Ozadali-Sari Keriman, Tüylü Küçükkılınç Tuba, Ayazgok Beyza, Balkan Ayla, Unsal-Tan Oya
Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara, Turkey.
Hacettepe University, Faculty of Pharmacy, Department of Biochemistry, Ankara, Turkey.
Bioorg Chem. 2017 Jun;72:208-214. doi: 10.1016/j.bioorg.2017.04.018. Epub 2017 May 2.
The present study describes the synthesis, pharmacological evaluation (BChE/AChE inhibition, Aβ antiaggregation, and neuroprotective effects), and molecular modeling studies of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazole derivatives. The alkyl-substituted derivatives exhibited selective inhibition on BChE with varying efficiency. Compounds 3b and 3d were found to be the most potent inhibitors of BChE with IC values of 5.18 and 5.22μM, respectively. The kinetic studies revealed that 3b is a partial non-competitive BChE inhibitor. Molecular modeling studies also showed that the alkyl-substituted derivatives were able to reach the catalytic anionic site of the BChE. The compounds with an inhibitory effect on BChE were subsequently screened for their Aβ antiaggregating and neuroprotective activities. Compounds 3a and 3b exerted a potential neuroprotective effect against HO and Aβ-induced cytotoxicity in SH-SY5Y cells. Collectively, 3b was found as the most promising compound for the development of multi-target directed ligands against Alzheimer's disease.
本研究描述了新型2-[4-(4-取代哌嗪-1-基)苯基]苯并咪唑衍生物的合成、药理学评价（丁酰胆碱酯酶/乙酰胆碱酯酶抑制、β-淀粉样蛋白抗聚集和神经保护作用）以及分子模拟研究。烷基取代衍生物对丁酰胆碱酯酶表现出不同效率的选择性抑制作用。发现化合物3b和3d是最有效的丁酰胆碱酯酶抑制剂，IC值分别为5.18和5.22μM。动力学研究表明3b是一种部分非竞争性丁酰胆碱酯酶抑制剂。分子模拟研究还表明，烷基取代衍生物能够到达丁酰胆碱酯酶的催化阴离子位点。随后对具有丁酰胆碱酯酶抑制作用的化合物进行了β-淀粉样蛋白抗聚集和神经保护活性筛选。化合物3a和3b对6-羟基多巴胺和β-淀粉样蛋白诱导的SH-SY5Y细胞毒性具有潜在的神经保护作用。总体而言，发现3b是开发针对阿尔茨海默病的多靶点定向配体最有前景的化合物。
