Lipase Catalyzed Synthesis of Alkyl Phenylacetates with Anticonvulsant Activity

Despite the wide spectra of available antiepileptic drugs, one third of the patients still suffer from drug-resistant epilepsy, justifying the ongoing search of novel therapies. The anticonvulsant activity of propyl 4-hydroxybenzoate was previously identified through in silico screening. Here, Candida antarctica B (CAL B) lipase was employed as biocatalyst for the enzymatic synthesis of a series of alkyl phenylacetates which, based on their molecular similarity to propylparaben, were tested in two acute mice models of seizure (maximal electroshock seizure and subcutaneous pentylenetetrazol tests). Molecular docking was later applied to explain the observed activities. All the synthesized compounds displayed some degree of protective activity in the maximal electroshock seizure model, whereas none of them showed protection against pentylenetetrazol-induced convulsions. Ethyl 4-methoxyphenylacetate and propyl phenylacetate showed the most promising in vivo results. In consistence with the observed anticonvulsant effects, propyl phenylacetate obtained the best predicted binding energy among the synthesized alkyl phenylacetates.