Design, synthesis and in vitro evaluation of indolotacrine analogues as multi-target-directed ligands for the treatment of Alzheimer’s disease

In this study, novel indolotacrine analogues have been designed, synthesized and evaluated as potential drugs for the treatment of Alzheimer’s disease. Based on a multi-target-directed ligand approach, novel compounds have been designed to act simultaneously as cholinesterase and monoamine oxidase (MAO) inhibitors. Prepared compounds were also evaluated for their antioxidant, cytotoxic, hepatotoxic and permeability (Blood-Brain Barrier penetration) 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 being a potent inhibitor of acetylcholinesterase (IC₅₀ = 1.5 µM), butyrylcholinesterase (IC₅₀ = 2.4 µM) and monoamine oxidase A (IC₅₀ = 0.49 µM) and a weak inhibitor of monoamine oxidase B (IC₅₀ = 53.9 µM). Although its cytotoxic (IC₅₀ = 5.5 ± 0.4 µM) and hepatotoxic (IC₅₀ = 1.22 ± 0.11 _µM) profile is not as good as the standard 7-methoxytacrine (IC₅₀ = 63 ± 4 µM and IC₅₀ = 11.50 ± 0.77 µM respectively), the overall improvement in the inhibitory activities and potential to cross blood-brain barrier make indolotacrine 9b a promising lead compound for further development and investigation.