Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, The Medical University of Silesia in Katowice Jagiellońska 4, 41-200 Sosnowiec, Poland.
Molecules. 2020 Jun 3;25(11):2604. doi: 10.3390/molecules25112604.
The inverse correlation observed between Alzheimer's disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological activity in anticancer polycyclic, tricyclic, and tetracyclic compounds. The virtual screening of a library of 120 ligands, which are the derivatives of azaphenothiazine, led to the identification of 25 compounds that can act as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Biological assays revealed the presence of selective inhibitors of AChE ( AChE) or BuChE ( BuChE) and nonselective inhibitors of both enzymes among the tested compounds. Their potencies against AChE were in a submicromolar-to-micromolar range with IC values from 0.78 to 19.32 μM, while their IC values against BuChE ranged from 0.46 to 10.38 μM. The most potent among the compounds tested was the tetracyclic derivative, 6-(4-diethylaminobut-2-ynyl)-9-methylthioquinobenzothiazine , which was capable of inhibiting both enzymes. 9-Fluoro-6-(1-piperidylethyl)quinobenzothiazine was found to act as a selective inhibitor of BuChE with an IC value of 0.46 μM. Compounds with such a dual antitumor and cholinesterase-inhibitory activity can be considered as a valuable combination for the treatment of both cancer and AD prevention. The results presented in this study might open new directions of research on the group of tricyclic phenothiazine derivatives.
阿尔茨海默病（AD）与癌症之间呈负相关关系，促使我们在具有抗癌特性的吩噻嗪衍生物中寻找具有抑制胆碱酯酶活性的物质。通过使用计算机筛选和体外筛选方法，我们在具有抗癌多环、三环和四环结构的化合物中发现了一种新的生物活性。对 120 种配体（氮杂吩噻嗪衍生物）文库进行虚拟筛选，鉴定出 25 种可作为乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）潜在抑制剂的化合物。生物测定结果表明，在所测试的化合物中，存在 AChE（AChE）或 BuChE（BuChE）的选择性抑制剂以及两种酶的非选择性抑制剂。它们对 AChE 的活性在亚微摩尔至微摩尔范围内，IC 值为 0.78 至 19.32 μM，而对 BuChE 的 IC 值范围为 0.46 至 10.38 μM。在所测试的化合物中，最有效的是四环衍生物 6-(4-二乙氨基丁-2-炔基)-9-甲基硫代喹喔啉苯并噻嗪，它能够抑制两种酶。9-氟-6-(1-哌啶基乙基)喹喔啉苯并噻嗪被发现是 BuChE 的选择性抑制剂，IC 值为 0.46 μM。具有这种双重抗肿瘤和胆碱酯酶抑制活性的化合物可被视为治疗癌症和预防 AD 的有价值组合。本研究结果可能为三环吩噻嗪衍生物的研究开辟新的方向。
