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Funct. Mater. 2019; 26 (4): 673-684.

doi:https://doi.org/10.15407/fm26.04.673

Formation of antibiotic cycloserine complexes with stearic acid and its calcium and magnesium salts: from quantum mechanical modeling to studies of membranotropic action

O.V.Vashchenko1, S.V.Shishkina2, N.A.Kasian1, L.V.Budianska1, L.A.Bulavin3, D.V.Soloviov3,4,5, V.A.Pashynska6, A.Gomory7, L.N.Lisetski1

1Institute for Scintillation Materials, STC "Institute for Single Crystals", National Academy of Sciences of Ukraine, 60 Nauky Ave., 61072 Kharkiv, Ukraine
2SSI "Institute for Single Crystals", STC "Institute for Single Crystals", 60 Nauky Ave., 61172 Kharkiv, Ukraine
3T.Shevchenko National University of Kyiv, 4 Academician Glushkov Ave., 03022 Kyiv, Ukraine
4Joint Institute for Nuclear Research, 6 Joliot-Curie Str., 141980 Dubna, Moscow region, Russian Federation
5Moscow Institute for Physics and Technology, 9 Institutskiy Per., 141701 Dolgoprudny, Russian Federation
6B.Verkin Institute for Low Temperature Physics and Engineering, National Academy of Sciences of Ukraine, 47 Nauky Ave., 61103 Kharkiv, Ukraine
7Institute of Organic Chemistry of Research Centre for Natural Sciences of the Hungarian Academy of Sciences, 2 Magyar tudosok korutja, H-1117 Budapest, Hungary

Abstract: 

Antibiotic cycloserine (CyS) is a highly efficient and widely used anti-tuberculosis drug, which is canonically formulated with such excipients as calcium stearate (CaSt) or magnesium stearate (MgSt). This makes interactions of CyS with CaSt, MgSt and structurally related stearic acid (StA), with eventual formation of intermolecular complexes in biological media, an important physico-chemical factor affecting pharmacological action of such drugs. A set of theoretical and experimental methods was applied to trace the complexes formation in vacuum and solvent media, as well as in model membranes of L-α-dipalmitoylphosphatidylcholine (DPPC). By means of quantum chemistry methods, a possibility of CyS complex formation with all the excipients has been shown. CyS-CaSt and CyS-MgSt complexes appeared to be much more stable than CyS-StA, both in vacuum and in water media due to involvement of the metal cations in the intermolecular interactions. The non-covalent complexes CyS-StA in polar solvent was experimentally observed by means of electrospray ionization mass spectrometry, which confirms the quantum chemical results on stability of CyS-StA complexes in different media. Meanwhile no evidence of CyS-StA clusters was observed in DPPC membranes. More stable complexes CyS-CaSt and CyS-MgSt were detectable in DPPC membranes via non-linearity of interlamellar repeat distance obtained in small-angle X-ray scattering (SAXS) experiments. A set of hydration parameters of the excipients elucidates important discrimination between CaSt and MgSt. A possible implication of our findings might be related to competing interactions of CyS with the excipients and with its molecular targets in organism, which could influence both its cytotoxic and neurotoxic effects.

Keywords: 
cycloserine, magnesium stearate, non-covalent complexes, quantum chemistry modeling, model lipid membranes, SAXS.
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