Details

Autor(en) / Beteiligte

• Xu, Yixiang
• Zhang, Jian
• Wang, Huan
• Mao, Fei
• Bao, Keting
• Liu, Wenwen
• Zhu, Jin
• Li, Xiaokang
• Zhang, Haiyan
• Li, Jian

Titel

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

Ist Teil von

• ACS chemical neuroscience, 2019-01, Vol.10 (1), p.482-496

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.