Design, physico-chemical properties and biological evaluation of some new N-[(phenoxy)alkyl]- and N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols as anticonvulsant agents

Waszkielewicz, Anna M.; Gunia‐Krzyżak, Agnieszka; Powroźnik, Beata; Słoczyńska, Karolina; Pękala, Elżbieta; Walczak, Maria; Bednarski, Marek; Żesławska, Ewa; Nitek, Wojciech; Marona, Henryk

doi:10.1016/j.bmc.2016.03.006

Cited by 15 publications

(30 citation statements)

References 22 publications

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“…(2) and (S)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium chloride (2c) were obtained as described previously (Waszkielewicz et al, 2015(Waszkielewicz et al, , 2016. Single crystals suitable for X-ray diffraction studies were recrystallized from a mixture of acetone and decane (1:1 v/v) for 1, and from isopropyl acetate for 2c by slow evaporation at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…Reports on the anticonvulsant activity of the cardiovascular drugs propranolol (Fischer et al, 1985;Fischer, 2002) and mexiletine (Chew et al, 1979) prompted many scientists to search for other aminoalkanol and/or aroxyalkyl derivatives possessing similar properties and functions. For the last two decades, a group of aminoalkanol and aroxyalkyl derivatives have gained much attention due to their anticonvulsant activity (Marona et al, 2005;Pę kala et al, 2011;Waszkielewicz et al, 2013Waszkielewicz et al, , 2015Waszkielewicz et al, , 2016Pań czyk et al, 2018Pań czyk et al, , 2019. Research carried out by our team involved the crystal structure analysis of the tested compounds and an analysis of their anticonvulsant activity.…”

Section: Introductionmentioning

confidence: 99%

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The conformational analyses of 2-amino-N-[2-(dimethylphenoxy)ethyl]propan-1-ol derivatives in different environments

Nitek¹,

Kania²,

Marona³

et al. 2020

Acta Crystallogr C

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Four crystal structures of 2-amino-N-(dimethylphenoxyethyl)propan-1-ol derivatives, characterized by X-ray diffraction analysis, are reported. The free base (R,S)-2-amino-N-[2-(2,3-dimethylphenoxy)ethyl]propan-1-ol, C13H21NO2, 1, crystallizes in the space group P21/n, with two independent molecules in the asymmetric unit. The hydrochloride, (S)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium chloride, C13H22NO2 +·Cl−, 2c, crystallizes in the space group P21, with one cation and one chloride anion in the asymmetric unit. The asymmetric unit of two salts of 2-picolinic acid, namely, (R,S)-N-[2-(2,3-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium pyridine-2-carboxylate, C13H22NO2 +·C6H4NO2 −, 1p, and (R)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium pyridine-2-carboxylate, C13H22NO2 +·C6H4NO2 −, 2p, consists of one cation and one 2-picolinate anion. Salt 1p crystallizes in the triclinic centrosymmetric space group P-1, while salt 2p crystallizes in the space group P41212. The conformations of the amine fragments are contrasted and that of 2p is found to have an unusual antiperiplanar arrangement about the ether group. The crystal packing of 1 and 2c is dominated by hydrogen-bonded chains, while the structures of the 2-picolinate salts have hydrogen-bonded rings as the major features. In both salts with 2-picolinic acid, the specific R 1 2(5) hydrogen-bonding motif is observed. Structural studies have been enriched by the generation of fingerprint plots derived from Hirshfeld surfaces.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The conformational analyses of 2-amino-N-[2-(dimethylphenoxy)ethyl]propan-1-ol derivatives in different environments

Nitek¹,

Kania²,

Marona³

et al. 2020

Acta Crystallogr C

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“…2-aminopropan-1-ol derivatives; Waszkielewicz et al, 2015) or for the preparation of crystals of other salts in order to study the structural properties of a compound in different environments (Ż esławska et al, 2018a). As a continuation of our medicinal chemistry and crystallographic studies of compounds showing anticonvulsant activity (Ż esławska et al, 2017, 2018b), we obtained further cyclic aminoalkanol derivatives, among which 1-[(2,3-dimethylphenoxy)ethyl]piperidin-4-ol hydrochloride is especially interesting, both from an activity and a chemical point of view (Waszkielewicz et al, 2016). Its activity was revealed in a 6 Hz test for the first 30 min of assessment and then disappeared, but reappeared after 4 h, however, at a lower level.…”

