Prediction of biological activity of compounds containing a 1,3,5-triazinyl sulfonamide scaffold by artificial neural networks using simple molecular descriptors.

Simple molecular descriptors of extensive series of 1,3,5-triazinyl sulfonamide derivatives, based on the structure of sulfonamides and their physicochemical properties, were designed and calculated. These descriptors were successfully applied as inputs for artificial neural network (ANN) modelling of the relationship between the structure and biological activity. The optimized ANN architecture was applied to the prediction of the inhibition activity of 1,3,5-triazinyl sulfonamides against human carbonic anhydrase (hCA) II, tumour-associated hCA IX, and their selectivity (hCA II/hCA IX).

Novel 1,3,5-Triazinyl Aminobenzenesulfonamides Incorporating Aminoalcohol, Aminochalcone and Aminostilbene Structural Motifs as Potent Anti-VRE Agents, and Carbonic Anhydrases I, II, VII, IX, and XII Inhibitors.

A series of 1,3,5-triazinyl aminobenzenesulfonamides substituted by aminoalcohol, aminostilbene, and aminochalcone structural motifs was synthesized as potential human carbonic anhydrase (hCA) inhibitors. The compounds were evaluated on their inhibition of tumor-associated hCA IX and hCA XII, hCA VII isoenzyme present in the brain, and physiologically important hCA I and hCA II. While the test compounds had only a negligible effect on physiologically important isoenzymes, many of the studied compounds significantly affected the hCA IX isoenzyme. Several compounds showed activity against hCA XII; (E)-4-{2-[(4-[(2,3-dihydroxypropyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (31) and (E)-4-{2-[(4-[(4-hydroxyphenyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (32) were the most effective inhibitors with KIs = 4.4 and 5.9 nM, respectively. In addition, the compounds were tested against vancomycin-resistant Enterococcus faecalis (VRE) isolates. (E)-4-[2-({4-[(4-cinnamoylphenyl)amino]-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)ethyl]benzenesulfonamide (21) (MIC = 26.33 µM) and derivative 32 (MIC range 13.80-55.20 µM) demonstrated the highest activity against all tested strains. The most active compounds were evaluated for their cytotoxicity against the Human Colorectal Tumor Cell Line (HCT116 p53 +/+). Only 4,4'-[(6-chloro-1,3,5-triazin-2,4-diyl)bis(iminomethylene)]dibenzenesulfonamide (7) and compound 32 demonstrated an IC50 of ca. 6.5 µM; otherwise, the other selected derivatives did not show toxicity at concentrations up to 50 µM. The molecular modeling and docking of active compounds into various hCA isoenzymes, including bacterial carbonic anhydrase, specifically α-CA present in VRE, was performed to try to outline a possible mechanism of selective anti-VRE activity.

Indol-2-Carboxylic Acid Esters Containing N-Phenylpiperazine Moiety - Preparation and Cholinesterase-inhibiting Activity.

