The multifactorial nature of most neurodegenerative diseases makes the development of multifunctional / dual-active drugs an emerging field of interest. Dual-active compounds are small molecules that stick to Lipinski’s rule of five in which merged entities are able to address two distinct biological targets. The development follows three common paradigms: designing in of desired pharmacophores, designing out of interactions with unwanted target and balancing of the activities. We hereby present a set of novel dual-acting compounds that act both as selective hCB2 receptor agonists and butyrylcholinesterase (BChE) inhibitors for the treatment of Alzheimer’s disease. All compounds show high selectivity over hCB1 receptor and acetylcholinesterase (AChE) and balanced submicromolar activities at both targets. Furthermore, activities in the micromolar range at the µ-opioid receptor were determined. The application of the three paradigms and the interplay of design, synthesis, pharmacological evaluation and computational studies led from first-generation leads – a set of benzimidazole-based molecules – to a second-generation leads with aminobenzimidazole core structure. The application of molecular dynamics and docking of both the first and second generation leads on both targets helps to understand their binding mode and pave the way for further investigations.

Aminobenzimidazoles and structural isomers: Design, synthesis, pharmacological evaluation and computational studies of novel dual-acting butyrylcholinesterase inhibitors and hCB2 receptor ligands for the treatment of Alzheimer’s disease

253rd National Meeting (2017)

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