Design, Synthesis and in vitro Evaluation of Indolotacrine Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease

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 9b (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 mu m), butyrylcholinesterase (BChE IC50: 2.4 mu m) and MAO A (IC50: 0.49 mu m), and it is also a weak inhibitor of MAO B (IC50: 53.9 mu m). Although its cytotoxic (IC50: 5.5 +/- 0.4 mu m) and hepatotoxic (IC50: 1.22 +/- 0.11 mu m) profiles are not as good as those of the standard 7-methoxytacrine (IC50: 63 +/- 4 and 11.50 +/- 0.77 mu m, respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9b a promising lead compound for further development and investigation.