BACKGROUND: The indole derivatives and the N-phenylpiperazine fragment represent interesting molecular moieties suitable for the research of new potentially biologically active compounds. This study was undertaken to identify if indol-2-carboxylic acid esters containing N-phenylpiperazine moiety possess acetylcholinesterase and butyrylcholinesterase inhibitory activity. MATERIALS AND METHODS: The study dealt with the synthesis of a novel series of analogs of 1H-indole-2- carboxylic acid and 3-methyl-1H-indole-2-carboxylic acid. The structure of the derivatives was represented by the indolylcarbonyloxyaminopropanol skeleton with the attached N-phenylpiperazine or diethylamine moiety, which formed a basic part of the molecule. The final products were synthesized as dihydrochloride salts, fumaric acid salts, and quaternary ammonium salts. The first step of the synthetic pathway led to the preparation of esters of 1H-indole-2-carboxylic acid from the commercially available 1H-indole-2-carboxylic acid. The Fischer indole synthesis was used to synthesize derivatives of 3-methyl-1H-indole-2-carboxylic acid. RESULTS AND DISCUSSION: Final 18 indolylcarbonyloxyaminopropanols in the form of dihydrochlorides, fumarates, and quaternary ammonium salts were prepared using various optimization ways. The very efficient way for the formation of 3-methyl-1H-indole-2-carboxylate (Fischer indole cyclization product) was the one-pot synthesis of phenylhydrazine with methyl 2-oxobutanoate with acetic acid and sulphuric acid as catalysts. CONCLUSION: Most of the derivatives comprised of an attached N-phenylpiperazine group, which formed a basic part of the molecule and in which the phenyl ring was substituted in position C-2 or C-4. The synthesized compounds were subjected to cholinesterase-inhibiting activity evaluation, by modified Ellman method. Quaternary ammonium salt of 1H-indole-2-carboxylic acid which contain N-phenylpiperazine fragment with nitro group in position C-4 (7c) demonstrated the most potent activity against acetylcholinesterase.

Arylaminopropanone Derivatives as Potential Cholinesterase Inhibitors: Synthesis, Docking Study and Biological Evaluation.

Neurodegenerative diseases in which the decrease of the acetylcholine is observed are growing worldwide. In the present study, a series of new arylaminopropanone derivatives with N-phenylcarbamate moiety (1-16) were prepared as potential acetylcholinesterase and butyrylcholinesterase inhibitors. In vitro enzyme assays were performed; the results are expressed as a percentage of inhibition and the IC50 values. The inhibitory activities were compared with reference drugs galantamine and rivastigmine showing piperidine derivatives (1-3) as the most potent. A possible mechanism of action for these compounds was determined from a molecular modelling study by using combined techniques of docking, molecular dynamics simulations and quantum mechanics calculations.

Antioxidative Activity of 1,3,5-Triazine Analogues Incorporating Aminobenzene Sulfonamide, Aminoalcohol/Phenol, Piperazine, Chalcone, or Stilbene Motifs.

A series of 1,3,5-triazine analogues, incorporating aminobenzene sulfonamide, aminoalcohol/phenol, piperazine, chalcone, or stilbene structural motifs, were evaluated as potential antioxidants. The compounds were prepared by using step-by-step nucleophilic substitution of chlorine atoms in starting 2,4,6-trichloro-1,3,5-triazine. Reactions were catalyzed by Cu(I)-supported on a weakly acidic resin. The radical scavenging activity was determined in terms of %inhibition activity and EC50, using the ABTS method. Trolox and ascorbic acid (ASA) were used as standards. In the lowest concentration 1 × 10-4 M, the %inhibition activity values at 0 min were comparable with both standards at least for 10 compounds. After 60 min, compounds 5, 6, 13, and 25 showed nearly twice %inhibition (73.44-87.09%) in comparison with the standards (Trolox = 41.49%; ASA = 31.07%). Values of EC50 at 60 min (17.16-27.78 µM) were 5 times lower for compounds 5, 6, 13, and 25 than EC50 of both standards (trolox = 178.33 µM; ASA = 147.47 µM). Values of EC50 correlated with %inhibition activity. Based on these results, the presented 1,3,5-triazine analogues have a high potential in the treatment of illnesses caused or related to oxidative stress.

Dibasic Derivatives of Phenylcarbamic Acid as Prospective Antibacterial Agents Interacting with Cytoplasmic Membrane.

