Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Faculty of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90d-151 Lodz, Poland.
Department of Medicinal Chemistry, Faculty of Pharmacy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland.
Int J Mol Sci. 2019 Jan 24;20(3):498. doi: 10.3390/ijms20030498.
Here we report the two-step synthesis of 8 new cyclopentaquinoline derivatives as modifications of the tetrahydroacridine structure. Next, the biological assessment of each of them was performed. Based on the obtained results we identified 6-chloro--[2-(2,3-dihydro--cyclopenta[b]quinolin-9-ylamino)-hexyl]]-nicotinamide hydrochloride () as the most promising compound with inhibitory potencies against EeAChE and EqBuChE in the low nanomolar level 67 and 153 nM, respectively. Moreover, compound is non-hepatotoxic, able to inhibit amyloid beta aggregation, and shows a mix-type of cholinesterase's inhibition. The mixed type of inhibition of the compound was confirmed by molecular modeling. Then, yeast three-hybrid (Y3H) technology was used to confirm the known ligand-receptor interactions. New derivatives do not show antioxidant activity (confirmed by the use of two different tests). A pKa assay method was developed to identify the basic physicochemical properties of compound. A LogP assay confirmed that compound fulfills Lipinsky's rule of five.
在这里，我们报告了 8 种新的环戊并喹啉衍生物的两步合成，作为四氢吖啶结构的修饰物。接下来，对它们中的每一种进行了生物评估。根据获得的结果，我们确定了 6-氯--[2-(2,3-二氢--环戊并[b]喹啉-9-基氨基)-己基]]-烟酰胺盐酸盐（）为最有前途的化合物，对 EeAChE 和 EqBuChE 的抑制活性分别在低纳摩尔水平 67 和 153 nM。此外，化合物是非肝毒性的，能够抑制淀粉样β聚合，并显示出混合类型的胆碱酯酶抑制作用。化合物的混合抑制类型通过分子建模得到了证实。然后，使用酵母三杂交（Y3H）技术来确认已知的配体-受体相互作用。新的衍生物不显示抗氧化活性（通过使用两种不同的测试方法来证实）。开发了一种 pKa 测定方法来确定化合物的基本物理化学性质。LogP 测定证实化合物符合 Lipinsky 的五规则。
