Benek_2016_ChemMedChem_11_1264

Novel indolotacrine analogues were designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease. By using a multitarget-directed ligand approach, compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The compounds were also evaluated for antioxidant, cytotoxic, hepatotoxic, and blood-brain barrier (BBB) permeability properties. Indolotacrine 9 b (9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment; it is a potent inhibitor of acetylcholinesterase (AChE IC50 : 1.5 mum), butyrylcholinesterase (BChE IC50 : 2.4 mum) and MAO A (IC50 : 0.49 mum), and it is also a weak inhibitor of MAO B (IC50 : 53.9 mum). Although its cytotoxic (IC50 : 5.5+/-0.4 mum) and hepatotoxic (IC50 : 1.22+/-0.11 mum) profiles are not as good as those of the standard 7-methoxytacrine (IC50 : 63+/-4 and 11.50+/-0.77 mum, respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9 b a promising lead compound for further development and investigation.