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

Abstract

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.

Predictive in silico Modeling of Ionic Liquids toward Inhibition of the Acetyl Cholinesterase Enzyme of Electrophorus electricus: A Predictive Toxicology Approach

“…In order to maintain simplicity and also considering their more contributing features, cations were considered for the docking study. Owing to the nonavailability of a suitable X-ray crystallographic structure of the Electrophorus electricus AChE receptor, we have employed the AChE enzyme structure (resolution 2.2 Å) of the organism Torpedo californica (the Pacific electric ray), which possesses a good degree of genetic homology with E. electricus. The X-ray crystal structure of the o -ethylmethylphosphonylated T. californica AChE enzyme 1VXR (EC- 3.1.1.7, resolution 2.2 Å) () was used as the target receptor.…”

Haloacetylated Enol Ethers: a Way Out for the Regioselective Synthesis of Biologically Active Heterocycles

“…[108] Additionally, β‐amino alcohols 80 were reacted with POCl 3 , followed by the addition of a oxygen nucleophile (aliphatic alcohols), which furnished alkyl phosphates 81 at 30–98 % yields (Scheme 24). [109] It is important to note that a silylated derivative (5‐bromo‐1,1,1‐trifluoro‐4‐methoxypent‐3‐en‐2‐yl)oxy)trimehtylsilane) was also prepared from the corresponding reduced enone 4 and TMSCl, at 90 % yield [110] …”

“…At a concentration of 1 μM, β‐aminoalcohol 84 was found to be active against the enzyme AChE, with inhibition of 70 %. Molecular docking of 85 was also conducted in order to better understand how the compound fit into the active site of the enzyme [109] …”

Conformational analysis of phloroglucinols from hypericum Brasiliense by using x-ray diffraction and molecular modeling

“…However, success in using conformational profiles in the study of biochemical interactions depends on how well computer simulation is able to reproduce the structural features of the species involved. [12][13][14][15][16][17] In this work we intend to verify the applicability of a computational methodology to predict structural features of organic compounds with biological activity. We selected the phloroglucinols 1, 2 and 3 and compared their calculated conformational data with X-ray experimental results.…”