1-[2-[({[2-/3-(Alkoxy)phenyl]amino}carbonyl)oxy]-3-(dipropylammonio)propyl]pyrrolidinium/azepan- ium oxalates or dichlorides (alkoxy = butoxy to heptyloxy) were recently described as very promising antimycobacterial agents. These compounds were tested in vitro against Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212 (reference and control strains), three methicillin-resistant isolates of S. aureus, and three isolates of vancomycin-resistant E. faecalis. 1-[3-(Dipropylammonio)-2-({[3-(pentyloxy-/hexyloxy-/heptyloxy)phenyl]carbamoyl}oxy)propyl]pyrrolidinium dichlorides showed high activity against staphylococci and enterococci comparable with or higher than that of used controls (clinically used antibiotics and antiseptics). The screening of the cytotoxicity of the compounds as well as the used controls was performed using human monocytic leukemia cells. IC50 values of the most effective compounds ranged from ca. 3.5 to 6.3 µM, thus, it can be stated that the antimicrobial effect is closely connected with their cytotoxicity. The antibacterial activity is based on the surface activity of the compounds that are influenced by the length of their alkoxy side chain, the size of the azacyclic system, and hydro-lipophilic properties, as proven by in vitro experiments and chemometric principal component analyses. Synergistic studies showed the increased activity of oxacillin, gentamicin, and vancomycin, which could be explained by the direct activity of the compounds against the bacterial cell wall. All these compounds demonstrate excellent antibiofilm activity, when they inhibit and disrupt the biofilm of S. aureus in concentrations close to minimum inhibitory concentrations against planktonic cells. Expected interactions of the compounds with the cytoplasmic membrane are proven by in vitro crystal violet uptake assays.

New Approach for the One-Pot Synthesis of 1,3,5-Triazine Derivatives: Application of Cu(I) Supported on a Weakly Acidic Cation-Exchanger Resin in a Comparative Study.

An efficient and simple methodology for Ullmann Cu(I)-catalyzed synthesis of di- and trisubstituted 1,3,5-triazine derivatives from dichlorotriazinyl benzenesulfonamide and corresponding nucleophiles is reported. Cations Cu(I) supported on macroporous and weakly acidic, low-cost industrial resin of polyacrylate type were used as a catalyst. The reaction times and yields were compared with traditional synthetic methods for synthesis of substituted 1,3,5-triazine derivatives via nucleophilic substitution of chlorine atoms in dichlorotriazinyl benzenesulfonamide. It was found that Ullmann-type reactions provide significantly shortened reaction times and, in some cases, also higher yields. Finally, trisubstituted s-triazine derivatives were effectively prepared via Ullmann-type reaction in a one-pot synthetic design. Six new s-triazine derivatives with potential biological activity were prepared and characterized.

Dibasic Derivatives of Phenylcarbamic Acid against Mycobacterial Strains: Old Drugs and New Tricks?

In order to provide a more detailed view on the structure⁻antimycobacterial activity relationship (SAR) of phenylcarbamic acid derivatives containing two centers of protonation, 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(dipropylammonio)propyl]pyrrolidinium oxalates (1a⁻d)/dichlorides (1e⁻h) as well as 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(di-propylammonio)propyl]azepanium oxalates (1i⁻l)/dichlorides (1m⁻p; alkoxy = butoxy to heptyloxy) were physicochemically characterized by estimation of their surface tension (γ; Traube's stalagmometric method), electronic features (log ε; UV/Vis spectrophotometry) and lipophilic properties (log kw; isocratic RP-HPLC) as well. The experimental log kw dataset was studied together with computational logarithms of partition coefficients (log P) generated by various methods based mainly on atomic or combined atomic and fragmental principles. Similarities and differences between the experimental and in silico lipophilicity descriptors were analyzed by unscaled principal component analysis (PCA). The in vitro activity of compounds 1a⁻p was inspected against Mycobacterium tuberculosis CNCTC My 331/88 (identical with H37Rv and ATCC 2794, respectively), M. tuberculosis H37Ra ATCC 25177, M. kansasii CNCTC My 235/80 (identical with ATCC 12478), the M. kansasii 6509/96 clinical isolate, M. kansasii DSM 44162, M. avium CNCTC My 330/80 (identical with ATCC 25291), M. smegmatis ATCC 700084 and M. marinum CAMP 5644, respectively. In vitro susceptibility of the mycobacteria to reference drugs isoniazid, ethambutol, ofloxacin or ciprofloxacin was tested as well. A very unique aspect of the research was that many compounds from the set 1a⁻p were highly efficient almost against all tested mycobacteria. The most promising derivatives showed MIC values varied from 1.9 µM to 8 µM, which were lower compared to those of used standards, especially if concerning ability to fight M. tuberculosis H37Ra ATCC 25177, M. kansasii DSM 44162 or M. avium CNCTC My 330/80. Current in vitro biological assays and systematic SAR studies based on PCA approach as well as fitting procedures, which were supported by relevant statistical descriptors, proved that the compounds 1a⁻p represented a very promising molecular framework for development of 'non-traditional' but effective antimycobacterial agents.

