A series of nineteen amino acid analogues of amantadine (Amt) and rimantadine (Rim) were synthesized and their antiviral activity was evaluated against influenza virus A (H3N2). Among these analogues, the conjugation of rimantadine with glycine illustrated high antiviral activity combined with low cytotoxicity. Moreover, this compound presented a profoundly high stability after in vitro incubation in human plasma for 24 h. Its thermal stability was established using differential and gravimetric thermal analysis. The crystal structure of glycyl-rimantadine revealed that it crystallizes in the orthorhombic Pbca space group. The structure–activity relationship for this class of compounds was established, with CoMFA (Comparative Molecular Field Analysis) 3D-Quantitative Structure Activity Relationships (3D-QSAR) studies predicting the activities of synthetic molecules. In addition, molecular docking studies were conducted, revealing the structural requirements for the activity of the synthetic molecules.

N-methyl-D-aspartate (NMDA) receptor blockade can improve L-DOPA (l-3,4-dihydroxyphenylalanine)-induced dyskinesias in Parkinson’s disease (PD) patients. Amantadine is a well-tolerated and effective antiparkinsonian agent, recently found to possess NMDA antagonistic properties. Oxidative damage may contribute to dopaminergic (DAergic) neurodegeneration in the substantia nigra of patients with PD. N,N-dimethylglycine (DMG) (also known as vitamin B15 or pangamic acid) acts as an antioxidant, extending the lifespan of animal cells through protection from oxidation. In this study, we synthesized and tested in vivo the newly obtained compound N,N-dimethylglycine-amantadine (DMG-Am) for antiparkinsonian activity. MPTP (1-methyl-4–phenyl-1, 2, 3, 6-tetrahydropyridine) is a widely used neurotoxin to induce an experimental model which mimics Parkinson disease-like symptoms. The neuroprotective capacity of the new amantadine derivative DMG-Am was evaluated by its potential to ameliorate the neuromuscular coordination and behavioral changes worsened by the toxin. Our experimental results showed that DMG-Am applied for 12 consecutive days, 5 days simultaneously and 7 days after MPTP, restored motor and memory performance of the animals to the control level, indication of beneficial protective effect of this compound. In summary, our results reveal the potential of newly synthesized DMG-Am as promising antiparkinsonian agent.

The objective of the current study was to develop novel compounds–memantine derivatives with antimicrobial activity designed for application in treatment of bacterial and fungal infections in patients suffering from Alzheimer’s disease. To realize this objective, a series of six memantine hybrid molecules were synthesized, characterized by ¹H NMR, ¹³C NMR, MS, X-ray, and tested for their biological properties as anti-Alzheimer agents and their antimicrobial potential.

In this study, we utilized the human coronavirus 229E (HCoV-229E) for evaluating the in vitro efficacy of some analogues of the ion-channel inhibitors and Amantadine and Rimantadine. The application of these investigated compounds did not result in any detectable cytotoxic effects. Furthermore, we observed that the derivatives of both analogues did not affect the viability of MDBK cells. Amantadine and Rimantadine applied at a concentration of 50 μg/mL inhibited the replication by 47% and 36%, respectively. The derivatives of Amantadine displayed a slightly weaker inhibitory effect in comparison with its own inhibitory effect. The derivative 4R of Rimantadine exhibited the same antiviral effect as the Rimantadine control, inhibiting viral replication by 37%. However, the other two derivatives of Rimantadine demonstrated lower activities. The molecular structures of the newly synthesized compounds were investigated thoroughly using single-crystal X-ray analysis. Molecular docking studies were performed using Autodock Vina. Two of the studied compounds 2A and 4A showed a promising binding affinity (−8.3 and −8.0 kcal/mol) towards SARS-CoV-2 RNA-dependent polymerase RNA site and SARS-CoV-2 Nsp3 (207-379, MES site) respectively.

Herein, the hydrolytic stability of new hybrid adamantane molecules modified with amino acid cysteine (Cys) at different pH is reported. Cys is a rare proteinogenic amino acid but it is a key structural unit in proteins. Cys is the only amino acid containing thiol group in the lateral chain which make it important source of sulphur for human organism. In addition, Cys has many biological functions such as antioxidant properties, immunomodulation activity by influence of the levels of the glutathione hormone, support liver function to eliminate toxins, help the breakdown of mucus in the lungs and improve breathing, etc. Adamantane derivatives are organic compounds largely used as antiviral therapeutics for treatment of influenza virus type A as well as neurodegenerative illnesses such as Parkinson’s and Alzheimer’s diseases. The adamantane motif assures high thermic stability and resistance. The modification of many adamantane derivatives such as amantadine, rimantadine and memantine with proteinogenic amino acid Cys could lead to increasing of activity and bioavailability of newly designed molecules. It is well known that hydrolytic stability is important feature for prodrug molecules related to the ability to penetrate cell membranes and to reach the specific receptors. A series of prodrugs based on adamantane motif including Cys-S-tert.-butylamantadine, Cys-S-tert.-butylrimantadine and Cys-S-tert.-butylmemantine was studied. The hydrolytic stability was determined at two different pH 1.0 and 7.4 at 37°C, similar to these in the human stomach and blood plasma. Kinetic of hydrolysis is monitored spectrophotometrically by specifically created UV-VIS method following the concentration of non-hydrolyzed part of the compounds. The most stable compound at pH 7.4 was Cys-S-tert.-butylamantadine with t1/2 = 8.5 h. The compound Cys-S-tert.-butylmemantine also has good hydrolytic stability with t1/2 = 6.7 h and Cys-S-tert.-butylrimantadine has t1/2 = 6.2 h. Almost identical are t1/2 values at acid pH 1.0: the most stable is Cys-S-tert.-butylamantadine with t1/2 = 4.7 h, followed by Cys-S-tert.-butylrimantadine with t1/2 = 3.9 h and Cys-S-tert.-butylmemantine with t1/2 = 3.5 h. However, it was revealed that hydrolytic stability of tested compounds in the two model systems at acid pH is relatively lower than those in neutral conditions.