Levetiracetam analogs: chemoenzymatic synthesis, absolute configuration assignment and evaluation of cholinesterase inhibitory activities
Título del documento: Levetiracetam analogs: chemoenzymatic synthesis, absolute configuration assignment and evaluation of cholinesterase inhibitory activities
Revue: Ecletica quimica
Base de datos:
Número de sistema: 000552409
ISSN: 0100-4670
Autores: 2
2
3
1
1
2
Instituciones: 1University of São Paulo, Faculty of Philosophy, Sciences and Letters, Ribeirão Preto, Brazil.,
2São Paulo State University, Institute of Chemistry, Araraquara, Brazil.,
3Federal University of São Carlos, Department of Chemistry, São Carlos, Brazil. Federal University of São Paulo, Institute of Science and Technology, São José dos Campos, Brazil.,
Año:
Volumen: 47
Número: 2
Paginación: 17-35
País: Brasil
Idioma: Inglés
Resumen en inglés A chemoenzymatic approach for the synthesis of α-N-heterocyclic ethyl- and phenylacetamides, levetiracetam analogs, is described. Eight nitrile substrates were prepared through the N-alkylation of heterocycles (2-pyrrolidinone, 2-piperidinone, 2-oxopiperazine and 1-methylpiperazine) directly from hydroxyl group of ethyl and phenyl α-hydroxynitriles with yield of 35−71% after 12 h. Twenty nitrile hydratases (NHases) were screened and showed that the N-derivatives lactam substrates led to their correspondent amides by Co-type NHase with conversion and enantiomeric excess of up to 47.5 and 52.3% for (S)-enantiomer, while the piperazine substrates underwent spontaneous decomposition by retro-Strecker reaction. In order to avoid a retro-Strecker reaction of α-aminonitriles, ionic liquids and polyethylene glycol (PEG400) were evaluated as alternative green solvents to aqueous buffered solutions in different proportions. Temperature was another parameter investigated during reaction-medium engineering for process optimization. However, unconventional reaction media and low temperature significantly reduced the NHase activity. The absolute configuration of α-N-heterocyclic ethyl- and phenylacetamides, some of which were new compounds, was determined using electronic circular dichroism (ECD) spectroscopy. Additionally, their potential as cholinesterase"s inhibitors was evaluated.
Texte intégral: Texto completo (Ver PDF)