Synthesis and cholinesterase activity of phenylcarbamates related to Rivastigmine, a therapeutic agent for Alzheimer's disease

Mustazza, Carlo; Borioni, Anna; Giudice, Maria Rosaria Del; Gatta, Franco; Ferretti, Rosella; Meneguz, Annarita; Volpe, Maria Teresa; Lorenzini, Paola

doi:10.1016/s0223-5234(01)01324-1

Cited by 38 publications

(27 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1120 the phosphorous atom (e.g. the alkoxy groups attached to the phosphorous atom); ii) the broad-band decoupled 13 C NMR spectra showed doublets for the carbons within 2 or 3 bonds from the phosphorous atom; iii) the 19 F and 31 P NMR spectra and the GC-MS spectra further confirm the structure of the obtained products.…”

Section: Synthesis Screening For Antiacetylcholinesterase Activity Amentioning

confidence: 61%

“…Os produtos foram caracterizados por espectroscopia de RMN de 1 H, 13 C, 31 P e 19 F, CG-EM e análise elementar. Todos os compostos sintetizados foram testados para a inibição da enzima acetilcolinesterase (AChE) usando o método de Ellman.…”

Section: Synthesis Screening For Antiacetylcholinesterase Activity Aunclassified

“…When the reaction was carried out in THF the products were obtained but, in low yields. The products 2a-i were purified by silica gel column chromatography and were analyzed by 1 H, 13 C, 19 F and 31 P NMR, GC-MS, and elemental analysis. These data are presented in the experimental section.…”

Section: Chemistrymentioning

confidence: 99%

“…[7][8][9][10] Examples are Metrifonate, ® used as antihelminthic and in the treatment of schistosamiasis, Echothiophate, ® used for the treatment of glaucoma, 11,12 and Rivastigmine ® (a carbamate) used for the treatment of Alzheimer's disease. 13 Therefore, phosphate and carbamate frameworks are important pharmacophores required for potent anticholinesterase activity. [14][15][16] Although, carbamates and OPs are potent inhibitors of AChE, the two chemical groups differ in the stability of their complexes with AChE.…”

Section: Introductionmentioning

confidence: 99%

“…17 In spite of the important molecular recognition process involved in AChE inhibition for either phosphate or carbamate groups, the presence of both chemical moieties in the same molecule (inhibitor) is rarely found in the literature. 18,19 In the present work, we have synthesized and fully characterized by means of 1 H, 13 C, 31 P and 19 F NMR spectroscopy, GC-MS, and elemental analysis, a new series of phosphate-carbamate compounds containing these two privileged pharmacophores in their structures, through the incorporation of phosphate groups in trifluoromethylated alcohols bearing a γ-ethyl carbamate function. In addition, the synthesized compounds were screened for AChE inhibitory activity and molecular modeling studies were subsequently carried out to investigate the preferred binding mode of these compounds in the AChE active site.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Synthesis, screening for antiacetylcholinesterase activity and binding mode prediction of a new series of [3-(disubstituted-phosphate)-4,4,4-trifluoro-butyl]-carbamic acid ethyl esters

Zanatta¹,

Borchhardt²,

Carpes³

et al. 2008

J. Braz. Chem. Soc.

View full text Add to dashboard Cite

adição de álcoois. Os produtos foram caracterizados por espectroscopia de RMN de 1 H, 13 C, 31 P e 19 F, CG-EM e análise elementar. Todos os compostos sintetizados foram testados para a inibição da enzima acetilcolinesterase (AChE) usando o método de Ellman. Todos os compostos analisados contendo os grupos carbamato e fosfato em sua estrutura, mostraram inibição enzimática, sendo que o composto contendo o grupo dietóxi (2b) apresentou a maior atividade inibitória. Estudos de modelagem molecular foram realizados para obter informações detalhadas entre o sítio ativo da enzima acetilcolinesterase e os compostos candidatos a inibição, obtendo-se valiosas informações estruturais com relação à inibição de enzima acetilcolinesterase.A series of nine new [3-(disubstituted-phosphate)-4,4,4-trifluoro-butyl]-carbamic acid ethyl esters (phosphate-carbamate compounds) was obtained through the reaction of (4,4,4-trifluoro-3-hydroxybut-1-yl)-carbamic acid ethyl esters with phosphorus oxychloride followed by the addition of alcohols. The products were characterized by 1 H, 13 C, 31 P, and 19 F NMR spectroscopy, GC-MS, and elemental analysis. All the synthesized compounds were screened for acetylcholinesterase (AChE) inhibitory activity using the Ellman method. All compounds containing phosphate and carbamate pharmacophores in their structures showed enzyme inhibition, being the compound bearing the diethoxy phosphate group (2b) the most active compound. Molecular modeling studies were performed to investigate the detailed interactions between AChE active site and small-molecule inhibitor candidates, providing valuable structural insights into AChE inhibition.

