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 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.

• Authors: Yixiang Xu, Jian Zhang, Huan Wang, Fei Mao, Keting Bao, Wenwen Liu, Jin Zhu, Xiaokang Li, Haiyan Zhang, Jian Li
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 10 Issue 1 Pg. 482-496 (01 16 2019) ISSN: 1948-7193 [Electronic] United States
• PMID: 30110536 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cholinesterase Inhibitors
• Monoamine Oxidase Inhibitors
• Monoamine Oxidase
• Acetylcholinesterase

Topics

• Acetylcholinesterase (metabolism)
• Alzheimer Disease (drug therapy, enzymology)
• Animals
• Blood-Brain Barrier (drug effects, metabolism)
• Cholinesterase Inhibitors (administration & dosage, chemistry, metabolism)
• Drug Delivery Systems (methods)
• Drug Design
• Mice
• Mice, Inbred ICR
• Monoamine Oxidase (metabolism)
• Monoamine Oxidase Inhibitors (administration & dosage, chemistry, metabolism)