Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Via Belmeloro 6/Via Irnerio 48/Via Selmi 3, 40126, Bologna, Italy.
Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
ChemMedChem. 2021 Jan 8;16(1):187-198. doi: 10.1002/cmdc.202000484. Epub 2020 Aug 31.
Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi-target-directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD-relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1-based MTDLs targeting Aβ and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4-naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the "physicochemical challenge" typical of large hybrid-based MTDLs. A preliminary investigation of their multi-target profile identified 9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug-like profile.
由于多奈哌齐（1）在治疗阿尔茨海默病（AD）中的广泛应用和安全性，通过连接携带额外 AD 相关生物学特性的第二个片段来修饰其分子结构是最广泛采用的多靶点定向配体（MTDL）设计策略之一。在此，基于 1 与醌类药物艾地苯醌联合治疗的建议，我们合理设计了针对 Aβ 和氧化途径的新型基于 1 的 MTDL。通过用 1,4-萘醌替代 1 的茚满酮核心，我们得到了一系列高度融合的衍生物，原则上没有大型混合 MTDL 典型的“理化挑战”。对它们的多靶点特征的初步研究确定了 9，其表现出强大、选择性的丁酰胆碱酯酶抑制活性，以及抗氧化和抗聚集特性。此外，它还表现出有前景的类药性。
