The role of histamine and acetylcholine in cognitive functions suggests that compounds able to increase both histaminergic and cholinergic neurotransmissions in the brain should be considered as promising therapeutic options. For this purpose, dual inhibitors of histamine H 3 receptors (H 3 R) and cholinesterases (ChEs) have been designed and assessed. In this context, this paper reviews the strategies used to obtain dual H 3 R/ChEs ligands using multitarget design approaches. Hybrid compounds designed by linking tacrine or flavonoid motifs to H 3 R antagonists were obtained with high affinity for both targets, and compounds designed by merging the H 3 R antagonist pharmacophore with known anticholinesterase molecules were also reported. These reports strongly suggest that key modifications in the lipophilic region (including a second basic group) seem to be a strategy to reach novel compounds, allied with longer linker groups to a basic region. Some compounds have already demonstrated efficacy in memory models, although the pharmacokinetic and toxicity profile should be considered when designing further compounds. In conclusion, the key features to be considered when designing novel H 3 R/ChEs inhibitors with improved pharmacological profile were herein summarized.

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Histamine is involved in several central nervous system processes including cognition. In the last years, H 3 receptor (H 3 R) antagonists have been widely explored for their potential on dementias and other cognitive dysfunctions, and the cooperative role between histamine and acetylcholine neurotransmissions on cognitive processes is widely known in literature. This motivated us to assess the potential of 1-[(2,3-dihydrobenzofuran-1-yl)methyl]piperazines (LINS01 compounds) as inhibitors of cholinesterases, and thus this work presents the inhibitory effect of such compounds against acetyl (AChE) and butyrylcholinesterase. A set of 16 selected compounds were evaluated, being compounds 2d and 2e the most potent inhibitors of both cholinesterases (IC 50 13.2-33.9 μM) by competitive mechanism, as indicated by the kinetic assays. Molecular docking simulations suggested that the allylpiperazine and dihydrobenzofuran motifs present in these compounds are important to perform πinteractions with key tryptophan residues from the enzymes, increasing their affinity for both H 3 R and cholinesterases. Metric analysis support that compound 2d (LINS01022) should be highlighted due to its balanced lipophilicity (ClogP 2.35) and efficiency (LE 0.32) as AChE inhibitor. The results add important information to future design of dual H 3 R-cholinesterases ligands.