Quinolinetrione-tacrine hybrids as multi-target-directed ligands against Alzheimer's disease

• Published in: Bioorganic & medicinal chemistry 2023-08, Vol.91, p.117419-117419, Article 117419
• Main Authors: Uliassi, Elisa, Bergamini, Christian, Rizzardi, Nicola, Naldi, Marina, Cores, Ángel, Bartolini, Manuela, Carlos Menéndez, J., Bolognesi, Maria Laura
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; Amyloid-β; Cholinesterase enzymes; Multi-target-directed ligands; Polypharmacology; Quinolinetrione; Tacrine
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2023.117419

[Display omitted] •Novel multi-target-directed ligands (MTDLs) against Alzheimer's disease have been developed.•The new hybrids have been obtained by linking tacrines with 4-methylquinoline-2,5,8(1H)-trione, as juglone replacement.•The most interesting hybrid 3 inhibited cholinesterase enzymes and modulated Aβ self-aggregation.•Hybrid 3 showed antioxidant effects and lower hepatoxicity. Multi-target drug discovery is one of the most active fields in the search for new drugs against Alzheimer's disease (AD). This is because the complexity of AD pathological network might be adequately tackled by multi-target-directed ligands (MTDLs) aimed at modulating simultaneously multiple targets of such a network. In a continuation of our efforts to develop MTDLs for AD, we have been focusing on the molecular hybridization of the acetylcholinesterase inhibitor tacrine with the aim of expanding its anti-AD profile. Herein, we manipulated the structure of a previously developed tacrine-quinone hybrid (1). We designed and synthesized a novel set of MTDLs (2–6) by replacing the naphthoquinone scaffold of 1 with that of 2,5,8-quinolinetrione. The most interesting hybrid 3 inhibited cholinesterase enzymes at nanomolar concentrations. In addition, 3 exerted antioxidant effects in menadione-induced oxidative stress of SH-SY5Y cells. Importantly, 3 also showed low hepatotoxicity and good anti-amyloid aggregation properties. Remarkably, we uncovered the potential of the quinolinetrione scaffold, as a novel anti-amyloid aggregation and antioxidant motif to be used in further anti-AD MTDL drug discovery endeavors.