| Title : Rational Design of Novel Selective Dual-Target Inhibitors of Acetylcholinesterase and Monoamine Oxidase B as Potential Anti-Alzheimer's Disease Agents - Xu_2019_ACS.Chem.Neurosci_10_482 |
| Author(s) : Xu Y , Zhang J , Wang H , Mao F , Bao K , Liu W , Zhu J , Li X , Zhang H , Li J |
| Ref : ACS Chem Neurosci , 10 :482 , 2019 |
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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 muM) and MAO-B (IC50 = 2.117 +/- 0.061 muM), 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. |
| PubMedSearch : Xu_2019_ACS.Chem.Neurosci_10_482 |
| PubMedID: 30110536 |
Xu Y, Zhang J, Wang H, Mao F, Bao K, Liu W, Zhu J, Li X, Zhang H, Li J (2019)
Rational Design of Novel Selective Dual-Target Inhibitors of Acetylcholinesterase and Monoamine Oxidase B as Potential Anti-Alzheimer's Disease Agents
ACS Chem Neurosci
10 :482
Xu Y, Zhang J, Wang H, Mao F, Bao K, Liu W, Zhu J, Li X, Zhang H, Li J (2019)
ACS Chem Neurosci
10 :482