Antitussive activity of alcoxyphenyl carbamic acid analogues.

In this study we report pharmacological evaluation of four newly synthetized analogues of alcoxyphenyl carbamic acid, structurally related to butamirate citrate that is frequently used as cough suppressing drug, and marked as ATK 231, ATK 241, ATK 251 and ATK 261. These agents with various modifications of the molecular structure have been tested for antitussive activity in cough induced by inhalation of aerosol of citric acid (0.3 M) over 3 minutes using conscious guinea pigs. Results revealed significant cough suppressing activity without significant influence on specific airways resistances in all tested substances. ATK 231 and ATK241 showed significantly higher total antitussive activities when compared to both codeine phosphate and butamirate citrate, while ATK 251 only comparing to butamirate citrate. We did not observe any notable adverse effects and these compounds could thus potentially represent promising new non-narcotic antitussives suitable for further studies.

Novel sulfonamide incorporating piperazine, aminoalcohol and 1,3,5-triazine structural motifs with carbonic anhydrase I, II and IX inhibitory action.

A new series of s-triazine derivatives incorporating sulfanilamide, homosulfanilamide, 4-aminoethyl-benzenesulfonamide and piperazine or aminoalcohol structural motifs is reported. Molecular docking was exploited to select compounds from virtual combinatorial library for synthesis and subsequent biological evaluation. The compounds were prepared by using step by step nucleophilic substitution of chlorine atoms from cyanuric chloride (2,4,6-trichloro-1,3,5-triazine). The compounds were tested as inhibitors of physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms. Specifically, against the cytosolic hCA I, II and tumor-associated hCA IX. These compounds show appreciable inhibition. hCA I was inhibited with KIs in the range of 8.5-2679.1 nM, hCA II with KIs in the range of 4.8-380.5 nM and hCA IX with KIs in the range of 0.4-307.7 nM. As other similar derivatives, some of the compounds showed good or excellent selectivity ratios for inhibiting hCA IX over hCA II, of 3.5-18.5. 4-[({4-Chloro-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)methyl] benzene sulfonamide demonstrated subnanomolar affinity for hCA IX (0.4 nM) and selectivity (18.50) over the cytosolic isoforms. This series of compounds may be of interest for the development of new, unconventional anticancer drugs targeting hypoxia-induced CA isoforms such as CA IX.

Synthesis and In Vitro Antimycobacterial Activity of Novel N-Arylpiperazines Containing an Ethane-1,2-diyl Connecting Chain.

