazolyl Tripeptides
Conditions: (i) EDC, Boc-amino acid, DMAP, THF, 0–20 °C, 54–67%; (ii) 4 M HCl-dioxan, CH2Cl2, 20 °C, 78–94%; (iii) Et3N, THF, 0–20 °C, 52–76%.
See this image and copyright information in PMC

References

    1. Rossignol J.-F. Nitazoxanide, a first-in-class broad-spectrum antiviral agent. Antiviral Res. 2014, 110, 94–103. 10.1016/j.antiviral.2014.07.014. - DOI - PMC - PubMed
    1. Korba B. E.; Montero A. B.; Farrar K.; Gaye K.; Mukerjee S.; Ayers M. S.; Rossignol J.-F. Nitazoxanide, tizoxanide and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication. Antiviral Res. 2008, 77, 56–63. 10.1016/j.antiviral.2007.08.005. - DOI - PubMed
    1. Stachulski A. V.; Pidathala C.; Row E.; Sharma R.; Berry N. G.; Iqbal M.; Bentley J.; Allman S. A.; Edwards G. E.; Helm A.; Hellier J.; Korba B. E.; Semple J. E.; Rossignol J.-F. Thiazolides as novel antiviral agents. 1. Inhibition of hepatitis B virus replication. J. Med. Chem. 2011, 54, 4119–4132. 10.1021/jm200153p. - DOI - PMC - PubMed
    1. Stachulski A. V.; Pidathala C.; Row E.; Sharma R.; Berry N. G.; Lawrenson A. S.; Moores S. L.; Iqbal M.; Bentley J.; Allman S. A.; Edwards G. E.; Helm A.; Hellier J.; Korba B. E.; Semple J. E.; Rossignol J.-F. Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication. J. Med. Chem. 2011, 54, 8670–8680. 10.1021/jm201264t. - DOI - PubMed
    1. Stachulski A. V.; Santoro M. G.; Piacentini S.; Belardo G.; La Frazia S.; Pidathala C.; Row E. C.; Berry N. G.; Iqbal M.; Allman S. A.; Semple J. E.; Eklov B. M.; O’Neill P. M.; Rossignol J.-F. Second-generation nitazoxanide derivatives: thiazolides are effective inhibitors of the influenza A virus. Future Med. Chem. 2018, 10, 851–862. 10.4155/fmc-2017-0217. - DOI - PubMed