Pharmaceutical Chemistry Section, Van Yuzuncu Yil University, 65080 Van, Turkey; SAFF Chemical Reagent R&D Lab. YYU-TEKNOKENT, 65080 Van, Turkey.
Department of Chemistry, Atatürk University, 25240 Erzurum, Turkey.
Bioorg Chem. 2019 May;86:187-196. doi: 10.1016/j.bioorg.2019.01.044. Epub 2019 Jan 24.
Mono- or di-substituted imidazole derivatives were synthesized using a one-pot, two-step strategy. All imidazole derivatives were tested for AChE and BChE inhibition and showed nanomolar activity similar to that of the test compound donepezil and higher than that of tacrine. Structure activity relationship studies, docking studies to on X-ray crystal structure of AChE with PDB code 1B41, and adsorption, distribution, metabolism, and excretion (ADME) predictions were performed. The synthesized core skeleton was bound to important regions of the active site of AChE such as the peripheral anionic site (PAS), oxyanion hole (OH), and anionic subsite (AS). Selectivity of the reported test compounds was calculated and enzyme kinetic studies revealed that they behave as competitive inhibitors, while two of the test compounds showed noncompetitive inhibitory behavior. ADME predictions revealed that the synthesized molecules might pass through the blood brain barrier and intestinal epithelial barrier and circulate freely in the blood stream without binding to human serum albumin. While the toxicity of one compound on the WS1 (skin fibroblast) cell line was 1790 µM, its toxicity on the SH-SY5Y (neuroblastoma) cell line was 950 µM.
采用一锅两步法合成了单取代或二取代咪唑衍生物。所有咪唑衍生物均进行了 AChE 和 BChE 抑制测试，其活性与测试化合物多奈哌齐相似，均为纳摩尔级，高于他克林。进行了构效关系研究、与 X 射线晶体结构（pdb 代码 1B41）对接研究以及吸收、分布、代谢和排泄（ADME）预测。合成的核心骨架与 AChE 的活性部位的重要区域结合，如外周阴离子部位（PAS）、氧阴离子穴（OH）和阴离子亚部位（AS）。计算了报告的测试化合物的选择性，酶动力学研究表明它们为竞争性抑制剂，而两种测试化合物表现出非竞争性抑制行为。ADME 预测表明，合成的分子可能穿过血脑屏障和肠上皮屏障，并在血液中自由循环，而不与人血清白蛋白结合。虽然一种化合物对 WS1（皮肤成纤维细胞）细胞系的毒性为 1790µM，但对 SH-SY5Y（神经母细胞瘤）细胞系的毒性为 950µM。