Novel 1-(2-{3-/4-[(alkoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)-piperazin-1-ium chlorides (alkoxy = methoxy to butoxy; 8a-h) have been designed and synthesized through multistep reactions as a part of on-going research programme focused on finding new antimycobacterials. Lipophilic properties of these compounds were estimated by RP-HPLC using methanol/water mobile phases with a various volume fraction of the organic modifier. The log kw values, which were extrapolated from intercepts of a linear relationship between the logarithm of a retention factor k (log k) and volume fraction of a mobile phase modifier (ϕM), varied from 2.113 (compound 8e) to 2.930 (compound 8h) and indicated relatively high lipophilicity of these salts. Electronic properties of the molecules 8a-h were investigated by evaluation of their UV/Vis spectra. In a next phase of the research, the compounds 8a-h were in vitro screened against M. tuberculosis CNCTC My 331/88 (identical with H37Rv and ATCC 2794), M. kansasii CNCTC My 235/80 (identical with ATCC 12478), a M. kansasii 6 509/96 clinical isolate, M. avium CNCTC My 330/80 (identical with ATCC 25291) and M. avium intracellulare ATCC 13950, respectively, as well as against M. kansasii CIT11/06, M. avium subsp. paratuberculosis CIT03 and M. avium hominissuis CIT10/08 clinical isolates using isoniazid, ethambutol, ofloxacin, ciprofloxacin or pyrazinamide as reference drugs. The tested compounds 8a-h were found to be the most promising against M. tuberculosis; a MIC = 8 µM was observed for the most effective 1-(2-{4-[(butoxycarbonyl)amino]phen-ylphenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)piperazin-1-ium chloride (8h). In addition, all of them showed low (insignificant) in vitro toxicity against a human monocytic leukemia THP-1 cell line, as observed LD50 values > 30 µM indicated. The structure-antimycobacterial activity relationships of the analyzed 8a-h series are also discussed.

An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors.

Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b]pyrimido[5,4-f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin-1-yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands.

The Structure-Antimicrobial Activity Relationships of a Promising Class of the Compounds Containing the N-Arylpiperazine Scaffold.

This research was focused on in silico characterization and in vitro biological testing of the series of the compounds carrying a N-arylpiperazine moiety. The in silico investigation was based on the prediction of electronic, steric and lipohydrophilic features. The molecules were screened against Mycobacterium avium subsp. paratuberculosis CIT03, M. smegmatis ATCC 700084, M. kansasii DSM 44162, M. marinum CAMP 5644, Staphylococcus aureus ATCC 29213, methicillin-resistant S. aureus 63718, Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, Candida albicans CCM 8261, C. parapsilosis CCM 8260 and C. krusei CCM 8271, respectively, by standardized microdilution methods. The eventual antiproliferative (cytotoxic) impact of those compounds was examined on a human monocytic leukemia THP-1 cell line, as a part of the biological study. Promising potential against M. kansasii was found for 1-[3-(3-ethoxyphenylcarbamoyl)oxy-2-hydroxypropyl]-4-(3-trifluoromethylphenyl)piperazin-1-ium chloride (MIC = 31.75 µM), which was comparable to the activity of isoniazid (INH; MIC = 29.17 µM). Moreover, 1-{2-hydroxy-3-(3-methoxyphenylcarbamoyl)oxy)propyl}-4-(4-fluorophenyl)piperazin-1-ium chloride was even more effective (MIC = 17.62 µM) against given mycobacterium. Among the tested N-arylpiperazines, 1-{2-hydroxy-3-(4-methoxyphenylcarbamoyl)oxy)propyl}-4-(3-trifluorometh-ylphenyl)piperazin-1-ium chloride was the most efficient against M. marinum (MIC = 65.32 µM). One of the common features of all investigated substances was their insignificant antiproliferative (i.e., non-cytotoxic) effect. The study discussed structure-antimicrobial activity relationships considering electronic, steric and lipophilic properties.

Application of BY-2 cell model in evaluating an effect of newly prepared potential calcium channel blockers.

