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

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 ( h AChE) and human butyrylcholinesterase ( h BChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybrid K1383 , bearing two methylene tether between two basic scaffolds, was found to be very potent h AChE inhibitor (IC ₅₀ = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC ₅₀ ≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed on h AChE with the most active compound in the study, K1383 , pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies.
Competing Interests: The authors declare no conflict of interest.