In the present work, the hydrolytic stability of new memantine analogues modified with amino acids, at different pH corresponding to the human biological liquids and organs, was evaluated. Memantine is an uncompetitive N-methyl-d-aspartate receptor antagonist with low-to moderate-affinity. In addition, it is the first representative of a novel class of Alzheimer’s disease (AD) medications acting on the glutamatergic system by blocking N-methyl-D-aspartate receptors. Generally, prodrugs are compounds aiming to improve stability of active fragment and to facilitate transportation across the cell membranes or lipid barriers. The investigated series of prodrugs include modified memantine with the following amino acids: alanine, β-alanine, glycine, phenylalanine, and valine. Hydrolytic stability was determined at two different pH values 2.0 and 7.4 at 37 °C, similar to those in the human stomach and blood plasma. Specially developed UV-VIS spectrophotometric method for quantification of the concentrations of unchanged compounds was applied in the kinetic studies. Val-MEM is the most stable in neutral medium and at 37 °C compound with t1/2 = 50.2 h. The compound Phe-MEM has also very good hydrolytic stability with t1/2 = 29.6 h. The order of other compounds is: Val-MEM ≫ Phe-MEM ≫ Ala-MEM ≈ Val-MEM > β-Ala-MEM. Ala-MEM and Gly-MEM are the most stable compounds at acid condition with almost identical values for t1/2 = 17.8 h and t1/2 = 16.3 h, respectively. The stability of tested compounds in acid conditions are relatively less than in neutral one. They are ordered as follows: Ala-MEM ≈ Gly-MEM > Val-MEM ≈ Phe-MEM ≈ β-Ala-MEM. All compounds have relatively good hydrolytic stability of more than 10 h at both neutral and acid conditions, which is quite enough in order to pass in the blood circulation and to be used as a potential antimicrobial agent.
Antibiotic-mediated transport of alkali ions across lipid barriers.