Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001, Lisboa, Portugal; Centre for Nano and Material Sciences, Jain University, Jain Global Campus, Kanakapura, Ramanagara, Bangalore 562112, India.
Centre for Nano and Material Sciences, Jain University, Jain Global Campus, Kanakapura, Ramanagara, Bangalore 562112, India.
Eur J Med Chem. 2018 Mar 25;148:255-267. doi: 10.1016/j.ejmech.2018.02.023. Epub 2018 Feb 12.
Alzheimer's disease (AD) is a severe age-dependent neurodegenerative disorder affecting millions of people, with no cure so far. The current treatments only achieve some temporary amelioration of the cognition symptoms. The main characteristics of the patient brains include the accumulation of amyloid plaques and neurofibrillary tangles (outside and inside the neurons) but also cholinergic deficit, increased oxidative stress and dyshomeostasis of transition metal ions. Considering the multi-factorial nature of AD, we report herein the development of a novel series of potential multi-target directed drugs which, besides the capacity to recover the cholinergic neurons, can also target other AD hallmarks. The novel series of tacrine-hydroxyphenylbenzimidazole (TAC-BIM) hybrid molecules has been designed, synthesized and studied for their multiple biological activities. These agents showed improved AChE inhibitory activity (IC in nanomolar range), as compared with the single drug tacrine (TAC), and also a high inhibition of self-induced- and Cu-induced-Aβ aggregation (up to 75%). They also present moderate radical scavenging activity and metal chelating ability. In addition, neuroprotective studies revealed that all these tested compounds are able to inhibit the neurotoxicity induced by Aβ and Fe/AscH(-) in neuronal cells. Hence, for this set of hybrids, structure-activity relationships are discussed and finally it is highlighted their real promising interest as potential anti-AD drugs.
阿尔茨海默病（AD）是一种严重的年龄相关性神经退行性疾病，影响着数以百万计的人，目前尚无治愈方法。目前的治疗方法只能暂时改善认知症状。患者大脑的主要特征包括淀粉样斑块和神经原纤维缠结（神经元内外）的积累，但也包括胆碱能缺乏、氧化应激增加和过渡金属离子的动态平衡失调。考虑到 AD 的多因素性质，我们在此报告了一系列新的潜在多靶标导向药物的开发，这些药物除了恢复胆碱能神经元的能力外，还可以针对其他 AD 特征。我们设计、合成了新型的他克林-羟苯基苯并咪唑（TAC-BIM）杂合分子，并研究了它们的多种生物学活性。与单药他克林（TAC）相比，这些药物显示出改善的乙酰胆碱酯酶抑制活性（IC 在纳摩尔范围内），并且对自诱导和 Cu 诱导的 Aβ 聚集也具有高抑制作用（高达 75%）。它们还具有中等的自由基清除活性和金属螯合能力。此外，神经保护研究表明，所有这些测试的化合物都能够抑制 Aβ 和 Fe/AscH（-）在神经元细胞中诱导的神经毒性。因此，对于这组杂合物，讨论了构效关系，并最终强调了它们作为潜在的抗 AD 药物的真正有希望的兴趣。
