Design, synthesis and biological evaluation of brain-specific glucosyl thiamine disulfide prodrugs of naproxen

Glucosyl derivates exhibited favorable distribution to the brain. However, bidirectional transport of glucose transporter 1 might decrease concentrations of the prodrugs in brain before the release of parent drugs. To overcome this defect, glucosyl thiamine disulfide prodrugs 1a–1c incorporating naproxen were designed and synthesized. Furthermore, prodrug 2 and 3 were also prepared as control. The favorable physicochemical properties of these prodrugs were verified by stability and metabolism studies. Results from the in vivo distribution study indicated that 1a–1c, and 1b in particular, significantly increased the level of naproxen in brain when compared to 2 and 3. The study suggested glucosyl thiamine disulfide was a promising carrier to enhance the brain bioavailability of central nervous system active drugs.

Graphical abstractSeveral novel brain specific prodrugs of naproxen have been synthesized, characterized and evaluated. Three of them exhibited enhanced brain targeted ablility.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Several novel brain specific prodrugs of naproxen were synthesized and evaluated. ► All the prodrugs could efficiently deliver naproxen across the BBB. ► Glucosyl thiamine disulfide prodrugs showed outstanding brain bioavailability. ► Glucosyl thiamine disulfide was a promising carrier for brain delivery of drugs.