Schaker-Hubner_2025_ACS.Pharmacol.Transl.Sci_8_831

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, IC(50) = 0.019 microM; HDAC6, IC(50) = 0.040 microM; AChE, IC(50) = 20.06 microM; BChE, IC(50) = 17.10 microM; MAO-B, IC(50) = 2.14 microM), and 9c (HDAC1, IC(50) = 0.126 microM; HDAC6, IC(50) = 0.020 microM; AChE, IC(50) = 2.73 microM; BChE, IC(50) = 4.03 microM; MAO-B, IC(50) = 1.18 microM) 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.