Kilic Burcu, Erdogan Merve, Gulcan Hayrettin O, Aksakal Fatma, Oruklu Nihan, Bagriacik Emin U, Dogruer Deniz S
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Eastern Mediterranean University, Gazimagosa, North Cyprus, Cyprus.
Med Chem. 2019;15(1):59-76. doi: 10.2174/1573406414666180524073241.
With respect to the increase in the average life expectancy, Alzheimer Disease (AD), the most common form of age-related dementia, has become a major threat to the population over the age of 65 during the past several decades. The majority of AD treatments are focused on cholinergic and amyloid hypotheses.
In this study, three series of diphenyl-2-(2-(4-substitutedpiperazin-1-yl)ethyl)pyridazin- 3(2H)-one derivatives were designed, synthesized and investigated for their ability to inhibit both cholinesterase enzymes and amyloid-β aggregation.
The inhibitory activities of the synthesized compounds on AChE (from electric eel) and BChE (from equine serum) were determined by the modified Ellman's method. The reported thioflavin T-based fluorometric assay was performed to investigate the effect of the selected compounds on the aggregation of Aβ1-42. The cytotoxic effect of the compounds (4g, 11g and 18g) was monitored in 3T3 cell lines to gain insight into therapeutic potential of the compounds by using MTT assay. The crystal structures of the AChE (1EVE) and BChE (1P0I) enzymes were retrieved from the RCSB Protein Data Bank and Molecular Operating Environment (MOE) software was used for molecular docking of the ligands.
Among the tested compounds, 5,6-diphenyl derivative 18g was identified as the most potent and selective AChE inhibitor (IC50 = 1.75 µM, Selectivity Index for AChE > 22.857). 4,6- Diphenyl derivative 11g showed the highest and the most selectivity for BChE (IC50= 4.97 µM, SI for AChE < 0.124). Interestingly, 4,5-diphenyl derivative 4g presented dual cholinesterase inhibition (AChE IC50= 5.11 µM; BChE IC50= 14.16 µM, SI for AChE = 2.771).
Based on biological activity results and low toxicity of the compounds, it can be said that diphenyl substituted pyridazinone core is a valuable scaffold. Especially, dual inhibitory potencies of 4,5-diphenylpyridazin-3(2H)-one core for the cholinesterase enzymes and Aβ- aggregation makes this core a promising disease-modifying agent.
随着平均预期寿命的增加，阿尔茨海默病（AD）作为年龄相关性痴呆最常见的形式，在过去几十年中已成为对65岁以上人群的主要威胁。大多数AD治疗方法集中在胆碱能和淀粉样蛋白假说上。
在本研究中，设计、合成了三个系列的2-（2-（4-取代哌嗪-1-基）乙基）哒嗪-3（2H）-酮二苯基衍生物，并研究了它们抑制胆碱酯酶和淀粉样β蛋白聚集的能力。
采用改良的Ellman法测定合成化合物对乙酰胆碱酯酶（来自电鳗）和丁酰胆碱酯酶（来自马血清）的抑制活性。采用报道的基于硫黄素T的荧光测定法研究所选化合物对Aβ1-42聚集的影响。通过MTT法监测化合物（4g、11g和18g）在3T3细胞系中的细胞毒性作用，以深入了解这些化合物的治疗潜力。从RCSB蛋白质数据库检索乙酰胆碱酯酶（1EVE）和丁酰胆碱酯酶（1P0I）的晶体结构，并使用分子操作环境（MOE）软件进行配体的分子对接。
在测试的化合物中，5,6-二苯基衍生物18g被确定为最有效和选择性最高的乙酰胆碱酯酶抑制剂（IC50 = 1.75 μM，乙酰胆碱酯酶选择性指数> 22.857）。4,6-二苯基衍生物11g对丁酰胆碱酯酶表现出最高和最具选择性（IC50 = 4.97 μM，乙酰胆碱酯酶选择性指数< 0.124）。有趣的是，4,5-二苯基衍生物4g呈现出双重胆碱酯酶抑制作用（乙酰胆碱酯酶IC50 = 5.11 μM；丁酰胆碱酯酶IC50 = 14.16 μM，乙酰胆碱酯酶选择性指数 = 2.771）。
基于化合物的生物活性结果和低毒性，可以说二苯基取代的哒嗪酮核心是一种有价值的骨架。特别是，4,5-二苯基哒嗪-3（2H）-酮核心对胆碱酯酶和Aβ聚集的双重抑制效力使其成为一种有前景的疾病修饰剂。
