Levetiracetam analogs: chemoenzymatic synthesis, absolute configuration assignment and evaluation of cholinesterase inhibitory activities

A chemoenzymatic approach for the synthesis of ?-N-heterocyclic ethyl- and phenylacetamides, levetiracetam analogs, is described. Eight nitrile substrates were prepared through N-alkylation heterocycles (2-pyrrolidinone, 2-piperidinone, 2-oxopiperazine 1-methylpiperazine) directly from hydroxyl group ethyl phenyl ?-hydroxynitriles with yield 35?71% after 12 h. Twenty hydratases (NHases) screened showed that N-derivatives lactam led to their correspondent amides by Co-type NHase conversion enantiomeric excess up 47.5 52.3% (S)-enantiomer, while piperazine underwent spontaneous decomposition retro-Strecker reaction. In order avoid a reaction ?-aminonitriles, ionic liquids polyethylene glycol (PEG400) evaluated as alternative green solvents aqueous buffered solutions in different proportions. Temperature was another parameter investigated during reaction-medium engineering process optimization. However, unconventional media low temperature significantly reduced activity. The absolute configuration ?-N-heterocyclic�ethyl- some which new compounds, determined using electronic circular dichroism (ECD) spectroscopy. Additionally, potential cholinesterase�s inhibitors evaluated.