Multitargeting Histamine H 3 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 H 3 receptors (H 3 Rs) antagonists/inverse agonists are indicated for CNS diseases. Combining AChEIs with H 3 R 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 H 3 Rs, 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 H 3 Rs ( K i : 30 nM and 42 nM, respectively), a good ability to inhibit cholinesterases ( 16 : AChE IC 50 = 3.60 µM, BuChE IC 50 = 0.55 µM; 17 : AChE IC 50 = 1.06 µM, BuChE IC 50 = 2.86 µM), and lack of cell toxicity up to 50 µM.