Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities.

Twenty-four novel compounds bearing tetrahydroacridine and N -propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC 50 = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC 50 = 78 nM) showed the best inhibitory human butyrylcholinesterase ( h BChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [ h AChE]: IC 50 = 0.095 ± 0.001 µM; h BChE: IC 50 = 0.093 ± 0.003 µM). Regarding MAO inhibition, compounds 7 , 15 , and 25 demonstrated the highest inhibitory potential towards h MAO-B (IC 50 = 163, 40, and 170 nM, respectively). In all, compounds 7 , 15 , 20 , 21 , 23 , and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy- N -(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride ( 15 ) has been identified as a permeable agent that shows a balanced pharmacological profile [IC 50 ( h AChE) = 1.472 ± 0.024 µM; IC 50 ( h BChE) = 0.659 ± 0.077 µM; IC 50 ( h MAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.