Synthesis, Anticonvulsant Activity and Metabolism of 4‐chlor‐3‐methylphenoxyethylamine Derivatives of Trans‐2‐aminocyclohexan‐1‐ol

Abstract

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.

Biotransformation of 4‐fluoro‐N‐(1‐{2‐[(propan‐2‐yl)phenoxy]ethyl}‐8‐azabicyclo[3.2.1]octan‐3‐yl)‐benzenesulfonamide, a novel potent 5‐HT7 receptor antagonist with antidepressant‐like and anxiolytic properties: In vitro and in silico approach

“…Moreover, our in silico data coincide with in vitro experiments, as three MetaSite metabolites of PZ‐1150 matched compounds identified in microsomal samples. Similar observations were made when the metabolism of some trans ‐2‐aminocyclohexan‐1‐ol derivatives with the use of C. blakesleeana , RLMs, and MetaSite was investigated . Metasite predicted two metabolites, which were also identified using the Cunninghamella model and RLMs .…”

“…This is consistent with previous reports comparing xenobiotics biotransformation by Cunninghamella spp. and microsomes, which indicated that the generated metabolites are comparable . Moreover, our in silico data coincide with in vitro experiments, as three MetaSite metabolites of PZ‐1150 matched compounds identified in microsomal samples.…”

“…and microsomes, which indicated that the generated metabolites are comparable. [14,27,34,35] Moreover, our in silico data coincide with in vitro experiments, as three MetaSite metabolites of PZ-1150 matched compounds identified in microsomal samples. Similar observations were made when the metabolism of some trans-2-aminocyclohexan-1ol derivatives with the use of C. blakesleeana, RLMs, and MetaSite was investigated.…”

“…The biotransformation was carried out for 7 days, and its progress was monitored using TLC, and further confirmed with liquid chromatography coupled with tandem mas spectrometry (LC‐MS/MS). All probes were done in duplicate …”

“…[27] Metasite predicted two metabolites, which were also identified using the Cunninghamella model and RLMs. [27] Similarly to our observations, more metabolites were seen with microsomal than with microbial model. PZ-1150 belongs to fluorinated compounds, representing a large group of currently used drugs.…”