Alzheimer's disease (AD) represents one of the main challenges for the 21st century medical research as no disease-modifying agent has been successfully progressed to the market, while the number of people affected by AD is estimated to grow exponentially over the next years. The complex network of triggering factors involved in the insurgence and progression of AD can be rightly addressed as one of the main reasons behind the difficulty in identifying new pharmacological approaches. For this reason, the discovery and development of drugs endowed with pleiotropic activity remain the most valuable, but at the same time challenging, approaches to tackle down AD. Interestingly, the combination of active pharmacophores through molecular hybridization – or Multi-Target Directed Ligand strategy (MTDL) - has not been explored enough for this disease, despite proving to be a successfully strategy in other field, such as oncology.To contribute to the development of new strategies against AD, we decided to explore the hybridization of the marketed drug rivastigmine - prescribed to ameliorate AD symptomatology - with moieties capable to release hydrogen sulfide (H₂S), a gasotransmitter with a key role in the neurological physiology of ageing. In particular, we identified compound 1, as a potent small molecule capable of inhibit AChE, preventing inflammation and ROS production in cultured neurons and microglia, triggering autophagy response and blocking Aβ fibrils propagation. Interestingly, the beneficial effects observed in vitro have been confirmed in vivo, since the rivastigmine derivative 1 improved the lifespan in a Caenorhabditis elegans model of AD.

中文翻译：

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释放 H2S 的新型卡巴拉汀衍生物作为神经保护分子的设计、合成和生物学评价


阿尔茨海默病 （AD） 是 21 世纪医学研究的主要挑战之一，因为没有疾病调节剂成功进入市场，而受 AD 影响的人数估计在未来几年将呈指数级增长。参与 AD 叛乱和进展的触发因素的复杂网络可以被正确解决为难以确定新药理学方法的主要原因之一。出于这个原因，发现和开发具有多效性活性的药物仍然是应对 AD 的最有价值但同时也具有挑战性的方法。有趣的是，通过分子杂交或多靶点定向配体策略 （MTDL） 组合活性药效团对于这种疾病尚未得到足够的探索，尽管在其他领域被证明是一种成功的策略， 比如肿瘤学。为了促进针对 AD 的新策略的开发，我们决定探索已上市药物卡巴拉汀（用于改善 AD 症状）与能够释放硫化氢 （H 2 S） 的部分的杂交，硫化氢 （H₂S） 是一种气体递质，在衰老的神经生理学中起关键作用。特别是，我们发现化合物 1 是一种有效的小分子，能够抑制 AChE，防止培养的神经元和小胶质细胞中的炎症和 ROS 产生，触发自噬反应并阻断 Aβ 原纤维的繁殖。有趣的是，在体外观察到的有益效果已在体内得到证实，因为卡巴拉汀衍生物 1 延长了 AD 秀丽隐杆线虫模型的寿命。