Stavrakov_2017_Chem.Biol.Drug.Des_90_709

Galantamine (GAL) as an acetylcholinesterase inhibitor (AChEI) is among the main drugs approved for the treatment of Alzheimer's disease. It fits perfectly into acetylcholinesterase (AChE) binding gorge, but it is too short to fill it. The amyloid beta (Abeta) peptide binds in the peripheral anionic site (PAS) at the entrance of the binding gorge of AChE and initiates the formation of amyloid plaques. The blockade of PAS prevents from AChE-induced Abeta aggregation. In this study, we describe the design of a series of galantamine-camphane hybrids as AChEIs. Camphane (CAM) is a bulky fragment that disposes well on the wide gorge entrance. The designed hybrids have linkers of different length. They were docked into AChE, and the highest scored compounds were synthesized and tested for AChE inhibitory activity. Some of the novel hybrids showed 191- and 369-fold better inhibition than GAL. The CAM fragment of the best binders fits in the same region, proximal to PAS, where the Omega-loop of Abeta binds to AChE. The hybrids cross blood-brain barrier by passive diffusion and are non-neurotoxic at the inhibitory concentrations.