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Future Medicinal Chemistry · 2021 ·Vol. 13 ·期 13 · IF 3.808

Synthesis and activity of miconazole derivatives as dual BChE/IDO1 inhibitors for the treatment of Alzheimer's disease

Xin Lu,Yijun Liu,Nan Qin,Hongyu Yang,Yuting Qiao,Xueyang Jiang,Yao Chen,Feng Feng,Wenyuan Liu,You Zhou,Haopeng Sun

Background: Alzheimer's disease is a multifactorial neurological disorder seen in elderly people. Loss of cholinergic transmission and unbalanced tryptophan metabolism kynurenine pathway have been demonstrated in neuropsychiatric diseases. Methods & results: Among the two series of synthesized compounds, compounds 5c and 5h were identified as effective dual BChE/IDO1 inhibitors, with well-balanced micromolar activity. Compounds 5c and 5h exhibited promising ability to ameliorate behavioral impairment by Morris water maze. The safety of miconazole analogs was also validated by PC12 and SH-SY5Y cell lines. Conclusion: These results highlight the ability of 5c and 5h to treat Alzheimer's disease.

研究领域: 神经科学 · 药物化学 · 老年医学

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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES · 2024 · IF 7.7

Affinity ultrafiltration based metabolomic profiling directed discovery novel butyrylcholinesterase inhibitors from Uncaria sessilifructus

Chang Xu,Xiao Yu,Guiyang Wang,Shiqing You,Linlin Zhu,Ying Liu,Nuan Zhang,Zhengdong Wang,Bin Liu,Wei Zhang

The butyrylcholinesterase (BChE) is an attractive target for treating Alzheimer's disease. In this study, we report the discovery of five new monoterpene indole alkaloids (MIAs) along with three known analogues from Uncaria sessilifructus Roxb. as BChE inhibitors using affinity ultrafiltration based metabolomic profiling directed isolation strategy. Their structures were well identified through comprehensive spectroscopic and chiroptical analyses. Compounds 1 – 2 featured unique glycosidic linkages with 1, 3-dioxane structure. All the compounds exhibited BChE inhibitory bioactivity without any cytotoxic effects. Enzymatic kinetic and molecular docking analyses of compounds 1 and 6 demonstrated their inhibiting mechanisms and binding patterns to BChE. These findings provide a valuable workflow for efficiently screening ligands that bind to proteins, and scientific recognition in the discovery of BChE inhibitors for treating neurodegenerative disorders.

CAS / MDL: 1953-04-4

研究领域: 药理学 · 神经科学 · 药物化学 · 植物化学

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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES · 2017 · IF 3.671

4- Substituted sampangine derivatives: Novel acetylcholinesterase and β-myloid aggregation inhibitors

Ke-Lin Chen,Ling Gan,Zhen-Hua Wu,Jin-Fang Qin,Wen-Xia Liao,Huang Tang

A series of 4- substituted sampangine derivatives (4-aminoalkylaminosampangine Ar–NH(CH 2 ) n NR 1 R 2 ) has been designed, synthesized, and tested for their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-myloid (Aβ) aggregation. The synthetic compounds exhibited high AChE inhibitory activity and a significant in vitro inhibitory potency toward the self-induced Aβ aggregation. While, treatment of SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw) with derivatives was associated with significant reduction of Aβ42 secretion levels. Moreover, most of the synthetic compounds were predicted to be able to cross the blood-brain barrier (BBB) to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay for BBB. The result encourages us to study this class of compounds thoroughly and systematically.

研究领域: 药理学 · 神经科学 · 化学

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Synthesis and activity of miconazole derivatives as dual BChE/IDO1 inhibitors for the treatment of Alzheimer's disease

Affinity ultrafiltration based metabolomic profiling directed discovery novel butyrylcholinesterase inhibitors from Uncaria sessilifructus

4- Substituted sampangine derivatives: Novel acetylcholinesterase and β-myloid aggregation inhibitors