Section: Introductionmentioning

confidence: 93%

Influence of the position of the methyl substituent and N-oxide formation on the geometry and intermolecular interactions of 1-(phenoxyethyl)piperidin-4-ol derivatives

et al. 2020

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Aminoalkanol derivatives have attracted much interest in the field of medicinal chemistry as part of the search for new anticonvulsant drugs. In order to study the influence of the methyl substituent and N-oxide formation on the geometry of molecules and intermolecular interactions in their crystals, three new examples have been prepared and their crystal structures determined by X-ray diffraction. 1-[(2,6-Dimethylphenoxy)ethyl]piperidin-4-ol, C15H23NO2, 1, and 1-[(2,3-dimethylphenoxy)ethyl]piperidin-4-ol, C15H23NO2, 2, crystallize in the orthorhombic system (space groups P212121 and Pbca, respectively), with one molecule in the asymmetric unit, whereas the N-oxide 1-[(2,3-dimethylphenoxy)ethyl]piperidin-4-ol N-oxide monohydrate, C15H23NO3·H2O, 3, crystallizes in the monoclinic space group P21/c, with one N-oxide molecule and one water molecule in the asymmetric unit. The geometries of the investigated compounds differ significantly with respect to the conformation of the O—C—C linker, the location of the hydroxy group in the piperidine ring and the nature of the intermolecular interactions, which were investigated by Hirshfeld surface and corresponding fingerprint analyses. The crystal packing of 1 and 2 is dominated by a network of O—H...N hydrogen bonds, while in 3, it is dominated by O—H...O hydrogen bonds and results in the formation of chains.

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“…Our research team achieved satisfying results in terms of design and synthesis of new compounds for antidepressant‐like, anticonvulsant and anxiolytic‐like activity in a group of phenoxyalkyl and phenoxyethoxyethyl derivatives of piperazine (particularly N ‐(2‐methoxyphenyl)piperazine), as well as derivatives of aminoalkanols . In case of piperazine derivatives our preliminary research has focused on the potential antidepressant‐like activity of new compounds, their potential anxiolytic‐like or anticonvulsant activities were usually tested only for selected compounds.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of N‐(phenoxyalkyl)‐, N‐{2‐[2‐(phenoxy)ethoxy]ethyl}‐ or N‐(phenoxyacetyl)piperazine Derivatives and Their Activity Within the Central Nervous System

et al. 2019

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Depression, anxiety and epilepsy share some etiology factors, causing frequently observed multimodal activity of centrally active compounds. This might raise the risk of central adverse effects of potential drugs, but on the other hand ‐ in a light of common comorbidity of these diseases ‐ also make an opportunity for avoiding polypragmasy. The presented study combines rational drug design methods, chemical synthesis, receptor studies and in vivo pharmacological screening (mice, i. p.) in order to obtain new centrally active piperazine derivatives in a context of their potential multimodality, investigate the mechanism of their activity and establish relationship between their structure, molecular mechanism and in vivo central activity(‐ies). The most promising pharmacological profile showed 1‐(2‐(2,5‐dimethylphenoxy)ethyl)‐4‐phenylpiperazine dihydrochloride (1), which was active in the four‐plate test (anxiolytic‐like activity) at 1.25 mg/kg b.w. and possessed high affinities towards several tested molecular targets (5‐HT1A Ki=35 nM ‐ weak antagonist, 5‐HT2A Ki=121 nM, 5‐HT7 Ki=130 nM ‐ weak antagonist, α1 Ki=82 nM, μ Ki=240 nM).

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Design, physico-chemical properties and biological evaluation of some new N-[(phenoxy)alkyl]- and N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols as anticonvulsant agents

Cited by 15 publications

References 22 publications

The conformational analyses of 2-amino-N-[2-(dimethylphenoxy)ethyl]propan-1-ol derivatives in different environments

The conformational analyses of 2-amino-N-[2-(dimethylphenoxy)ethyl]propan-1-ol derivatives in different environments

Influence of the position of the methyl substituent and N-oxide formation on the geometry and intermolecular interactions of 1-(phenoxyethyl)piperidin-4-ol derivatives

Synthesis of N‐(phenoxyalkyl)‐, N‐{2‐[2‐(phenoxy)ethoxy]ethyl}‐ or N‐(phenoxyacetyl)piperazine Derivatives and Their Activity Within the Central Nervous System

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