Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation

Abstract

A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer's agents was assessed. Their inhibitory activity towards human acetylcholinesterase (<i>h</i>AChE) and human butyrylcholinesterase (<i>h</i>BChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybrid <b>K1383</b>, bearing two methylene tether between two basic scaffolds, was found to be very potent <i>h</i>AChE inhibitor (IC₅₀ = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC₅₀ ≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed on <i>h</i>AChE with the most active compound in the study, <b>K1383</b>, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies.