Cunninghamella as a Microbiological Model for Metabolism of Histamine H3 Receptor Antagonist 1-[3-(4-tert-Butylphenoxy)propyl]piperidine

Abstract

The aim of the study was to analyze the ability of the microorganism Cunninghamella to carry out the biotransformation of 1-[3-(4-tert-butylphenoxy)propyl]piperidine (DL76) and to compare the obtained results with in silico models. Biotransformation was carried out by three strains of filamentous fungus: Cunninghamella echinulata, Cunninghamella blakesleeana, and Cunninghamella elegans. Most probable direction of DL76 metabolic transition was the oxidation of the methyl group in the tert-butyl moiety leading to the formation of the metabolite with I° alcohol properties. This kind of reaction was conducted by all three strains tested. However, only in the case of C. blakesleeana that biotransformation product had a structure of carboxylic acid. CYP2C19 was identified by Metasite software to be the isoform of major importance in the oxidation process in the tert-butyl moiety of DL76. In silico data coincide with the results of experiments conducted in vitro. It was confirmed that Cunninghamella fungi are a very good model to study the metabolism of xenobiotics. The computational methods and microbial models of metabolism can be used as useful tools in early ADME-Tox assays in the process of developing new drug candidates.

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

“…16 Computational simulation of metabolism of the title compound was carried out by using MetaSite software, demo version 2.1.0.…”

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

“…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 …”

“…All probes were done in duplicate. [11,27] Moreover, MetaSite is employed to predict the structures of the most probable metabolites and identifies cytochrome P450 isoforms (CYPs) involved in metabolic pathways. [28][29][30] The probability of a certain atom to be a SOM depends on the accessibility of this atom toward the heme and the chemical reactivity of atom in the specific reaction.…”

“…Additionally, various microbial systems employing bacteria, yeast, and fungi may constitute an alternative to the use of animal models in the study of NCEs metabolism . The zygomycete fungus Cunninghamella can perform both phase I and phase II biotransformation reactions and was shown to metabolize chemical compounds in a way similar to mammals …”

“…[7][8][9] The zygomycete fungus Cunninghamella can perform both phase I and phase II biotransformation reactions and was shown to metabolize chemical compounds in a way similar to mammals. [7,[10][11][12][13][14][15] Recently, a series of novel arylsulfonamide/amide derivatives of (aryloxy)ethyl alkyl amines was designed and synthesized in the Department of Medicinal Chemistry, Jagiellonian University Medical College. Subsequently, representative compounds affinity for 5-HT 7 receptors (Rs) and selectivity over related 5-HTRs (5-HT 1A Rs, 5-HT 2A Rs, 5-HT 6 Rs), dopamine D 2 Rs, and adrenergic 1 Rs was estimated.…”