HYDROLYTIC STABILITY OF ADAMANTANE HYBRID MOLECULES

Antoniya   Stoymirska; Radoslav Chayrov; Kiril Chuchkov; Dancho Danalev; Ivanka Stankova

doi:10.59957/jctm.v60.i6.2025.7

Authors

Antoniya Stoymirska South-West University “Neofit Rilski”
Radoslav Chayrov South-West University “Neofit Rilski”
Kiril Chuchkov South-West University “Neofit Rilski”
Dancho Danalev University of Chemical Technology and Metallurgy
Ivanka Stankova South-West University “Neofit Rilski”

DOI:

https://doi.org/10.59957/jctm.v60.i6.2025.7

Keywords:

cysteine, adamantane derivatives, hydrolytic stability, prodrug, physiological pH, non-linear calibration, first order kinetics.

Abstract

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 t_1/2 = 8.5 h. The compound Cys-S-tert.-butylmemantine also has good hydrolytic stability with t_1/2 = 6.7 h and Cys-S-tert.-butylrimantadine has t_1/2 = 6.2 h. Almost identical are t_1/2 values at acid pH 1.0: the most stable is Cys-S-tert.-butylamantadine with t_1/2 = 4.7 h, followed by Cys-S-tert.-butylrimantadine with t_1/2 = 3.9 h and Cys-S-tert.-butylmemantine with t_1/2 = 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 ADAMANTANE HYBRID MOLECULES

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