Browsing by Author "Stankova I."

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    ANTIMICROBIAL ACTIVITY OF AMINO ACID DERIVATIVES OF MEMANTINE
    (2022-01-01) Tencheva A.; Stankova I.; Angelova T.; Nemska V.; Georgieva N.; Danalev D.
    Memantine is adamantane derivative used in medicinal practice. It is well-proven inhibitors of the M2 ion channel of influenza virus. In addition, it is applied for treatment of patients with Alzheimer’s disease. Herein, we report the antimicrobial activity of specifically designed memantine derivatives containing spatially compact (Gly, Ala, β-Ala) and bulky (Val and Phe) amino acids. New compounds were synthesized in a solution using 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) as a coupling agent. All derivatives were obtained with good yields. Newly synthesized molecules at concentration 100 mM were tested for their antimicrobial activity using model strains of Gram-positive (Bacillus subtilis NBIMCC 3562), Gram-negative (Escherichia coli NBIMCC K12 407) microorganisms and fungal strain Candida albicans NBIMCC 74. The active compounds against model G+ microorganism are Val-MEM followed by Ala-MEM and Gly-MEM. All compounds show good activity against model G-microorganism. Introducing of bulky amino acid Phe, containing aromatic core, and Val, containing aliphatic core, leads to good antifungal activity
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    HYDROLYTIC STABILITY OF ADAMANTANE HYBRID MOLECULES
    (2025-11-02) Stoymirska A.; Chayrov R.; Chuchkov K.; Danalev D.; Stankova I.
    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.
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    Hydrolytic stability of new amino acids analogues of memantine
    (2020-09-01) Tencheva A.; Chayrov R.; Mandjukov P.; Stankova I.; Danalev D.
    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.