Calcium channel blockers represent a group of therapeutically important compounds that have found an application in treatment of systemic vascular resistance and arterial pressure, eventually angina pectoris. We studied possibility of application of a BY-2 cell model to evaluate the potential of newly prepared potential calcium channel blockers. In the preliminary experiment, toxicity of studied compounds was determined. In the next experiment, we evaluated possible protective effect of studied compounds on programmed cell death induced by hydrogen peroxide on the BY-2 cells. Calcium channel blocker lanthanum ions and imidazole, inhibitor of NAD(P)H oxidase (EC 1.6.3.1) that prevents reactive oxygen species formation and programmed cell death, were used as reference compounds to compare the effect of studied compounds. We studied changes in the cell viability and growth as well as markers of cell proliferation, levels of intracellular free calcium ions, reactive oxygen species, lipid peroxidation, and markers of programmed cell death, mitochondrial membrane potential and caspase-like activity. Late signs of programmed cell death (changes in nuclear architecture) were also evaluated. Our experiments revealed protective potential of studied compounds against programmed cell death induced by hydrogen peroxide and possibility of application of the BY-2 cell culture to evaluate pharmacological effects of studied compounds in preliminary tests.

Dibasic esters of ortho-/meta-alkoxyphenylcarbamic acid containing 1-dipropylamino-3-piperidinopropan-1-yl and their antimicrobial activity.

In Europe, the presence of microorganisms that have become resistant to antimicrobials as the most significant disease threat has remained. The aim of the current research was to screen the in vitro susceptibility of Staphylococcus aureus, Escherichia coli and Candida albicans to the series of dibasic esters of ortho-/meta-alkoxyphenylcarbamic acid previously known for their local anaesthetic effectiveness and to contribute for the structure - antimicrobial potency relationships study within that class of the compounds. The antimicrobial activity investigation involved determination of the minimum inhibitory concentration (MIC) by applying the microdilution method; quantitative screening was performed on a blood agar (S. aureus), Endo agar (E. coli) or on Sabouraud's agar (C. albicans). The activity against all the microorganisms tested was primarily influenced by the position of alkoxy side chain attached to lipophilic aromatic ring and by its length as well. Inspected meta-alkoxy substituted derivatives have shown higher efficiency against all chosen microorganisms than their ortho-alkoxy positional isomers. The most promising results were observed when investigating the activity of meta-alkoxy substituted molecules against E. coli with the estimated MICs in the range of 12-49 microg/ml. Furthermore, such potency was found to be quasi parabolically dependent on alkoxy chain length achieving a maximum for meta-hexyloxy derivative which has shown MIC= 12 microg/ml. Considered compound was also regarded as the most effective against S. aureus with MIC = 98 microg/ml. Evaluating the potency against C. albicans, it was revealed that no molecule within the tested set displayed MIC < 100 microg/ml.

Anti-infective and herbicidal activity of N-substituted 2-aminobenzothiazoles.

In this study, a series of N-substituted 2-aminobenzothiazoles was prepared according to a recently developed method. Twelve compounds were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Primary in vitro screening of the discussed compounds was also performed against fungal, bacterial and mycobacterial species. The biological activities of some compounds were comparable or higher than the standards phenoxymethylpenicillin or pyrazinamide. The most effective compounds demonstrated insignificant toxicity against the human monocytic leukemia THP-1 cell line. For all compounds, the structure-activity relationships are discussed.

[Analytical profile of mono[{3-[4-(2-ethoxyethoxy)-benzoyloxy]-2-hydroxypropyl}-tert-butylammonium] fumarate]. / Analytické hodnotenie mono[{3-[4-(2-etoxyetoxy)- -benzoyloxy]-2-hydroxypropyl}-terc-butylamónium]fumarátu.

