A computational study on phenibut lactamization mechanism and the pH effects on the process
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A computational study on phenibut lactamization mechanism and the pH effects on the process Saba Hadidi1 · Farshad Shiri1 · Mohammadsaleh Norouzibazaz2,3 Received: 4 January 2020 / Accepted: 25 May 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract The current work investigates the lactamization reaction of neuropsychotropic medicine phenibut to higher toxicity phenibutlactam. The reaction is considered as an intramolecular cyclization which finally leads to generation of phenibut-lactam component. Herein, we considered three different structural forms for the chemically intact phenibut which consist of two stable R1, R2, and a relatively distorted isomer R*. The initial stage in this reaction is the transformation of two stable isomers into the unstable form, R*. The calculations showed that there is a transition state (TS) close to the unstable geometry, R*. This transition state possesses 31.30 kcal/mol more energy compared to the isomer R* (5.98 kcal/mol). By studying the thermodynamic stability of the lactam structure (− 13.55 kcal/mol), we can clearly conclude that pheni-l component has higher thermal stability compared to its related phenibut. Also, from the investigation of this reaction in various pH, it was found that the rate of reaction reduces under both basic and acidic conditions. Keywords Phenibut · Lactamization reaction · Theoretical study · Degradation process
1 Introduction In recent years, anxiolytic and nootropic drugs have attracted the attention of scientists. Phenibut (β-phenyl-γaminobutyric acid or phenyl GABA) is a well-known and useful neuropsychotropic medicine which can be employed in the treatment of several kinds of diseases, including anxiety, asthenia, depression, insomnia, vestibular disorders, stuttering in children and alcohol withdrawal symptoms. Phenibut also can be utilized as a tranquilizer and mood elevator due to its nootropic and anxiolytic effects [1–6]. This medicine which is one of the derivatives of GABA Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00214-020-02617-9) contains supplementary material, which is available to authorized users. * Saba Hadidi [email protected] 1
Department of Inorganic Chemistry, Faculty of Chemistry, Razi University, Kermanshah, Iran
2
Department of Nano Chemistry, Faculty of Chemistry, Razi University, Kermanshah, Iran
3
Department of Organic Chemistry, Faculty of Chemistry, Razi University, Kermanshah, Iran
(γ-aminobutyric acid), has similar characteristics to gabapentin and can be eliminated by kidneys. Some investigations depicted that the elimination half-life of this drug is around 5.3 h [1]. Phenibut contains an asymmetric carbon atom and exists in both R(−) and S(+) enantiomeric forms. The biological activity of this medicine is highly dependent on its absolute configuration. Phenibut is available and used clinically in racemic mixtures however, existing studies have revealed that only the R-enantiomer is effective
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