How can fluorine directly and indirectly affect the hydrogen bonding in molecular systems? - A case study for monofluoroanilines.

Hydrogen bonds (HBs) directly engaging fluorine has been extensively studied, but the indirect effect of fluorine on adjacent donors and acceptors is poorly understood and still difficult to predict. The indirect and direct effect of the fluorination of aniline on HB patterns observed in monofluoroanilines was studied via experimental (vibrational spectroscopy and crystal structure analysis) and theoretical (ab initio molecular dynamics and electrostatic surface potential) methods. It was found that a fluorine substituent decreases the strength and frequency of N-H⋯N HBs and, at the same time, increases the acidity of CH protons, enhancing the competitiveness of weaker interactions. Additionally, the position of fluorine in the aromatic ring strongly affects the C-F bond length, and a direct intramolecular N-H⋯F HB causes an increase in the N-H bond stability. We also provide a methodology to identify and separate individual HBs concerning the type of donor or acceptor from the ab initio molecular dynamics trajectories.

Antibacterial properties of 5-substituted derivatives of rhodanine-3-carboxyalkyl acids. Part II.

Two series of rhodanine-3-acetic and rhodanine-3-propionic acids derivatives having benzylidene and cinnamylidene substituents with additional electron donating and withdrawing groups at the C-5 position, were synthesised. The structures of the obtained derivatives were confirmed by spectroscopic methods and their lipophilicity was screened. The crystal structures were determined for selected compounds. The antibacterial activity of the derivatives was depended on the type of carboxyalkyl group in the N-3 position and on the type of the substituent in the C-5 position. The derivatives of rhodanine-3-propionic acid demonstrated the highest activity against Gram-positive bacteria. However, none of tested derivatives showed activity against Gram-negative bacteria and yeast. We believe that the presence of the N,N-diethylamine group in the aromatic system and the number of carbon atoms in the carboxyalkyl group is more significant for the biological activity than the fact that the benzylidene or cinnamylidene substituent was present at the C-5 position.

Antibacterial properties of 5-substituted derivatives of rhodanine-3-carboxyalkyl acids.

A series of rhodanine 3-carboxyalkanoic acid derivatives possessing 4'-(N,N-dialkyl-amino or diphenylamino)-benzylidene moiety as a substituent at the C-5 position were synthesised and their antibacterial activity was screened. All the rhodanine derivatives showed bacteriostatic or bactericidal activity to the reference gram-positive bacterial strains, but lack of activity to the reference Gram-negative bacterial strains and yeast strains was observed.

Synthesis of strong polycations with improved biological properties.

Poly(allylamine hydrochloride) (PAH) has found many applications both in biotechnology and biomedical fields. However, its high toxicity toward various mammalian cells significantly limits its effective usage. This study focuses on improving the biological properties of PAH by its modification to strong polyelectrolytes. The strong polycations were prepared by the direct quaternization of PAH amino groups or by the attachment of glycidyltrimethylammonium chloride to these groups. The biological properties, such as cytotoxicity toward human skin fibroblasts (HSFs), proliferation and migration of the cells on a polymeric surface, and antibacterial activities against two pathogenic bacteria, Staphylococcus aureus and Escherichia coli, were determined. All the modified polyelectrolytes are considerably less toxic to HSFs as compared to PAH. Moreover, the directly quaternized polycations are stronger biocides against S. aureus than the parent polymer. Contrary to PAH, thin films of the modified polyelectrolytes improve or do not affect HSFs proliferation and can stimulate cell migration into the wound, as was demonstrated using an in vitro model. The relationship between the structure of the modified polymers (amount and localization of the quaternary ammonium groups) and the biological activity is discussed. Due to the improved biological properties, the obtained polycations may be potentially useful for a variety of biotechnological and biomedical applications.

Studies on novel pyridine and 2-pyridone derivatives of N-arylpiperazine as α-adrenoceptor ligands.

This paper describes the synthesis of a series of new N-arylpiperazine derivatives of pyridine and 2-pyridone. The in vitro pharmacological study indicated that all of the compounds possess affinity towards α1-adrenoceptors, with exception of 6d, and are selective over α2 receptor. The most potent compound 5f displayed 62-fold α2/α1 selectivity with Ki value of 27.3 nM for α1 receptor. Selectivity of other ligands ranged from 6 to more than 146-fold. Hydrochlorides of selected compounds with the best α1-adrenoceptor affinity (7b, 7e, 7f, 8b) were tested in vivo (hypotensive activity test in rats) and the results proved their α-adrenoreceptor antagonistic activity. Furthermore, the lipophilicity of the investigated compounds has been assessed experimentally and in silico.

