Contilisant-Belinostat Hybrids: Polyfunctionalized Indole Derivatives as Multineurotarget Drugs for the Potential Treatment of Alzheimer’s Disease

In this work, we designed, synthesized, and evaluated two types of multineurotargeting compounds using a pharmacophore merging strategy, aiming to develop potential treatments for Alzheimer's disease. We combined belinostat, an FDA-approved unselective histone deacetylase (HDAC) inhibitor, with the 5-substituted indole core of contilisant, known for its antioxidant and neuroprotective properties as well as its potent inhibitory activity against monoamine oxidases (MAOs), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Among these, compounds 8c (HDAC1, IC₅₀ = 0.019 μM; HDAC6, IC₅₀ = 0.040 μM; AChE, IC₅₀ = 20.06 μM; BChE, IC₅₀ = 17.10 μM; MAO-B, IC₅₀ = 2.14 μM), and 9c (HDAC1, IC₅₀ = 0.126 μM; HDAC6, IC₅₀ = 0.020 μM; AChE, IC₅₀ = 2.73 μM; BChE, IC₅₀ = 4.03 μM; MAO-B, IC₅₀ = 1.18 μM) emerged as the most promising candidates. These compounds warrant further investigation as potential treatments for Alzheimer's disease due to their unique inhibition profiles and favorable mode of inhibition.