Synthetic analogues of memantine as neuroprotective and influenza viral inhibitors: in vitro and physicochemical studies
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ORIGINAL ARTICLE
Synthetic analogues of memantine as neuroprotective and influenza viral inhibitors: in vitro and physicochemical studies Aleksandra Tencheva1 · Rui Liu2 · Tatyana V. Volkova3 · Radoslav Chayrov1 · Yavor Mitrev4 · Martin Štícha5 · Yuhuan Li2 · Hailun Jiang2 · Zhuorong Li2 · Ivanka Stankova1 · German L. Perlovich3 Received: 28 October 2019 / Accepted: 6 November 2020 © Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract 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. T C50 and I C50 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. Keywords Memantine · Amino acids · Alzheimer’s disease
Handling editor: K. Aoyama. Aleksandra Tencheva and Rui Liu have the same contribution. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00726-020-02914-4) contains supplementary material, which is available to authorized users.
Abbreviations NMDA N-Methyl-d-aspartate NMDARs N-Methyl-d-aspartate receptors AD Alzheimer’s disease L-DOPA L-3,4-Dihydroxyphenylalanine TBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylamonium tetrafluoroborate
* Ivanka Stankova [email protected]
3
Krestov’s Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo, Russia
* German L. Perlovich glp@isc‑ras.ru
4
Institute of Organic Chemi
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