Synthesis, antiviral activity, preliminary pharmacokinetics and structural parameters of thiazolide amine salts

• Published in: Future medicinal chemistry 2021-10, Vol.13 (20), p.1731-1741
• Main Authors: Stachulski, Andrew V, Rossignol, Jean-Francois, Pate, Sophie, Taujanskas, Joshua, Robertson, Craig M, Aerts, Rudi, Pascal, Etienne, Piacentini, Sara, Frazia, Simone La, Santoro, M Gabriella, O'Neill, Paul M
• Format: Article
• Language: English
• Subjects: A549 Cells; amine salts; Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; antiviral; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cell Survival - drug effects; Cells, Cultured; Humans; Influenza A virus - drug effects; Microbial Sensitivity Tests; Molecular Structure; pharmacokinetics; Salts - chemical synthesis; Salts - chemistry; Salts - pharmacology; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; thiazolides; x-ray structure
• ISSN: 1756-8919; 1756-8927
• DOI: 10.4155/fmc-2021-0055

The thiazolides, typified by nitazoxanide, are an important class of anti-infective agents. A significant problem with nitazoxanide and its active circulating metabolite tizoxanide is their poor solubility. We report the preparation and evaluation of a series of amine salts of tizoxanide and the corresponding 5-Cl thiazolide. These salts demonstrated improved aqueous solubility and absorption, as shown by physicochemical and measurements. They combine antiviral activity against influenza A virus with excellent cell safety indices. We also report the x-ray crystal structural data of the ethanolamine salt. The ethanol salt of thiazolide retains the activity of the parent together with an improved cell safety index, making it a good candidate for further evaluation. Tizoxanide was readily converted into its stable, highly crystalline ethanolamine salt on warming with ethanolamine in methanol. Similar salts resulted from reaction of or the corresponding 5′-chlorothiazolide with a range of amines; we report on the pharmacokinetic properties and structure of .