Synthesis, anticonvulsant activity and metabolism of 4-chlor-3-methylphenoxyethylamine derivatives of trans-2-aminocyclohexan-1-ol.

In this study, we report the synthesis, spectral characterization, antiepileptic activity and biotransformation of three new, chiral, N-aminoalkyl derivatives of trans - 2 aminocyclohexan-1-ol: (R enantiomer), (S enantiomer) and (racemate). Antiepileptic activity of the titled compounds was studied using MES and scMet. Moreover, in this study, the biotransformation of , and in microbial model (Cunninghamella), liver microsomal assay as well as in silico studies (MetaSite) was evaluated. Studies have indicated that , and have good antiepileptic activity in vivo, comparable to valproate. Biotransformation assays showed that the most probable metabolite (indicated in every tested assays) was . The microbial model as well as in silico study showed no difference in biotransformation between tested enantiomers. However, in a rat liver microsomal study compound and (R and S enantiomer) had different main metabolite - for and for . MS/MS fragmentation allowed us to predict the structures of obtained metabolites, which were in agreement with 1°alcohol () and carboxylic acid (). Our research has shown that microbial model, microsomal assay, and computational methods can be included as useful and reliable tools in early ADME-Tox assays in the process of developing new drug candidates.
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