Aranha_2022_Bioorg.Med.Chem_78_117132

Multitargeting ligands on enzymes and receptors may generate a profile for a potential treatment of cognitive impairment. Considering this, a set of 21 substituted aryl-alkyl-piperazines were designed, prepared and tested for their binding affinities at histamine H(3) and dopamine D(3) receptors (H(3)R and D(3)R, respectively) as well as acetyl- and butyrylcholinesterases (AChE/BChE) as potentially synergistic profile. Initial screening of the compounds at H(3)R and D(3)R was done at 1 or 10smicroM and 100smicroM at AChE and BChE assays. The most promising compounds were then evaluated in full concentration-response curves to estimate the K(i) and IC(50) values. Results showed that several compounds were ligands at H(3)R (n = 10), D(3)R (n = 6), AChE (ns=s3), and BChE (n = 9). Compounds LINS05006 (K(i) H(3)R 2.8 microM; D(3)R 0.7 microM; IC(50) BChE 26.3 microM) and LINS05015 (K(i) H(3)R 1.1 microM; D(3)R 3.1 microM; IC(50) AChE 97.8 microM; BChE 43.7 microM) are highlighted since presented affinity in three different. These results suggest that methylpiperazine moiety led to balanced activity at all three classes of targets, and longer linker provided the best affinities. These compounds presented high ligand efficiency values (LE > 0.3) and may have adequate pharmacokinetic profile as suggested by calculated physicochemical properties.