Abstract

Pursuing the widespread interest on multi-target drugs to combat Alzheimer´s disease (AD), a new series of hybrids was designed and developed based on the repositioning of the well-known acetylcholinesterase (AChE) inhibitor, tacrine (TAC), by its coupling to benzofuran (BF) derivatives. The BF framework aims to endow the conjugate molecules with ability for inhibition of AChE (bimodal way) and of amyloid-beta peptide aggregation, besides providing metal (Fe, Cu) chelating ability and concomitant extra anti-oxidant activity, for the hybrids with hydroxyl substitution. The new TAC-BF conjugates showed very good activity for AChE inhibition (sub-micromolar range) and good capacity for the inhibition of self- and Cu-mediated Aβ aggregation, with dependence on the linker size and substituent groups of each main moiety. Neuroprotective effects were also found for the compounds through viability assays of neuroblastoma cells, after Aβ_1-42 induced toxicity. Structure-activity relationship analysis provides insights on the best structural parameters, to take in consideration for future studies in view of potential applications in AD therapy.

抽象的

为寻求对抗阿尔茨海默氏病（AD）的多靶点药物的广泛兴趣，基于众所周知的乙酰胆碱酯酶（AChE）抑制剂他克林（TAC）的重新定位，设计并开发了一系列新的杂种与苯并呋喃（BF）衍生物偶联。BF框架旨在赋予共轭分子以抑制AChE（双峰方式）和淀粉样β肽聚集的能力，此外还为具有羟基的杂合体提供金属（Fe，Cu）螯合能力和伴随的额外抗氧化活性。代换。新的TAC-BF共轭物显示出非常好的AChE抑制活性（亚微摩尔范围），并且具有抑制自身和Cu介导的Aβ聚集的能力，这取决于每个主要部分的接头大小和取代基。_1-42诱导的毒性。结构-活性关系分析提供了最佳结构参数的见解，以考虑到未来在AD治疗中的潜在应用。