Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan.
Applied Chemistry Research Centre, PCSIR Laboratories Complex, Lahore 54600, Pakistan.
Molecules. 2021 Jan 27;26(3):656. doi: 10.3390/molecules26030656.
Alzheimer's disease (AD), a progressive neurodegenerative disorder, characterized by central cognitive dysfunction, memory loss, and intellectual decline poses a major public health problem affecting millions of people around the globe. Despite several clinically approved drugs and development of anti-Alzheimer's heterocyclic structural leads, the treatment of AD requires safer hybrid therapeutics with characteristic structural and biochemical properties. In this endeavor, we herein report a microwave-assisted synthesis of a library of quinoline thiosemicarbazones endowed with a piperidine moiety, achieved via the condensation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes and (un)substituted thiosemicarbazides. The target -heterocyclic products were isolated in excellent yields. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, H- and C-NMR). Anti-Alzheimer potential of the synthesized heterocyclic compounds was evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vitro biochemical assay results revealed several compounds as potent inhibitors of both enzymes. Among them, five compounds exhibited IC values less than 20 μM. -(3-chlorophenyl)-2-((8-methyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)hydrazine carbothioamide emerged as the most potent dual inhibitor of AChE and BChE with IC values of 9.68 and 11.59 μM, respectively. Various informative structure-activity relationship (SAR) analyses were also concluded indicating the critical role of substitution pattern on the inhibitory efficacy of the tested derivatives. In vitro results were further validated through molecular docking analysis where interactive behavior of the potent inhibitors within the active pocket of enzymes was established. Quinoline thiosemicarbazones were also tested for their cytotoxicity using MTT assay against HepG2 cells. Among the 26 novel compounds, there were five cytotoxical and 18 showed proliferative properties.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，以中枢认知功能障碍、记忆丧失和智力下降为特征，是全球数百万人面临的主要公共卫生问题。尽管有几种临床批准的药物和抗阿尔茨海默病杂环结构先导物的开发，但 AD 的治疗需要具有特征结构和生化特性的更安全的杂合疗法。在这项努力中，我们在此报告了通过 6/8-甲基-2-（哌啶-1-基）喹啉-3-甲醛和（未）取代的硫代卡巴肼的缩合，微波辅助合成了一系列带有哌啶部分的喹啉缩硫代氨基脲文库。目标杂环产物以优异的产率分离。所有合成化合物的结构均通过易于获得的光谱技术（FTIR、H 和 C-NMR）充分建立。使用乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）酶评估合成杂环化合物的抗阿尔茨海默病潜力。体外生化测定结果表明，几种化合物是两种酶的有效抑制剂。其中，有 5 种化合物的 IC 值小于 20 μM。-(3-氯苯基）-2-((8-甲基-2-(哌啶-1-基)喹啉-3-基)亚甲基)肼基硫代甲酰胺表现出对 AChE 和 BChE 的最强双重抑制作用，IC 值分别为 9.68 和 11.59 μM。还得出了各种有意义的构效关系（SAR）分析，表明取代模式对测试衍生物的抑制效果具有关键作用。通过分子对接分析进一步验证了体外结果，其中建立了强效抑制剂在酶活性口袋内的相互作用行为。还使用 MTT 测定法通过对 HepG2 细胞的细胞毒性测试了喹啉缩硫代氨基脲。在 26 种新化合物中，有 5 种具有细胞毒性，18 种具有增殖特性。