The present paper aims at a complex spectral and physicochemical evaluation of mono[{3-[4-(2-eth-oxyethoxy)-benzoyloxy]-2-hydroxypropyl)-tert-butyl-ammonium] fumarate, the potential ultra-short acting blocker of beta1-adrenergic receptors. The identity of the evaluated compound (labelled as UPB-2) was confirmed by 1H-, 13C-NMR and IR spectral data as well. The estimated physicochemical parameters included melting point data, solubility in various media, purity checking (adsorption thin-layer chromatography), surface activity determination (non-direct Traube stalagmometric method), acidobasic characteristics (pKa value determination by alkalimetric titration), log epsilon values estimation (spectrophotometrically in UV/VIS region) and a study of the influence of acidic and alkaline media towards the stability of UPB-2. Other experimentally estimated values were lipohydrophilic descriptors using RP-HPLC (log k') and the log PexpS in various lipohydrophilic media by the shake flask method. Based on the log Pexp readouts, the ability to permeate across the brain-blood barrier was predicted. For the content determination of UBP-2 the RP-HPLC (reversed-phase HPLC), the method of an internal standard and UV/VIS spectrophotometry at the wavelength of 260 nm (aqueous medium) and at 258 nm (methanolic medium) was applied.

[Synthesis and basic physicochemical properties of 1-[3-(Y-alkoxyphenylcarbamoyloxy)-2-hydroxypropyl]-4-(2-methylphenyl)piperazinium chlorides]. / Syntéza a základné fyzikálno-chemické vlastnosti 1-[3-(Y-alkoxyfenylkarbamoyl- oxy)-2-hydroxypropyl]-4-(2-metylfenyl)- piperazíniumchloridov.

1-[3-(Y-Alkoxyphenylcarbamoyloxy)-2-hydroxypropyl]-4-(2-methylphenyl)piperazinium chlorides (labelled as 7a-7d) were prepared within a complex study of the relationships between the chemical structure, physicochemical properties and biological (antiarrhythmic, antihypertensive) activity of dual acting compounds. Chemical structures of basic forms (labelled as 7a2C-7d2C) and appropriate monochlorides (labelled as 7a-7d) were confirmed by 1H-NMR, 13C-NMR, MS and IR spectral and elemental analysis. The estimated physicochemical parameters included the melting point data, solubility profile in various media, purity checking (adsorption thin-layer chromatography), surface activity determination (Traube stalagmometric method), acidobasic characteristics (pKa value determination by alkalimetric titration) as well as the log epsilon values estimation by UV/VIS spectrophotometry. Other experimental values under consideration were lipohydrophilic characteristics using reversed-phase thin-layer chromatography (R(M) readouts) RP-HPLC (log k' data) and the log P(exp) s estimated in octan-1-ol/phosphate buffer medium.

[Analytical evaluation of mono[{3-[4-(2-etoxyetoxy)-benzoyloxy]-2-hydroxypropyl}-isopropylammonium]fumarate]. / Analytické hodnotenie mono[{3-[4-(2- -etoxyetoxy)-benzoyloxy]-2- -hydroxypropyl}-izo- propylamónium]fumarátu.

The present paper deals with a complex spectral and physicochemical evaluation of mono[{3-[4-(2-etoxyetoxy)-benzoyloxy]-2-hydroxypropyl}-isopropylammonium]fumarate, a potential ultrashort acting beta1-blocker. The identity of the substance under study (labelled as UPB-1) was confirmed by 1H- and 13C-NMR spectra as well as IR spectrometry. The determined fundamental physicochemical characteristics included the determination of the melting point, solubility in a spectrum of solvents, verification of purity (adsorption thin-layer chromatography), determination of surface activity (Traube's stalagmometric method), acidobasic characteristics (pK(a) value by means of alkalimetric titration), determination of log epsilon values using spectrophotometry in UV/VIS region, as well as the evaluation of the effect of acid and basic media on the stability of the substance under the study. Other experimentally determined parameters were lipohydrophilic characteristics essayed by means of RP-HPLC (log k'), and the shake-flask method was employed to determine the values of the partition coefficients P(exp) (resp. log P(exp)) in different lipohydrophilic media. On the basis of log P(exp-) data, the ability of the substance to penetrate the hematoencephalic barrier was predicted. To determine the UPB-1 content, RP-HPLC (reversed-phase HPLC) method of the internal standard and UV/VIS spectrophotometry at the wavelength of 260 nm (aqueous medium) and 258 nm (methanol medium) were used.