Cabrera-Pardo Jaime R, Fuentealba Jorge, Gavilán Javiera, Cajas Daniel, Becerra José, Napiórkowska Mariola
Departamento de Química, Facultad de Ciencias, Universidad del Bio-Bio, Concepción, Chile.
Departamento de Botánica, Facultad de Ciencias Naturales y Oceanográficas, Universidad de Concepción, Concepción, Chile.
Front Pharmacol. 2020 Jan 31;10:1679. doi: 10.3389/fphar.2019.01679. eCollection 2019.
Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder that slowly destroys memory. The precise mechanism of AD is still not entirely understood and remains under discussion; it is believed to be a multifactorial disease in which a number of mechanisms are involved in its pathogenesis. Worldwide, near 37 million people suffer from the effects of AD. As a cause of death for elderly, it is predicted that AD will rank third in the coming years, just behind cancer and heart disease. Unfortunately, AD remains an incurable condition. Despite the devastating problems associated with AD, there are only four FDA approved drugs for palliative treatment of this pathology. Hence, renewed scientific efforts are required not only to uncover more insights into the AD process but also to develop more efficient pharmacological tools against this disease. Due to the complexity and multiple mechanisms at play in the progression of AD, the development of drugs by rational design is extremely difficult. The existing drugs to fight against Alzheimer's have had limited success, mainly due to their ability to modulate only one of the mechanisms involved in AD. As opposed to single-targeted strategies, the identification of small molecules able to affect multiple pathways involved in Alzheimer's is a promising strategy to develop more efficient medicines against this disease. Central to existing efforts to develop pharmaceuticals controlling AD is the discovery of new chemicals displaying strong neuroactivity. Benzofurans are privileged oxygen containing heterocycles that have a strong neuroprotective behavior, inhibiting several of the important events involved in the AD process. In this review, an approach is presented that relies on expanding the neuroprotective chemical space of benzofuran scaffolds by accessing them from Andean-Patagonian fungi and synthetic sources (chemical libraries). The exploration of the neuroprotective chemical space of these scaffolds has the potential to allow the discovery of substitution patterns that display multi-target neuroactivity against multiple events involved in AD. This benzofuran chemical framework will establish a multi-target chemical space that could set the basis for the development of super drugs against AD.
阿尔茨海默病（AD）是一种不可逆转的进行性神经退行性疾病，会缓慢破坏记忆。AD的确切机制仍未完全明了，仍在探讨之中；人们认为它是一种多因素疾病，其发病机制涉及多种机制。在全球范围内，近3700万人受到AD的影响。作为老年人的死因之一，预计AD在未来几年将排名第三，仅次于癌症和心脏病。不幸的是，AD仍然无法治愈。尽管与AD相关的问题具有毁灭性，但美国食品药品监督管理局（FDA）仅批准了四种药物用于这种病症的姑息治疗。因此，不仅需要重新做出科学努力以更深入了解AD的发病过程，还需要开发更有效的抗这种疾病的药物工具。由于AD进展过程中存在复杂性和多种机制，通过合理设计开发药物极其困难。现有的抗阿尔茨海默病药物取得的成功有限，主要是因为它们只能调节AD所涉及的一种机制。与单靶点策略不同，识别能够影响AD所涉及的多种途径的小分子是开发更有效抗这种疾病药物的一种有前景的策略。现有开发控制AD药物的努力的核心是发现具有强大神经活性的新化学物质。苯并呋喃是具有特殊结构的含氧杂环化合物，具有很强的神经保护作用，可抑制AD过程中涉及的一些重要事件。在本综述中，提出了一种方法，该方法依赖于通过从安第斯 - 巴塔哥尼亚真菌和合成来源（化学文库）获取苯并呋喃支架来扩展其神经保护化学空间。对这些支架的神经保护化学空间的探索有可能发现针对AD所涉及的多个事件具有多靶点神经活性的取代模式。这种苯并呋喃化学框架将建立一个多靶点化学空间，可为开发抗AD超级药物奠定基础。
