Search for multifunctional agents against Alzheimer's disease among non-imidazole histamine H3 receptor ligands. In vitro and in vivo pharmacological evaluation and computational studies of piperazine derivatives.

• Cholinesterase inhibition ability of fifty histamine H3 receptor ligands was assessed in vitro. • Four promising multi-target-directed ligands were discovered. • Chosen ligands displayed high drug-likeness and good blood–brain barrier penetration. • Binding mode of the most active compounds was explained by molecular docking. • Procognitive effect in passive avoidance test was revealed. In the search for new treatments for complex disorders such as Alzheimer's disease the Multi-Target-Directed Ligands represent a very promising approach. The aim of the present study was to identify multifunctional compounds among several series of non-imidazole histamine H3 receptor ligands, derivatives of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4- n -propylpiperazine, 1-[2-thiazol-4-yl-(2-aminoethyl)]-4- n -propylpiperazine and 1-phenoxyalkyl-4-(amino)alkylopiperazine using in vitro and in vivo pharmacological evaluation and computational studies. Performed in vitro assays showed moderate potency of tested compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Molecular modeling studies have revealed possible interactions between the active compounds and both AChE and BuChE as well as the human H3 histamine receptor. Computational studies showed the high drug-likeness of selected compounds with very good physicochemical profiles. The parallel artificial membrane permeation assay proved outstanding blood–brain barrier penetration in test conditions. The most promising compound, A12 , chemically methyl(4-phenylbutyl){2-[2-(4-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethyl}amine, possesses good balanced multifunctional profile with potency toward studied targets - H3 antagonist activity (pA 2 = 8.27), inhibitory activity against both AChE (IC 50 = 13.96 μM), and BuChE (IC 50 = 14.62 μM). The in vivo pharmacological studies revealed the anti-amnestic properties of compound A12 in the passive avoidance test on mice. [ABSTRACT FROM AUTHOR]