Synthesis and pre-clinical studies of new amino-acid ester thiazolide prodrugs

• Published in: European journal of medicinal chemistry 2017-01, Vol.126, p.154-159
• Main Authors: Stachulski, Andrew V., Swift, Karl, Cooper, Mark, Reynolds, Stephen, Norton, Daniel, Slonecker, Steven D., Rossignol, Jean-François
• Format: Article
• Language: English
• Subjects: Amino Acids - chemistry; Animals; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - metabolism; Antiviral Agents - pharmacology; Antiviral Agents - toxicity; Biodisposition; Biological Availability; Chemical synthesis; Chemistry Techniques, Synthetic; Drug Evaluation, Preclinical; Esters - chemistry; Female; Male; Oral absorption; Orthomyxoviridae - drug effects; Orthomyxoviridae - physiology; Paramyxoviridae - drug effects; Paramyxoviridae - physiology; Pharmacology; Prodrugs; Prodrugs - metabolism; Rats; Research Paper; Safety; Stability; Thiazoles - chemical synthesis; Thiazoles - metabolism; Thiazoles - pharmacology; Thiazoles - toxicity; Toxicology; Virus Replication - drug effects
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.09.080

Thiazolides are polypharmacology agents with at least three mechanisms of action against a broad spectrum of parasites, bacteria and viruses. In respiratory viruses they inhibit the replication of orthomyxoviridae and paramyxoviridae at a post-translational level. Nitazoxanide 1a, the prototype thiazolide, was originally developed as an antiparasitic agent and later repurposed for the treatment of viral respiratory infections. The second generation thiazolides following nitazoxanide, such as the 5-chloro analogue RM-5038 2a, are also broad-spectrum antiviral agents as we have reported. Both 1a and its effective circulating metabolite, tizoxanide 1b, are 5-nitrothiazole derivatives, while RM-5038 2a and its de-acetyl derivative RM-4848 2b are the corresponding 5-chloro derivatives. Recently 1a has completed phase II-III clinical trials in the United States, Canada, Australia and New Zealand in a total of 2865 adults and adolescents of at least 12 months of age with viral acute respiratory illness. Since its biodisposition is primarily seen in the gastro-intestinal tract, its efficacy in systemic viral diseases requires relatively high oral doses. The chemical synthesis of new derivatives with a better systemic absorption was therefore urgently needed. In order to improve their systemic absorption, new amino-ester prodrug derivatives of 1b and RM4848 2b were prepared and tested for their animal pharmacology, pharmacokinetics and toxicology. RM-5061 8a in rats showed 7-fold higher blood concentration compared to 1a: absolute bioavailability increased from 3 to 20%, with a good safety profile in animal safety pharmacology and toxicology. [Display omitted] •An effective phenolic prodrug for the antiviral agent tizoxanide and a 5-Cl analogue is described.•These derivatives employ the amino-acid L-tertiary-leucine.•The stability of this prodrug significantly exceeds that of the Val or Ile analogues.•Good blood levels are obtainable by oral or IV administration.•The compounds show a good safety profile.