An Expedient Synthesis of Tacrine-Squaric Hybrids as Potent, Selective and Dual-Binding Cholinesterase Inhibitors

Abstract

The restoration of acetylcholine levels in the brain by inhibition of cholinesterases is currently the most successful therapeutic strategy to treat neurodegenerative disorders. In this context, tacrine has been largely investigated as a starting scaffold for the development of promising new anticholinesterases compounds for the treatment of neurodegenerative illnesses, including Alzheimer’s disease. Here we present a series of compounds containing the tacrine nucleus connected with squaric moiety by a diaminoalkylene chain. The compounds were obtained through a simple and short synthetic route and showed high inhibitory activity against acetylcholinesterase (AChE) within nanomolar IC₅₀ (half maximal inhibitory concentration). The molecular modelling study showed that these compounds act as dual-binding inhibitors of AChE, interacting with both catalytic active site (CAS) and peripheral anionic site (PAS) of the enzyme’s binding cavity. The investigated compounds also demonstrated outstanding selectivity for AChE than in butyrylcholinesterase (BuChE). These results evince these compounds as promising agents for the treatment of neurodegenerative disorders and a fuller synthetic scope jointly with complementary biological evaluations are currently under investigation in our laboratory.

Keywords:
tacrine; cholinesterase inhibitors; AChE; hybrids; squaric acid; molecular docking