The study of the lipophilicity of some aminoalkanol derivatives with anticonvulsant activity

A series of new (phenoxyethyl)aminoalkanol derivatives were synthesized and evaluated for their anticonvulsant activity. The most promising compound seemed to be (R,S)‐1N‐[(2,6‐dimethyl)phenoxyethyl]amino‐2‐butanol, which displayed anti‐MES activity (in mice, i.p.) with protective index (TD₅₀/ED₅₀) of 5.712, corresponding to that of phenytoin (6.6), carbamazepine (4.9) and valproate (1.7). The lipophilicity of compounds 1–17 exhibiting anticonvulsant activity was investigated. Their lipophilicities (R_M0) were determined using reversed‐phase thin‐layer chromatography (RP‐TLC) with a mixture of acetone and water as mobile phases. The partition coefficients of 1–17 (logP) were also calculated using two computer programs (Pallas and ALOGPS) and compared with R_M0. The relationship between anticonvulsant activity and lipophilicity of the tested substances was estimated. Copyright © 2010 John Wiley & Sons, Ltd.     

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

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, 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 R₁²(5) hydrogen‐bonding motif is observed. Structural studies have been enriched by the generation of fingerprint plots derived from Hirshfeld surfaces.     

Estimating the lipophilicity of a number of 2‐amino‐1‐cyclohexanol derivatives exhibiting anticonvulsant activity

The lipophilicity of a number of N‐acyl derivatives of trans‐ or cis‐: racemic, (1R,2R)‐ or (1S,2S)‐aminocyclohexanol (1–13) exhibiting anticonvulsant activity was investigated. Their lipophilicity (R_{m 0}) was determined using reversed‐phase thin‐layer chromatography (RP‐TLC) with mixtures of methanol and water as mobile phases. The partition coefficients of compounds 1–13 (log P) were also calculated using two computer programs (Pallas and Chem DU) and compared with R_{m 0}. Copyright © 2009 John Wiley & Sons, Ltd.     

Influence of protonation on the geometry of 2-{[(2,6-dimethylphenoxy)ethyl]amino}-1-phenylethan-1-ol: crystal structures of the free base and of its chloride and 3-hydroxybenzoate salt forms

The aroxyalkylaminoalcohol derivatives are a group of compounds known for their pharmacological action. The crystal structures of four new xylenoxyaminoalcohol derivatives having anticonvulsant activity are reported, namely, 2-{[2-(2,6-dimethylphenoxy)ethyl]amino}-1-phenylethan-1-ol, C₁₈H₂₃NO₂, 1 , the salt N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxy-1-phenylethan-2-aminium 3-hydroxybenzoate, C₁₈H₂₄NO₂⁺·C₇H₅O₃^?, 2 , and two polymorphs of the salt (R)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxy-1-phenylethan-2-aminium chloride, C₁₈H₂₄NO₂⁺·Cl^?, 3 and 3p . Both polymorphs crystallize in the space group P2₁2₁2 and each has two cations and two anions in the asymmetric unit (Z′ = 2). The molecules in the polymorphs show differences in their molecular conformations and intermolecular interactions. The crystal packing of neutral 1 is dominated by intermolecular O—H…N hydrogen bonds, resulting in the formation of one-dimensional chains. In the crystal structures of the salt forms ( 2 , 3 and 3p ), each protonated N atom is engaged in a charge-assisted hydrogen bond with the corresponding anion. The protonation of the N atom also influences the conformation of the molecular linker between the two aromatic rings and changes the orientation of the rings. The crystal packing of the salt forms is dominated by intermolecular O—H…O hydrogen bonds, resulting in the creation of chains and rings. Structural studies have been enriched by the calculation of Hirshfeld surfaces and the corresponding fingerprint plots.     

Interaction of iron(III) tetrasulphonated phthalocyanine with cytochrome c oxidase apoprotein

A complex of bovine cytochrome c oxidase protein with iron(III) tetrasulphonated phthalocyanine in place of hemes has been prepared. Its structure and properties have been investigated by difference spectroscopy, electrophoresis, molecular weight estimation, potentiometric measurements and polypeptide fragments examination. The visible absorption spectrum of Fe^III-apo-oxidase shows the main intense peak at 657 nm and weaker one at 700 nm. Molecular weight estimation demonstrated that one mole of the complex includes three functional units of MW 130,000 per unit. Spectroscopic examination of dithionite reduced Fe^III-apo-oxidase suggests the open crevice structure of the subunits containing iron tetrasulphonated phthalocyanine which is supported by the results of circular dichroism studies. Deep conformational changes of the protein upon displacement of hemes a and a₃ are not reversed upon Fe^IIIL⁺ incorporation into the protein. The molar ratio of the protein to Fe^IIIL in the complex (MW 130,000) was found to be 1:2. In the reduced form Fe^IIIL-apo-oxidase reacts with CN⁻, N^-₃ imidazole and molecular oxygen. Oxygen binding is irreversible, which indicates that the oxygen adduct is not of the oxyhemoglobin type. Electrophoretic and gel filtration studies of the SDS-urea dissociation products of cytochrome c oxidase and its phthalocyanine derivative suggest that Fe^IIIL and hemes a and a₃ are located on the same polypeptide fragments of the protein. Fe^IIIL-apo-oxidase is reduced by ferrous cytochrome c in agreement with their midpoint potentials which are 315.5 and 260 mV, respectively. However, the rate of the reaction of Fe^IIIL-apo-oxidase with ferrous cytochrome c is markedly lower than that of the native cytochrome c oxidase suggesting different mechanisms for this process in both cases.     

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

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.     

Interaction between some metal tetrasulphonated phthalocyanines and apocytochrome-c

Artificial cytochromes-c have been prepared with zinc and vanadyl tetrasulphonated phthalocyanines in place of heme. Their structure and properties have been investigated by CD and difference spectroscopy, molecular weight determination and peptide fragments examination.     

Cavity-Free Lasing and 2D Plasma Oscillations in Optically Excited InGaN Heterostructures

We demonstrate lasing emission of optically excited InGaN LD structures without intentional resonant cavity formation. We observe the equal mode-spacing character of this effect in the back-scattering geometry after exceeding the threshold excitation intensity. The homogeneity of the effect and stable mode spacing exclude participation of defects or wafer edges in lasing. We propose a lasing mechanism based on optically excited 2D electron–hole plasma oscillations, which act as a dynamical grating and resonantly couple the lasing modes separated by the plasma frequency, similar to the case of DFB lasers. The observed anomalous mode spacing is determined by the eigenfrequency of the plasma oscillations.