Drug compounds including
memantine moieties are an important group of biologically active agents for different pathologies, including the
Alzheimer's disease. In the present study, a series of
memantine derivatives incorporating
amino acid residues have been synthesized and their neuroprotective in vitro evaluation in respect of the
Alzheimer's disease, involving the effects on the resistance to Aβ toxicity, excitotoxicity, oxidative stress,
hypoxia, and
neuroinflammation has been studied. The cytotoxicities of the compounds were detected by CPE assay. TC50 and IC50 were determined using Reed and Muench method. Solubility and distribution were measured using a shake-flask method. Permeability of the compounds was studied using Franz diffusion cell and Permeapad™ barrier. These compounds displayed apparent multi-
neuroprotective effects against
copper-triggered Aβ toxicity,
glutamate-induced excitotoxicity, and oxidative and hypoxic
injuries. They also showed the ability to inhibit the inflammatory
cytokine release from the activated microglia and potential anti-neuroinflammatory effects. Especially, two most promising compounds H-4-F-Phe-memantine and H-Tyr-
memantine demonstrated the equivalent functional bioactivities in comparison with the positive control
memantine hydrochloride. Higher solubility in muriatic
buffer than in
phosphate buffer was detected. The distribution coefficients showed the optimal lipophilicity for compounds. The presented results propose new class of
memantine derivatives as potential drug compounds. Based on the experimental results, the correlations have been obtained between the biological, physicochemical parameters and structural descriptors. The correlation equations have been proposed to predict the properties of new
memantine derivatives knowing only the structural formula.