Yoon Hyo-Jeong, Yang Seung-Ju, Gong Young-Dae
Innovative Drug Library Research Center, Department of Chemistry, College of Science, Dongguk University , 26, 3-ga, Pil-dong Jung-gu, Seoul 100-715, Korea.
ACS Comb Sci. 2017 Dec 11;19(12):738-747. doi: 10.1021/acscombsci.7b00106. Epub 2017 Nov 30.
2-Alkoxy/thioalkoxy benzo-[d]-imidazole and 2-thione benzo-[d]-imidazole libraries were constructed in solution phase and on solid phase, respectively. The key step in this work is the phase-based chemoselective reaction of the 2-mercaptobenzo-[d]-imidazole intermediate with benzyl chloride (solution phase) and Merrifield resin (solid phase). In the solution-phase case, benzyl chloride reacted with the thiol group of 2-mercaptobenzo-[d]-imidazole, whereas in the solid-phase case, Merrifield resin was introduced at an internal amine group of benzo-[d]-imidazole. To afford the desired 2-alkoxy/thioalkoxy benzo-[d]-imidazole analogues, we used various alkyl halides, alcohols, and thiols in solution phase, and to obtain 2-thione benzo-[d]-imidazole derivatives on solid phase, we used diverse alkyl halides and boronic acids. Finally, to measure the drug potential to be orally active and the molecular diversity in three-dimensional (3D) space, we calculated physicochemical properties and displayed energy-minimized 3D structures. As a result, the libraries from solution phase and solid phase show distinct features in physicochemical properties and skeletal diversities in 3D space.
2-烷氧基/硫代烷氧基苯并[d]咪唑和2-硫酮苯并[d]咪唑文库分别在溶液相和固相中构建。这项工作的关键步骤是2-巯基苯并[d]咪唑中间体与苄基氯（溶液相）和 Merrifield 树脂（固相）的基于相的化学选择性反应。在溶液相的情况下，苄基氯与2-巯基苯并[d]咪唑的硫醇基团反应，而在固相的情况下，Merrifield 树脂被引入到苯并[d]咪唑的内胺基团处。为了得到所需的2-烷氧基/硫代烷氧基苯并[d]咪唑类似物，我们在溶液相中使用了各种卤代烃、醇和硫醇，并且为了在固相中获得2-硫酮苯并[d]咪唑衍生物，我们使用了不同的卤代烃和硼酸。最后，为了测量口服活性的药物潜力和三维（3D）空间中的分子多样性，我们计算了物理化学性质并展示了能量最小化的3D结构。结果，溶液相和固相的文库在物理化学性质和3D空间中的骨架多样性方面表现出明显的特征。
