Memantine-Derived Schiff Bases as Transdermal Prodrug Candidates

Condensation reactions
of salicylaldehyde, 2-pyridinecarboxaldehyde,
and pyridoxaldehyde with memantine (Me) produced novel
memantine-derived Schiff bases (1–3). Speciation predictions and calculations of Log P, Log D, and of
the percentage (%) of neutral species for (1–3) were carried out. In comparison with Me, the
Schiff bases presented increased log P and log D in all cases and
pH values, suggesting higher hydrophobicity. The determined solubilities
in n-octanol were 34.7 mg/mL for memantine hydrochloride
and 67.3 mg/mL for (3). According to the molecular weights
and calculated logP, compounds (1–3) are suitable for transdermal administration, especially compound
(3). In addition, hydrolysis of 3 with the
release of pyridoxal, a daily cofactor in human metabolism, was observed.
The results suggested that 3 is the most promising compound
and that formation of the pyridoxal Schiff base with Me might be an effective strategy to obtain a prodrug candidate with
increased lipophilicity, which would be able to passively cross biological
barriers during transdermal delivery and might have applications in
the treatment of Alzheimer’s disease and other neurological
disorders.