Institute for Medical Research and Occupational Health, Ksaverska c. 2, HR-10001 Zagreb, Croatia.
Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloska 4, SLO-1001 Ljubljana, Slovenia.
Int J Mol Sci. 2020 Oct 29;21(21):8088. doi: 10.3390/ijms21218088.
We evaluated the potential of nine vitamin B3 scaffold-based derivatives as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors, as a starting point for the development of novel drugs for treating disorders with cholinergic neurotransmission-linked pathology. As the results indicate, all compounds reversibly inhibited both enzymes in the micromolar range pointing to the preference of AChE over BChE for binding the tested derivatives. Molecular docking studies revealed the importance of interactions with AChE active site residues Tyr337 and Tyr124, which dictated most of the observed differences. The most potent inhibitor of both enzymes with of 4 μM for AChE and 8 μM for BChE was the nicotinamide derivative 1-(4'-phenylphenacyl)-3-carbamoylpyridinium bromide. Such a result places it within the range of several currently studied novel cholinesterase inhibitors. Cytotoxicity profiling did not classify this compound as highly toxic, but the induced effects on cells should not be neglected in any future detailed studies and when considering this scaffold for drug development.
我们评估了基于 9 种维生素 B3 支架的衍生物作为乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）抑制剂的潜力，作为开发用于治疗与胆碱能神经递质传递相关疾病的新型药物的起点。结果表明，所有化合物均以微摩尔范围可逆地抑制这两种酶，表明与结合测试衍生物相比，AChE 对 BChE 具有更高的亲和力。分子对接研究表明，与 AChE 活性位点残基 Tyr337 和 Tyr124 的相互作用非常重要，这决定了大部分观察到的差异。对两种酶均具有最强抑制作用的抑制剂是烟酰胺衍生物 1-(4'-苯基苯甲酰基）-3-氨甲酰基吡啶溴化物，对 AChE 的 IC50 为 4 μM，对 BChE 的 IC50 为 8 μM。这样的结果使其处于几种目前正在研究的新型胆碱酯酶抑制剂的范围内。细胞毒性分析并未将该化合物归类为高毒性，但在任何未来的详细研究中，以及在考虑将该支架用于药物开发时，都不应忽视其对细胞的诱导作用。
