Coumarin-Rasagiline Hybrids as Potent and Selective hMAO-B Inhibitors, Antioxidants, and Neuroprotective Agents.,ChemMedChem

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Coumarin-Rasagiline Hybrids as Potent and Selective hMAO-B Inhibitors, Antioxidants, and Neuroprotective Agents.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-02-10 , DOI: 10.1002/cmdc.202000018
Maria J Matos _{1,

2} , Diana M Herrera Ibatá ₃ , Eugenio Uriarte _{2,

4} , Dolores Viña ₃

Affiliation

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.

中文翻译：

香豆素-雷沙吉兰杂种作为有效的和选择性的hMAO-B抑制剂，抗氧化剂和神经保护剂。

神经退行性疾病的频率，复杂性和发病率使它们成为当今医学的巨大挑战。目前用于帕金森氏病的大多数疗法（第二多见）只是有症状的。因此，迫切需要开发一种能够同时作用于不同靶点，能够停止神经元死亡并促进已经受影响的神经元种群恢复的药物。在这项工作中，我们研究了一系列杂合分子的活性，这些杂合分子结合了香豆素和受雷沙吉兰启发的炔基基团的结构，作为MAO抑制剂，抗氧化剂和神经保护剂。研究的杂种中有一半是微/纳摩尔范围低的选择性单胺氧化酶B（hMAO-B）抑制剂，表明香豆素支架的位置3（化合物1-3）和7（化合物8和10）最适合于炔基胺链的掺入。所有研究的化合物都证明能够中和自由基（DPPH）。最后，4-（but-2-yn-1-ylamino）香豆素（5）对神经胶质细胞有神经保护作用，而4-methyl-7-（pent-2-yn-1-ylamino）香豆素（8）被抑制。神经内ROS的产生也是如此。

更新日期：2020-02-27

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