Design, synthesis, and biological evaluation of aromatic tertiary amine derivatives as selective butyrylcholinesterase inhibitors for the treatment of Alzheimer's disease

Lü, Xin; Qin, Nan; Liu, Yijun; Du, Chenxi; Feng, Feng; Liu, Wenyuan; Chen, Yao; Sun, Haopeng

doi:10.1016/j.ejmech.2022.114729

Cited by 14 publications

(7 citation statements)

References 40 publications

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“…The water maze experiment of the Aβ 1–42 -induced cognitive impairment mouse model was continued. , As shown in Figure B, surgery had no significant effect on the cognitive behavior of mice (model group vs sham group, ns.). Injection of Aβ 1–42 into the hippocampus of mice caused significant cognitive impairment (model group 52.7 ± 15.6 s vs sham group 16.7 ± 2.9 s).…”

Section: Resultsmentioning

confidence: 99%

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Discovery, Structure-Based Modification, In Vitro, In Vivo, and In Silico Exploration of m-Sulfamoyl Benzoamide Derivatives as Selective Butyrylcholinesterase Inhibitors for Treating Alzheimer’s Disease

Lu,

Li,

Guan

et al. 2024

ACS Chem. Neurosci.

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For the potential therapy of Alzheimer's disease (AD), butyrylcholinesterase (BChE) has gradually gained worldwide interest in the progression of AD. This study used a pharmacophore-based virtual screening (VS) approach to identify Z32439948 as a new BChE inhibitor. Aiding by molecular docking and molecular dynamics, essential binding information was disclosed. Specifically, a subpocket was found and structure-guided design of a series of novel compounds was conducted. Derivatives were evaluated in vitro for cholinesterase inhibition and physicochemical properties (BBB, log P, and solubility). The investigation involved docking, molecular dynamics, enzyme kinetics, and surface plasmon resonance as well. The study highlighted compounds 27a (hBChE IC 50 = 0.078 ± 0.03 μM) and (R)-37a (hBChE IC 50 = 0.005 ± 0.001 μM) as the top-ranked BChE inhibitors. These compounds showed anti-inflammatory activity and no apparent cytotoxicity against the human neuroblastoma (SH-SY5Y) and mouse microglia (BV2) cell lines. The most active compounds exhibited the ability to improve cognition in both scopolamine-and Aβ 1−42 peptide-induced cognitive deficit models. They can be promising lead compounds with potential implications for treating the late stage of AD.

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Section: Resultsmentioning

confidence: 99%

“…to mice 30 min before the intraperitoneal administration of scopolamine or saline. The detailed experiment procedure of the Morris water maze test was described as before. , …”

Section: Methodsmentioning

confidence: 99%

Discovery, Structure-Based Modification, In Vitro, In Vivo, and In Silico Exploration of m-Sulfamoyl Benzoamide Derivatives as Selective Butyrylcholinesterase Inhibitors for Treating Alzheimer’s Disease

Lu,

Li,

Guan

et al. 2024

ACS Chem. Neurosci.

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“…In a similar study conducted by Lu et al Structured-based molecular modification guided the synthesis of an aromatic tertiary amine derivatives. Two optimal compounds presented selective BChE inhibitory (hBChE < 20 nM, eeAChE > 10 μM), good BBB permeation, primary cell safety, and restorative effect on cognitive impairment in vivo test 21 .…”

Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of substituted acetamide derivatives as potential butyrylcholinestrase inhibitors

Yang

Liu

et al. 2023

Sci Rep

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Alzheimer’s disease (AD) is the most common type of age-related dementia. Inhibition of butyrylcholinesterase (BChE) emerge as an effective therapeutic target for AD. A series of new substituted acetamide derivatives were designed, synthesized and evaluated for their ability to inhibit BChE. The bioassay results revealed that several compounds displayed attractive inhibition against BChE). Among them, compound 8c exhibited the highest BChE inhibition with IC50 values of 3.94 μM. Lineweaver Burk plot indicated that 8c acted as a mixed-type BChE inhibitor. In addition, docking studies confirmed the results obtained through in vitro experiments, and showed that 8c bound to the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE active site. Meanwhile, its ADME parameters were approximated using in silico method. Molecular dynamics simulation studies on the complex of 8c-BChE were performed, RMSD, RMSF, Rg, SASA, and the number of hydrogen bonds were calculated as well. These results implied that 8c could serve as appropriate lead molecule for the development of BChE inhibitor.

