Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo, Russia.
Mol Pharm. 2011 Oct 3;8(5):1807-20. doi: 10.1021/mp2003237. Epub 2011 Aug 10.
Novel 1,2,4-thiadiazoles were synthesized. Crystal structures of these compounds were solved by X-ray diffraction experiments, and comparative analysis of packing architecture and hydrogen bond networks was carried out. Thermodynamic aspects of sublimation processes of the compounds under study were analyzed using temperature dependencies of vapor pressure. Thermophysical characteristics of the molecular crystals were obtained and compared with the sublimation and structural parameters. The melting points correlate with sublimation Gibbs energies. Moreover, an increase of donor-acceptor interactions in crystal structures leads to growth of Gibbs energy values. Relationships between the melting points and the fragmental contributions to the packing energies were established: R(1)-R(4) fragmental interactions are responsible for the fusion processes of this class of compounds. Solubility and solvation processes of 1,2,4-thiadiazoles in buffer, n-hexane and n-octanol were studied within a wide range of temperature intervals, and their thermodynamic functions were calculated. Specific and nonspecific interactions of molecules resolved in crystals and solvents were estimated and compared. It was found that the melting points correlate with sublimation Gibbs energies. Distribution processes of compounds in buffer/n-octanol and buffer/n-hexane systems (describing different types of membranes) were investigated. Transfer processes of the studied molecules from the buffer to n-octanol/n-hexane phases were analyzed by the diagram method with evaluation of the enthalpic and entropic terms. This approach allowed us to design drug molecules with optimal passive transport properties. Calcium-blocking properties of the substances were evaluated. The trend between the ability to inhibit Glu-Ca uptake and the distribution coefficients in buffer/hexane system was observed.
合成了新型 1,2,4-噻二唑。通过 X 射线衍射实验解决了这些化合物的晶体结构，并对堆积结构和氢键网络进行了比较分析。利用化合物升华过程的温度依赖性分析了其升华过程的热力学方面。获得了分子晶体的热物理特性，并与升华和结构参数进行了比较。熔点与升华吉布斯能量相关。此外，晶体结构中供体-受体相互作用的增加导致吉布斯能量值的增长。建立了熔点与堆积能片段贡献之间的关系：R(1)-R(4)片段相互作用负责这一类化合物的熔融过程。在较宽的温度范围内研究了 1,2,4-噻二唑在缓冲液、正己烷和正辛醇中的溶解度和溶解过程，并计算了它们的热力学函数。估计并比较了晶体和溶剂中分子的特异性和非特异性相互作用。发现熔点与升华吉布斯能量相关。研究了化合物在缓冲液/辛醇和缓冲液/己烷体系（描述不同类型的膜）中的分配过程。通过图表法分析了研究分子从缓冲液到辛醇/己烷相的转移过程，并评估了焓和熵项。这种方法允许我们设计具有最佳被动传输特性的药物分子。评估了物质的钙阻断特性。观察到抑制 Glu-Ca 摄取的能力与在缓冲液/己烷体系中的分配系数之间的趋势。
