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.

Automated summary

In this study, novel memantine-derived Schiff bases were synthesized through condensation reactions of salicylaldehyde, 2-pyridinecarboxaldehyde, and pyridoxaldehyde with memantine. The results showed that these Schiff bases exhibited increased lipophilicity and hydrophobicity in all conditions and pH values. Compound (3) had the highest solubility and also demonstrated the release of pyridoxal through hydrolysis, indicating potential pharmacological effects. Therefore, this study suggests that synthesizing Schiff bases could be an effective strategy to enhance the lipophilicity of drugs.