Alzheimer's disease (AD) is the most common form of dementia worldwide with an increasing prevalence for the next years. The multifactorial nature of AD precludes the design of new drugs directed to a single target being probably one of the reasons for recent failures. Therefore, dual binding site acetylcholinesterase (AChE) inhibitors have been revealed as cognitive enhancers and β-amyloid modulators offering an alternative in AD therapy field. Based on the dual ligands NP61 and donepezil, the present study reports the synthesis of a series of indolylpiperidines hybrids to optimize the NP61 structure preserving the indole nucleus, but replacing the tacrine moiety of NP61 by benzyl piperidine core found in donepezil. Surprisingly, this new family of indolylpiperidines derivatives showed very potent and selective hBuChE inhibition. Further studies of NMR and molecular dynamics have showed the capacity of these hybrid molecules to change their bioactive conformation depending on the binding site, being capable to inhibit with different shapes BuChE and residually AChE.

阿尔茨海默氏病（AD）是全世界痴呆症最常见的形式，并且在接下来的几年中患病率会不断提高。AD的多因素性质使得针对单一靶标的新药的设计可能是近期失败的原因之一。因此，已经揭示了双结合位点乙酰胆碱酯酶（AChE）抑制剂作为认知增强剂和β-淀粉样调节剂，在AD治疗领域提供了替代方案。基于双配体NP61和多奈哌齐，本研究报道了一系列吲哚基哌啶杂化物的合成，以优化NP61结构，保留吲哚核，但用多奈哌齐中的苄基哌啶核取代了NP61的他克林部分。令人惊讶的是，这个新的吲哚基哌啶衍生物家族显示出非常有效和选择性的hBuChE抑制。NMR和分子动力学的进一步研究表明，这些杂合分子具有根据结合位点改变其生物活性构象的能力，能够抑制不同形状的BuChE和残留的AChE。