Application of NMR spectroscopy for assignment of the absolute configuration of 8-tert-butyl-2-hydroxy-7-methoxy-8-methyl-9-oxa-6-azaspiro[4.5]dec-6-en-10-one.

In order to assign the absolute configurations of 8-tert-butyl-2-hydroxy-7-methoxy-8-methyl-9-oxa-6-azaspiro[4.5]dec-6-en-10-one (2a,b), their esters (5a-d) with (R)- or (S)-2-methoxyphenylacetic acid (4a,b) have been synthesized. The absolute configurations of these compounds have been determined on the basis of NOESY correlations between the protons of the tert-butyl group and the cyclopentane fragment of the molecules. The crucial part of this analysis was assignment of the absolute configuration at C-5. Additionally, by calculation of the chemical shift anisotropy, δ(RS), for the relevant protons, it was also possible to confirm the absolute configurations at the C-2 centres of compounds 2a,b and 5a-d.

Kinetic and thermodynamic studies of moxifloxacin hydrolysis in the presence and absence of metal ions in acidic solutions.

Chromatographic and densitometric method for determination of moxifloxacin in the presence of products of acidic hydrolysis was developed. The established method had suitable specificity, precision, good accuracy, and high sensitivity. In addition, stability of moxifloxacin in acidic solutions at temperature 90 degrees C and 110 degrees C in the presence and absence of metal ions, such as Cu(II), Fe(III), Zn(II), and Al(III) was studied. It was proved that decomposition of moxifloxacin proceeds according to kinetics of the first-order reaction and is dependent on temperature, incubation time and the type of the metal ion. Based on the calculated kinetic (k, t0, and t0.5) and thermodynamic (Ea) parameters, it was observed that among studied ions the highest effect on decomposition process of moxifloxacin had Cu(II) ions. The liquid chromatography coupled with mass spectrometry detection (LC-MS) and proton nuclear magnetic resonance (1H NMR) techniques have been used to identify degradation products for the compound.

Kinetic and thermodynamic studies of moxifloxacin hydrolysis in the presence and absence of metal ions in acidic solutions.

Chromatographic and densitometric method for determination of moxifloxacin in the presence of products of acidic hydrolysis was developed. The established method had suitable specificity, precision, good accuracy and high sensitivity. In addition, stability of moxifloxacin in acidic solutions at temperature 90 degrees C and 110 degrees C in the presence and absence of metal ions, such as Cu(II), Fe(III), Zn(II), and Al(III) was studied. It was proved that decomposition of moxifloxacin proceeds according to kinetics of the first-order reaction and is dependent on temperature, incubation time and the type of the metal ion. Based on the calculated kinetic (k, t0.1, and t0.5) and thermodynamic (E(a)) parameters, it was observed that among studied ions the highest effect on decomposition process of moxifloxacin had Cu(II) ions. The liquid chromatography coupled with mass spectrometry detection (LC-MS) and proton nuclear magnetic resonance (1H NMR) techniques have been used to identify degradation products of moxifloxacin.

Determination of photostability and photodegradation products of moxifloxacin in the presence of metal ions in solutions and solid phase. Kinetics and identification of photoproducts.

Photostability of moxifloxacin (MOXI) after UVA irradiation in solutions and solid phase, with and without participation of Cu(II), Zn(II), Al(III), and Fe(III) was tested. The studies were carried out by the TLC-densitometric method and LC-MS/MS method. Elaborated and validated chromatography-densitometric method was used for assaying. It was shown that the number and type of photoproducts depend on the environment and type of the metal ion. The studied ions enhanced the degradation of MOXI in solutions, and the influence of Cu(II) and Fe(III) ions was higher than that of Zn(II) and Al(III) ions. In solid phase, in contrast to solutions, all metal ions decreased the photodegradation, however the influence of ions, Al(III) and Zn(II), was weaker than that of Cu(II) and Fe(III) ions. Identification of the degradation products performed with LC-MS/MS and (1)H NMR identified them as: 1-cyclopropyl-6-fluoro-7-amino-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-(2-oxo-octahydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-1,4-dihydroquinoline-3-carboxylic acid, 7-[3-hydroxyamino-4-(2-carboxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

Structural analysis of 1L-chiro-inositol diester from Taraxacum udum.

