CIQUP/Department of Chemistry and Biochemistry Faculty of Sciences, University of Porto, 4169-007, Porto, Portugal.
Departamento de Química Orgánica Facultad de Farmacia, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, Spain.
ChemMedChem. 2020 Mar 18;15(6):532-538. doi: 10.1002/cmdc.202000018. Epub 2020 Feb 27.
The frequency, complexity and morbidity of neurodegenerative diseases make them a great challenge for nowadays medicine. Most of the treatments currently used for Parkinson's disease - the second most prevalent - are only symptomatic. Therefore, it is urgent to develop drugs that are able to act simultaneously on different targets, being able to stop neuronal death and promote the recovery of neuronal populations already affected. In this work, we studied the activity of a series of hybrid molecules, which combine the structure of both coumarin and an alkynylamine group inspired on rasagiline, as MAO inhibitors, antioxidants and neuroprotective agents. Half of the studied hybrids turned out to be selective monoamine oxidase B (hMAO-B) inhibitors in the low micro/nanomolar range, demonstrating that positions 3 (compounds 1-3) and 7 (compounds 8 and 10) of the coumarin scaffold are the most suitable for the incorporation of the alkynylamine chain. All the studied compounds proved to be capable of neutralizing free radicals (DPPH). Finally, the 4-(but-2-yn-1-ylamino)coumarin (5) showed neuroprotective effects on glial cells and the 4-methyl-7-(pent-2-yn-1-ylamino)coumarin (8) inhibited intraneuronal ROS production as well.
神经退行性疾病的频率、复杂性和发病率使其成为当今医学的一大挑战。目前用于帕金森病（第二大常见疾病）的大多数治疗方法只是对症治疗。因此，迫切需要开发能够同时针对不同靶点的药物，既能阻止神经元死亡，又能促进已受影响的神经元群体的恢复。在这项工作中，我们研究了一系列杂合分子的活性，这些分子结合了香豆素和炔丙胺基团的结构，灵感来自于雷沙吉兰，作为 MAO 抑制剂、抗氧化剂和神经保护剂。所研究的杂合分子中有一半对单胺氧化酶 B（hMAO-B）具有选择性抑制作用，抑制浓度在低微/纳摩尔范围内，这表明香豆素支架的 3 位（化合物 1-3）和 7 位（化合物 8 和 10）最适合引入炔丙胺链。所有研究的化合物都被证明能够中和自由基（DPPH）。最后，4-（丁-2-炔-1-基氨基）香豆素（5）对神经胶质细胞表现出神经保护作用，而 4-甲基-7-（戊-2-炔-1-基氨基）香豆素（8）也抑制了细胞内 ROS 的产生。
