Rational Design of Novel Selective Dual-Target Inhibitors of Acetylcholinesterase and Monoamine Oxidase B as Potential Anti-Alzheimer’s Disease Agents

Abstract

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 IC values in the micro- or nanomolar ranges. Compound 1c displayed the dual functional profile of targeting the AChE (IC = 0.032 ± 0.007 μM) and MAO-B (IC = 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.

Reconsideration of Anticholinesterase Therapeutic Strategies against Alzheimer’s Disease

“…We also used ex vivo animal studies to verify that the optimal compound could cross the BBB and target both cerebral AChE and MAO-B. An animal behavior test showed that this compound could also significantly improve cognitive ability in the scopolamine-injected model at a lower dosage (10 mg/kg, po) …”

“…An animal behavior test showed that this compound could also significantly improve cognitive ability in the scopolamine-injected model at a lower dosage (10 mg/kg, po). 118 Novel AChEIs Regulating the 5-HTergic System. On the basis of the clinical situation in which >50% of AD patients suffer from symptoms of depression, antidepressants are often used as an adjunctive therapy of AD.…”

Design, Synthesis, and Evaluation of Novel Ferulic Acid Derivatives as Multi-Target-Directed Ligands for the Treatment of Alzheimer’s Disease

“…Recombinant Human MAO-A and MAO-B Inhibition Studies. 40 Recombinant human MAO-A and MAO-B were purchased from Sigma-Aldrich and stored at −80 °C. Tested compounds were diluted with potassium phosphate buffer (100 mM, pH 7.40, containing KCl, 20.2 mM) to a final volume of 500 μL, containing various concentrations of test compounds (0−100 μM) and kynuramine (45 μM for MAO-A and 30 μM for MAO-B).…”

Multi-target design strategies for the improved treatment of Alzheimer's disease

“…MAO-A inhibitors are used in the clinic to treat anxiety and depression, which are also common symptoms considered to be risk factors in AD progression [51], while MAO-B inhibitors are used in the treatment of PD [52]. MAOs inhibitors can increase monoaminergic neurotransmission, decrease ROS formation and oxidative stress, and exert pharmacological effects including antioxidation, neuroprotection and cognitive improvement [53], which are potentially valuable for the treatment of AD. Rasagiline (11) from Teva pharma (Figure 2) is a potent and irreversible selective MAO-B inhibitor approved in 2005 for the treatment of PD and has been in Phase II clinical trials for the treatment of AD.…”