Multitargeting Histamine H₃ Receptor Ligands among Acetyl- and Propionyl-Phenoxyalkyl Derivatives

Alzheimer's disease (AD) is a neurodegenerative disorder, for which there is no effective cure. Current drugs only slow down the course of the disease, and, therefore, there is an urgent need to find effective therapies that not only treat, but also prevent it. Acetylcholinesterase inhibitors (AChEIs), among others, have been used for years to treat AD. Histamine H₃ receptors (H₃Rs) antagonists/inverse agonists are indicated for CNS diseases. Combining AChEIs with H₃R antagonism in one structure could bring a beneficial therapeutic effect. The aim of this study was to find new multitargetting ligands. Thus, continuing our previous research, acetyl- and propionyl-phenoxy-pentyl(-hexyl) derivatives were designed. These compounds were tested for their affinity to human H₃Rs, as well as their ability to inhibit cholinesterases (acetyl- and butyrylcholinesterases) and, additionally, human monoamine oxidase B (MAO B). Furthermore, for the selected active compounds, their toxicity towards HepG2 or SH-SY5Y cells was evaluated. The results showed that compounds 16 (1-(4-((5-(azepan-1-yl)pentyl)oxy)phenyl)propan-1-one) and 17 (1-(4-((6-(azepan-1-yl)hexyl)oxy)phenyl)propan-1-one) are the most promising, with a high affinity for human H₃Rs (K: 30 nM and 42 nM, respectively), a good ability to inhibit cholinesterases (16: AChE IC₅₀ = 3.60 µM, BuChE IC₅₀ = 0.55 µM; 17: AChE IC₅₀ = 1.06 µM, BuChE IC₅₀ = 2.86 µM), and lack of cell toxicity up to 50 µM.