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“…Alzheimer's disease (AD) is the most common cause of dementia which is clinically characterized by memory impairment and cognitive decline. [44,45] This disease is one of the 21 st century's major healthcare and development challenges. [46] In this study, target hybrid compounds (5)(6)(7)(8)(9)(10)(11)(12)(13)(14) were tested against human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE) for the determination of ChEs inhibitory properties.…”

Section: In Vitro Enzyme Inhibition Studiesmentioning

confidence: 99%

4‐Furfuryloxymethyl‐1,2,3‐triazol‐1‐yl‐acetohydrazide Hybrids as Cholinesterase and Carbonic Anhydrase Inhibitors: Synthesis, Characterization and Comprehensive Biological Activity Studies

Şenol

2024

ChemistrySelect

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This study focused on the synthesis and evaluation of the biological activity of ten novel acetohydrazide hybrid derivatives, having furfuryloxy‐1,2,3‐triazole ring. All the target compounds were tested in vitro and in silico for their inhibitory potential against key enzymes: hAChE, hBChE, hCAI, and hCAII, all involved in significant physiological processes. Remarkably, two compounds, namely (E)‐2‐(4‐((furan‐2‐ylmethoxy)methyl)‐1H‐1,2,3‐triazol‐1‐yl)‐N′‐(4‐hydroxy‐3‐methoxybenzylidene)acetohydrazide (9) and (E)‐N′‐(4‐chlorobenzylidene)‐2‐(4‐((furan‐2‐ylmethoxy)methyl)‐1H‐1,2,3‐triazol‐1‐yl)acetohydrazide (11), exhibited strong inhibitory activity. Compound 9 emerged as the top‐performing inhibitor for both hAChE (IC50 of 0.23 μM) and hBChE (IC50 of 0.74 μM). Additionally, compounds 9 and 11 displayed potent inhibitory effects on hCAI and hCAII, with IC50 values of 0.18 μM and 0.15 μM, respectively. Furthermore, in silico studies provided valuable insights into the interaction mechanisms and stability of the ligand‐protein complexes. Compound 9 demonstrated strong binding scores of −12.063 kcal/mol for hAChE and −9.359 kcal/mol for hBChE, while Compound 11 exhibited substantial scores of −7.040 kcal/mol for hCAI and −8.216 kcal/mol for hCAII. In conclusion, they stand out as promising inhibitors of hAChE, hBChE, hCAI and hCAII enzymes. Their inhibitory activity, supported by low IC50 values, indicated their potential to inhibit enzymes associated with neurological and metabolic processes.

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Design, synthesis, and biological evaluation of aromatic tertiary amine derivatives as selective butyrylcholinesterase inhibitors for the treatment of Alzheimer's disease

Cited by 14 publications

References 40 publications

Discovery, Structure-Based Modification, In Vitro, In Vivo, and In Silico Exploration of m-Sulfamoyl Benzoamide Derivatives as Selective Butyrylcholinesterase Inhibitors for Treating Alzheimer’s Disease

Discovery, Structure-Based Modification, In Vitro, In Vivo, and In Silico Exploration of m-Sulfamoyl Benzoamide Derivatives as Selective Butyrylcholinesterase Inhibitors for Treating Alzheimer’s Disease

Synthesis and biological evaluation of substituted acetamide derivatives as potential butyrylcholinestrase inhibitors

4‐Furfuryloxymethyl‐1,2,3‐triazol‐1‐yl‐acetohydrazide Hybrids as Cholinesterase and Carbonic Anhydrase Inhibitors: Synthesis, Characterization and Comprehensive Biological Activity Studies

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