Kravtsova Anna A, Skuredina Anna A, Malyshev Alexander S, Le-Deygen Irina M, Kudryashova Elena V, Budynina Ekaterina M
Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia.
Faculty of Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia.
Pharmaceutics. 2023 Jan 9;15(1):228. doi: 10.3390/pharmaceutics15010228.
In this work, we first improved the aqueous solubility of biologically active spiro[cyclopropane-1,3′-oxindoles] (SCOs) via their complexation with different β-cyclodextrins (β-CDs) and proposed a possible mechanism of the complex formation. β-CDs significantly increased the water solubility of SCOs (up to fourfold). Moreover, the nature of the substituents in the β-CDs influenced the solubility of the guest molecule (MβCD > SBEβCD > HPβCD). Complexation preferably occurred via the inclusion of aromatic moieties of SCOs into the hydrophobic cavity of β-CDs by the numerous van der Waals contacts and formed stable supramolecular systems. The phase solubility technique and optical microscopy were used to determine the dissociation constants of the complexes (Kc~102 M−1) and reveal a significant decrease in the size of the formed crystals. FTIR-ATR microscopy, PXRD, and 1H-1H ROESY NMR measurements, as well as molecular modeling studies, were carried out to elucidate the host−guest interaction mechanism of the complexation. Additionally, in vitro experiments were carried out and revealed enhancements in the antibacterial activity of SCOs due to their complexation with β-CDs.
在本研究中，我们首先通过生物活性螺环[环丙烷-1,3′-吲哚酮]（SCOs）与不同的β-环糊精（β-CDs）络合来提高其水溶性，并提出了络合物形成的可能机制。β-环糊精显著提高了SCOs的水溶性（高达四倍）。此外，β-环糊精中取代基的性质影响客体分子的溶解度（甲基化β-环糊精>MβCD>磺丁基醚β-环糊精>羟丙基β-环糊精）。络合作用优选通过SCOs的芳香部分通过大量范德华接触被包含在β-环糊精的疏水腔内而发生，并形成稳定的超分子体系。采用相溶解度技术和光学显微镜来测定络合物的解离常数（Kc~102 M−1），并揭示所形成晶体尺寸的显著减小。进行了傅里叶变换红外衰减全反射显微镜（FTIR-ATR）、粉末X射线衍射（PXRD）和1H-1H旋转坐标系 Overhauser 效应光谱（ROESY）核磁共振测量以及分子模拟研究，以阐明络合作用的主客体相互作用机制。此外，还进行了体外实验，结果表明SCOs与β-环糊精络合后其抗菌活性增强。
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