Aminobenzimidazoles and Structural Isomers as Templates for Dual-Acting Butyrylcholinesterase Inhibitors and hCB2 R Ligands To Combat Neurodegenerative Disorders

• Published in: ChemMedChem 2016-06, Vol.11 (12), p.1270-1283
• Main Authors: Dolles, Dominik, Nimczick, Martin, Scheiner, Matthias, Ramler, Jacqueline, Stadtmüller, Patricia, Sawatzky, Edgar, Drakopoulos, Antonios, Sotriffer, Christoph, Wittmann, Hans-Joachim, Strasser, Andrea, Decker, Michael
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Benzimidazoles - chemistry; Benzimidazoles - metabolism; Benzimidazoles - therapeutic use; Binding Sites; Butyrylcholinesterase - chemistry; Butyrylcholinesterase - metabolism; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - metabolism; Cholinesterase Inhibitors - therapeutic use; Drug Design; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Sequence Data; Neurodegenerative Diseases - drug therapy; Protein Structure, Tertiary; Receptor, Cannabinoid, CB1 - chemistry; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Cannabinoid, CB2 - antagonists & inhibitors; Receptor, Cannabinoid, CB2 - metabolism; Sequence Alignment; Stereoisomerism; Structure-Activity Relationship
• ISSN: 1860-7187
• DOI: 10.1002/cmdc.201500418

A pharmacophore model for butyrylcholinesterase (BChE) inhibitors was applied to a human cannabinoid subtype 2 receptor (hCB2 R) agonist and verified it as a first-generation lead for respective dual-acting compounds. The design, synthesis, and pharmacological evaluation of various derivatives led to the identification of aminobenzimidazoles as second-generation leads with micro- or sub-micromolar activities at both targets and excellent selectivity over hCB1 and AChE, respectively. Computational studies of the first- and second-generation lead structures by applying molecular dynamics (MD) on the active hCB2 R model, along with docking and MD on hBChE, has enabled an explanation of their binding profiles at the protein levels and opened the way for further optimization. Dual-acting compounds with "balanced" affinities and excellent selectivities could be obtained that represent leads for treatment of both cognitive and pathophysiological impairment occurring in neurodegenerative disorders.