k-858 and Alzheimer-Disease

The limited clinical efficacy of current symptomatic treatment and minute effect on progression of Alzheimer's disease has shifted the research focus from single targets towards multi-target-directed ligands. Here, a potent selective inhibitor of human butyrylcholinesterase was used as the starting point to develop a new series of multifunctional ligands. A focused library of derivatives was designed and synthesised that showed both butyrylcholinesterase inhibition and good antioxidant activity as determined by the DPPH assay. The crystal structure of compound 11 in complex with butyrylcholinesterase revealed the molecular basis for its low nanomolar inhibition of butyrylcholinesterase (Ki = 1.09 ± 0.12 nM). In addition, compounds 8 and 11 show metal-chelating properties, and reduce the redox activity of chelated Cu

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Butyrylcholinesterase; Caco-2 Cells; Cell Line, Tumor; Cholinesterase Inhibitors; Drug Design; Humans; Ligands; Models, Molecular; Neuroprotective Agents; Piperidines