Department of Biotechnology, Alagappa University, Karaikudi 630003, India.
Department of Industrial Chemistry, Alagappa University, Karaikudi 630003, India.
Bioorg Chem. 2018 Dec;81:340-349. doi: 10.1016/j.bioorg.2018.08.037. Epub 2018 Aug 28.
Synthesis of natural products has speeded up drug discovery process by minimizing the time for their purification from natural source. Several diseases like Alzheimer's disease (AD) demand exploring multi targeted drug candidates, and for the first time we report the multi AD target inhibitory potential of synthesized dihydroactinidiolide (DA). Though the activity of DA in several solvent extracts have been proved to possess free radical scavenging, anti bacterial and anti cancer activities, its neuroprotective efficacy has not been evidenced yet. Hence DA was successfully synthesized from β-ionone using facile two-step oxidation method. It showed potent acetylcholinesterase (AChE) inhibition with half maximal inhibitory concentration (IC) 34.03 nM, which was further supported by molecular docking results showing strong H bonding with some of the active site residues such as GLY117, GLY119 and SER200 of AChE. Further it displayed DPPH and (.NO) scavenging activity with IC value 50 nM and metal chelating activity with IC >270 nM. Besides, it significantly prevented amyloid β self-aggregation and promoted its disaggregation at 270 nM. It did not show cytotoxic effect towards Neuro2a (N2a) cells up to 24 h at 50 and 270 nM while it significantly increased viability of amyloid β treated N2a cells through ROS generation at both the concentrations. Cytotoxicity profile of DA against human PBMC was quite impressive. Hemolysis studies also revealed very low hemolysis i.e. minimum 2.35 to maximum 5.61%. It also had suitable ADME properties which proved its druglikeness. The current findings demand for further in vitro and in vivo studies to develop DA as a multi target lead against AD.
天然产物的合成通过最大限度地减少从天然来源中对其进行纯化的时间，加快了药物发现的过程。阿尔茨海默病（AD）等几种疾病需要探索多靶向药物候选物，我们首次报告了合成二氢猕猴桃内酯（DA）的多 AD 靶标抑制潜力。虽然已经证明 DA 在几种溶剂提取物中的活性具有自由基清除、抗菌和抗癌活性，但尚未证明其神经保护功效。因此，成功地从β-紫罗兰酮使用简便的两步氧化法合成了 DA。它显示出强烈的乙酰胆碱酯酶（AChE）抑制作用，半数最大抑制浓度（IC）为 34.03 nM，分子对接结果进一步支持了这一结果，表明它与 AChE 的一些活性位点残基（如 GLY117、GLY119 和 SER200）具有强烈的氢键。此外，它还显示出 DPPH 和（.NO）清除活性，IC 值为 50 nM，金属螯合活性，IC 值>270 nM。此外，它在 270 nM 时可显著防止淀粉样β自聚集并促进其解聚。在 50 和 270 nM 时，它在 24 小时内对神经细胞（N2a）没有细胞毒性作用，但在两个浓度下均通过 ROS 生成显著增加了淀粉样β处理的 N2a 细胞的活力。DA 对人 PBMC 的细胞毒性特征令人印象深刻。溶血研究也显示出非常低的溶血，即最低 2.35 至最高 5.61%。它还具有合适的 ADME 特性，证明了它的成药性。目前的研究结果需要进一步的体外和体内研究，以开发 DA 作为治疗 AD 的多靶先导化合物。
