Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Rm # 123, Varanasi 221005, India.
Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam 781032, India.
ACS Chem Neurosci. 2024 Aug 7;15(15):2756-2778. doi: 10.1021/acschemneuro.4c00130. Epub 2024 Jul 30.
Alzheimer's disease (AD) is the most prevalent cause of dementia and is characterized by low levels of acetyl and butyrylcholine, increased oxidative stress, inflammation, accumulation of metals, and aggregations of Aβ and tau proteins. Current treatments for AD provide only symptomatic relief without impacting the pathological hallmarks of the disease. In our ongoing efforts to develop naturally inspired novel multitarget molecules for AD, through extensive medicinal chemistry efforts, we have developed , harboring the key functional groups to provide not only symptomatic relief but also targeting oxidative stress, able to chelate iron, inhibiting NLRP3, and Aβ aggregation in various AD models. exhibited promising anticholinesterase activity against AChE (IC = 0.59 ± 0.19 μM) and BChE (IC = 5.02 ± 0.14 μM) with excellent antioxidant properties in DPPH assay (IC = 5.88 ± 0.21 μM) over ferulic acid (56.49 ± 0.62 μM). The molecular docking and dynamic simulations further corroborated the enzyme inhibition studies and confirmed the stability of these complexes. Importantly, in the PAMPA-BBB assay, turned out to be a promising molecule that can efficiently cross the blood-brain barrier. Notably, also exhibited iron-chelating properties. Furthermore, effectively inhibited self- and metal-induced Aβ aggregation. It is worth mentioning that demonstrated no symptom of cytotoxicity up to 30 μM concentration in PC-12 cells. Additionally, inhibited the NLRP3 inflammasome and mitigated mitochondrial-induced reactive oxygen species and mitochondrial membrane potential damage triggered by LPS and ATP in HMC-3 cells. could effectively reduce mitochondrial and cellular reactive oxygen species (ROS) in the Drosophila model of AD. Finally, was found to be efficacious in reversing memory impairment in a scopolamine-induced AD mouse model in the in vivo studies. In ex vivo assessments, notably modulates the levels of superoxide, catalase, and malondialdehyde along with AChE and BChE. These findings revealed that holds promise as a potential candidate for further development in AD management.
阿尔茨海默病（AD）是痴呆症最常见的病因，其特征是乙酰胆碱和丁酰胆碱水平降低，氧化应激增加、炎症、金属积累以及 Aβ和 tau 蛋白聚集。目前用于 AD 的治疗方法只能提供症状缓解，而不能影响疾病的病理特征。在我们为开发受自然启发的用于 AD 的新型多靶标分子而进行的持续努力中，通过广泛的药物化学努力，我们开发了 ，它具有提供不仅症状缓解，而且靶向氧化应激、能够螯合铁、抑制 NLRP3 和在各种 AD 模型中抑制 Aβ聚集的关键功能基团。 在 AChE（IC = 0.59 ± 0.19 μM）和 BChE（IC = 5.02 ± 0.14 μM）上表现出有希望的抗胆碱酯酶活性，并且在 DPPH 测定中具有极好的抗氧化特性（IC = 5.88 ± 0.21 μM），超过阿魏酸（56.49 ± 0.62 μM）。分子对接和动态模拟进一步证实了酶抑制研究，并确认了这些配合物的稳定性。重要的是，在 PAMPA-BBB 测定中， 被证明是一种有前途的分子，可以有效地穿过血脑屏障。值得注意的是， 还表现出铁螯合特性。此外， 有效抑制了自身和金属诱导的 Aβ聚集。值得一提的是， 在 PC-12 细胞中，浓度高达 30 μM 时也没有表现出细胞毒性症状。此外， 在 HMC-3 细胞中， 抑制了 LPS 和 ATP 触发的 NLRP3 炎性小体和线粒体诱导的活性氧和线粒体膜电位损伤，并减轻了线粒体诱导的活性氧和线粒体膜电位损伤。 在 AD 的果蝇模型中， 可以有效降低线粒体和细胞内的活性氧（ROS）。最后， 在体内研究中， 在东莨菪碱诱导的 AD 小鼠模型中被发现能有效逆转记忆障碍。在离体评估中， 显著调节超氧化物、过氧化氢酶和丙二醛以及 AChE 和 BChE 的水平。这些发现表明， 作为 AD 管理的进一步开发的潜在候选药物具有前景。
