Anti‐Alzheimer's multitarget‐directed ligands with serotonin 5‐HT 6 antagonist, butyrylcholinesterase inhibitory, and antioxidant activity

: Serotonin 5-HT6 receptors, butyrylcholinesterase (BuChE) and oxidative stress are related to the pathophysiology of Alzheimer's disease. Inhibition of BuChE provides symptomatic treatment of the disease and the same effect was demonstrated for 5-HT 6 antagonists in clinical trials. Oxidative stress is regarded as a major and primary factor contributing to the development of Alzheimer's disease; therefore, antioxidant agents may provide a disease-modifying effect. Combining BuChE inhibition, 5-HT 6 antagonism, and antioxidant properties may result in multitarget-directed ligands providing cognition-enhancing properties with neuroprotective activity. On the basis of the screening of the library of 5-HT 6 antagonists against BuChE, we selected two compounds and designed their structural modifications that could lead to improved BuChE inhibitory activity. We synthesized two series of compounds and tested their affinity and functional activity at 5-HT 6 receptors, BuChE inhibitory activity and antioxidant properties. Compound 12 with K i and K b values against 5-HT 6 receptors of 41.8 and 74 nM, respectively, an IC 50 value of 5 µM against BuChE and antioxidant properties exceeding the activity of ascorbic acid is a promising lead structure for further development of anti-Alzheimer's agents.