1l-1,5-Di-O-p-hydroxyphenylacetyl-chiro-inositol was isolated from the leaves of Taraxacumudum, along with seven other secondary metabolites. Identification of the inositol derivative, based on extensive spectroscopic analyses ((1)H, (13)C and 2D NMR) in two solvents, allowed the correction of previously published data and conformational studies. This is the second report on the presence of inositol esters with p-hydroxyphenylacetic acid in plants.

Synthesis of betulin derivatives and the determination of their relative lipophilicities using reversed-phase thin-layer chromatography.

A series of superlipophilic or highly lipophilic semisynthetic betulin derivatives was prepared and their relative lipophilicity was measured by reversed-phase thin-layer chromatography (RP-TLC) at different pH values using 1,4-dioxane-acetate buffer mixtures as mobile phases. Cholesterol, 17beta-estradiol and pure betulin were used as the reference compounds. Linear relationships were found between R(M) values and 1,4-dioxane concentrations in the mobile phases. LogP values were also calculated with computer programs ACD/LogP (ChemSketch 11.0, Advanced Chemistry Development Inc.) and ClogP (Daylight Chemical Information Systems Inc.). The empirical and theoretical data were compared, and the R(M0) values correlated well with logP. Two of the synthesized betulin derivatives are reported for the first time.

Structure elucidation and complete NMR spectral assignments of two new sesquiterpene lactone xylosides from Lactuca triangulata.

Two new sesquiterpene lactone xylosides, derivatives of the guaianolides 9alpha-hydroxyleucodin and 9alpha-hydroxy-11,13-dehydroleucodin, were isolated from roots of Lactuca triangulata. Their structures were established on the basis of (1)H and (13)C NMR spectra, 2D NMR (HMQC, HMBC, COSY, NOESY) techniques and comparison with the literature data. The compounds represent the first example of sesquiterpene lactone xylosides.

Stability of chosen beta-adrenolytic drugs of different polarity in basic environment.

The stability of atenolol, acebutolol, and propranolol was investigated in sodium hydroxide solutions at concentrations of 0.1, 0.3, 0.5, and 1 M at 3 temperatures ranging from 37 to 95 degrees C. The degradation processes that occurred in drugs under investigation were described with kinetic parameters (k, t0.1, and t0.5) and energy of activation (Ea). It was found that the stability of the drugs increased toward lipophilic propranolol in the assumed experimental model. The rate constants k decreased, contrary to t0.1, t0.5, and Ea, which varied comparably to log P (partition coefficient), thus increasing from the most hydrophilic atenolol, through acebutolol of lower polarity, to the most lipophilic propranolol. The identification of degradation products was performed with the application of proton nuclear magnetic resonance spectrometry and thin-layer chromatography-densitometry and data from the literature.

Stability of atenolol, acebutolol and propranolol in acidic environment depending on its diversified polarity.

The main objective of this research was to investigate the relationship between the polarity of atenolol, acebutolol, and propranolol described by logP and kinetic and thermodynamic parameters characterizing their degradation process in acidic solution. Hydrolysis was carried out in hydrochloric acid at molal concentrations of 0.1 mol/L, 0.5 mol/L, and 1 mol/L for 2 hr at 40 degrees C, 60 degrees C, and 90 degrees C. Chromatographic-densitometric method was used for the determination of drugs under investigation. The identification of degradation products was carried out by using 1H NMR. The degradation processes that occurred in drugs under investigation are described with kinetic parameters (k, t0.1, and t0.5) and energy of activation (Ea). It has been found that the stability of drugs increases toward lipophilic propranolol in the assumed experimental model. The rate constants k decrease, contrary to t0.1, t0.5, and Ea, which vary comparably to logP, thus increasing from the most hydrophilic atenolol, through acebutolol, of lower polarity, to the most lipophilic propranolol. This study demonstrated that the stability of chosen beta-adrenergic blocking agents increases with their lipophilicity.