show abstract

Section: Synthesis Screening For Antiacetylcholinesterase Activity Amentioning

confidence: 61%

Section: Synthesis Screening For Antiacetylcholinesterase Activity Aunclassified

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Synthesis, screening for antiacetylcholinesterase activity and binding mode prediction of a new series of [3-(disubstituted-phosphate)-4,4,4-trifluoro-butyl]-carbamic acid ethyl esters

Zanatta¹,

Borchhardt²,

Carpes³

et al. 2008

J. Braz. Chem. Soc.

View full text Add to dashboard Cite

show abstract

Hybridization‐based design of novel anticholinesterase indanone–carbamates for Alzheimer's disease: Synthesis, biological evaluation, and docking studies

Shahrivar-Gargari

Hamzeh‐Mivehroud

Hemmati

et al. 2021

Archiv der Pharmazie

View full text Add to dashboard Cite

Inspired by the structures of donepezil and rivastigmine, a novel series of indanone–carbamate hybrids was synthesized using the pharmacophore hybridization‐based design strategy, and their biological activities toward acetylcholinesterase (AChE) and butyrylcholinesterase were evaluated. Among the synthesized compounds, 4d and 4b showed the highest AChE inhibitory activities with IC50 values in the micromolar range (compound 4d: IC50 = 3.04 μM; compound 4b: IC50 = 4.64 μM). Moreover, the results of the Aβ1–40 aggregation assay revealed that compound 4b is a potent Aβ1–40 aggregation inhibitor. The kinetics of AChE enzymatic activity in the presence of 4b was investigated, and the results were indicative of a reversible partial noncompetitive type of inhibition. A molecular docking study was conducted to determine the possible allosteric binding mode of 4b with the enzyme. The allosteric nature of AChE inhibition by these compounds provides the opportunity for the design of subtype‐selective enzyme inhibitors. The presented indanone–carbamate scaffold can be structurally modified and optimized through medicinal chemistry‐based approaches for designing novel multitargeted anti‐Alzheimer agents.

show abstract

Analysis of acetylcholinesterase inhibitors: bioanalysis, degradation and metabolism

Marques¹,

Giera²,

Lingeman³

et al. 2010

Biomedical Chromatography

View full text Add to dashboard Cite

Alzheimer's is a neurodegenerative disease. Its symptoms are attributed to a deficiency of cholinergic neurotransmission. The drugs of choice for the treatment of Alzheimer's disease are acetylcholinesterase (AChE) inhibitors. Starting in the 1980's from non-specific AChE inhibitors, the first-generation drugs such as physostigmine, a second generation of more selective and better tolerated products has been developed. Methods to detect and quantify these drugs and their metabolites in biological samples have been developed for analysis in plasma, blood, urine and cerebrospinal fluid. Diverse detection techniques have been used, such as ultraviolet, fluorescence, electrochemical and mass spectrometry. In this review, the methods applied to the analysis of these drugs and their metabolites in different biological matrices are reviewed and discussed. The stability of these drugs in biological matrices and under stress-conditions is also included in the discussion.

show abstract

Synthesis and cholinesterase activity of phenylcarbamates related to Rivastigmine, a therapeutic agent for Alzheimer's disease

Cited by 38 publications

References 29 publications

Synthesis, screening for antiacetylcholinesterase activity and binding mode prediction of a new series of [3-(disubstituted-phosphate)-4,4,4-trifluoro-butyl]-carbamic acid ethyl esters

Synthesis, screening for antiacetylcholinesterase activity and binding mode prediction of a new series of [3-(disubstituted-phosphate)-4,4,4-trifluoro-butyl]-carbamic acid ethyl esters

Hybridization‐based design of novel anticholinesterase indanone–carbamates for Alzheimer's disease: Synthesis, biological evaluation, and docking studies

Analysis of acetylcholinesterase inhibitors: bioanalysis, degradation and metabolism

Contact Info

Product

Resources

About