Katarina Spilovska 1 , 2 , Jan Korabecny 1 , 3 , Vendula Sepsova 1 , 3 , Daniel Jun 1 , 3 , Martina Hrabinova 1 , 3 , Petr Jost 1 , Lubica Muckova 1 , Ondrej Soukup 2 , 3 , Jana Janockova 3 , Tomas Kucera 1 , Rafael Dolezal 3 , Eva Mezeiova 2 , 3 , Daniel Kaping 2 , Kamil Kuca 3 , *
16 June 2017
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 ( hAChE) and human butyrylcholinesterase ( hBChE), 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 hAChE 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 hAChE 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.