Multifunctional agents aiming at cholinesterases (ChEs) and monoamine oxidases (MAOs) are promising therapy for Alzheimer's disease (AD). Herein, a series of novel propargylamine-modified pyrimidinylthiourea derivatives (1-4) were designed and synthesized as dual inhibitors of ChEs and MAOs with other functions against AD. Most of these derivatives inhibited ChEs and MAOs with IC50 values in the micro- or nanomolar ranges. Compound 1c displayed the dual functional profile of targeting the AChE (IC50 = 0.032 ± 0.007 μM) and MAO-B (IC50 = 2.117 ± 0.061 μM), along with the improved blood-brain barrier (BBB) permeability, antioxidant ability, and good copper chelating property in vitro. Animal studies showed that compound 1c·HCl could inhibit the cerebral AChE/MAO-B activities and alleviate scopolamine-induced cognitive impairment in mice. Combined with good oral bioavailability ( F = 45.55%), these findings demonstrated that compound 1c may be a potent brain permeable multifunctional candidate for the treatment of AD.
Keywords: AChE inhibitors; Alzheimer’s disease; MAO-B inhibitors; metal chelating agents; multifunctional agents.