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Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT receptors, acetyl/butyrylcholinesterase inhibition, and amyloid β antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT receptors ( K = 18 nM) and noncompetitive inhibitor of cholinesterases (IC = 14 nM, IC = 22 nM). In further in vitro studies, compound 12 has shown amyloid β antiaggregation activity (IC = 1.27 μM) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.

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The lack of negative influence of tiagabine on cognitive functions in animals with scopolamine-induced memory impairments may be relevant for patients treated with this drug.

No abstract