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The present work describes the synthesis, physico-chemical characteristics, antioxidative properties, and high-performance liquid chromatography (HPLC) enantioseparation of novel, potentially bioactive aryloxyaminopropanols – derivatives of naphthalen-2-ol modified in the basic part of their molecules. Reaction of naphthalene-2-ol with chloromethyloxirane leads to 2-[(naphthalen-2-yloxy)methyl]oxirane, which reacts in the next step with branched aliphatic amines (isopropylamine, tert-butylamine, and dimethylamine), aromatic amines (aniline, 3,4-dimethoxyphenylethylamine), and heterocyclic amines (pyrrolidine, imidazole, 2-methylimidazole, piperidine, morpholine, 4-methylpiperidine, or 2-methoxyphenylpiperidine). The target compounds were isolated in the form of free bases, as well as their salts with fumaric or hydrochloric acid. Their purity was established by thin-layer chromatography and their IR, UV, 1H-NMR, and 13C-NMR spectra were recorded. The antioxidant activities of prepared compounds were measured by the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) method and they were compared with the values for the corresponding salts. Enantioseparation was accomplished by means of enantioselective HPLC using amylose tris(3,5-dimethylphenyl)carbamate (Chiralpak AD), as well as Chirobiotic T (native teicoplanin) in some cases.

A homologous series of (3-alkoxymethyl-4-hydroxyphenyl)propan-1-ones was prepared by the reaction of (3-chloromethyl-4-hydroxyphenyl)propan-1-ones with the corresponding alcohols (methanol – decan-1-ol, propan-2-ol, 2-methylpropan-1-ol, 3-methylbutan-1-ol, cyclopentanol, benzylalcohol) in the presence of sodium hydrogen carbonate. The composition of the synthesised compounds was elucidated by IR, UV and 1H-NMR and 13C-NMR spectra. Selected compounds were tested against human pathogens: gram-positive bacterium Staphylococcus aureus (CNCTC Mau 29/58), gram-negative bacterium Escherichia coli (CNCTC 377/79) and yeast Candida albicans (CCM 8186). Their antimicrobial activities were expressed as minimum inhibitory concentrations. Antioxidant activity was determined using DPPH and ABTS.+ methods. It could be shown that both biological activities, antimicrobial and antioxidant, were lower in comparison with the (2RS)-bis [3-(4-acetyl-2-propoxymethyl)phenoxy-2-hydroxypropyl]isopropylammonium fumarate type of beta blockers.

An enantioseparation study of nitro-substituted aryloxyaminopropanols was performed using HPLC on a teicoplanin chiral stationary phase and TLC impregnated with L-aspartic and L-tartaric acid as chiral selectors. The type of substituent on the nitrogen in the hydrophilic part of molecule is essential for excellent separation by HPLC. L-aspartic acid seems to be a suitable chiral selector for enantioseparation by TLC.

The macrocyclic antibiotic type chiral stationary phases based on native vancomycin, teicoplanin and teicoplanin aglycone (Chirobiotic V, Chirobiotic T and Chirobiotic TAG) were used for the HPLC separation of enantiomers of potential beta-blockers of the aryloxyaminopropanol type with a morpholino moiety in the hydrophilic part of the molecule. The chromatographic results presented include: retention, separation and resolution factors along with the enantioselective free energy difference corresponding to the separation of the enantiomers. Comparison of the results obtained on the three macrocyclic chiral stationary phases showed that in most cases the teicoplanin aglycone is responsible for enantioseparation of morpholino derivatives. By application of these chiral stationary phase highest resolution factors were achieved with a polar organic mobile phase system.

Besides chromatographic methods and biocatalyzed reactions, another alternative method of obtaining enantiomeric forms of beta-blockers is stereoselective synthesis. This paper links up with two preceding surveys concerning beta-blockers--groups of chiral agents and presents a survey of the hitherto published enantioselective syntheses of (R)- and (S)-enantiomers of beta-blockers. In the group of arylaminoethanols, mainly selective reduction of prochiral ketones in the presence of metallic complexes is used in this type of synthesis. Enantiomerically pure beta-blockers of the aryloxyaminopropanol type are synthesized by means of a reaction of pertinent phenols with different chiral precursors, such as (R) and (S)-chloromethyloxirans, (S)-glycidoltosylate, (S)- or (R)-2,3-O-isopropylideneglyceroltosylate, E-(2S,3S)-3-trimethylsilylglycidol and (S)-3-terc-butyl-5-phenyl-oxazolidine-5-ylmethanol. Many of these chiral semiproducts can be prepared from natural substances, such as D-mannitol and L-ascorbic acid.

This paper presents the results of HPLC enantioseparation of derivatives of aryloxyaminopropanols obtained using six chiral stationary phases [macrocyclic antibiotic (vancomycin, teicoplanin, teicoplanin aglycone, and methylated teicoplanin aglycone) and cyclodextrin (beta and gamma)] and a mixture of methanol/acetonitrile/acetic acid/triethylamine (45/55/0.3/0.2) as the mobile phase. No significant difference was observed in the separation of the enantiomers on the vancomycin and teicoplanin chiral stationary phases. Comparing the separation of enantiomers on teicoplanin-based columns the retention factors were increased in the order: native teicoplanin < teicoplanin aglycone < methylated teicoplanin aglycone. The highest values of resolution were obtained on the column containing carbohydrate moieties. The presence of saccharide moieties in the chiral stationary phase plays an important role, together with charge interactions and steric interactions, in the separation of enantiomers of derivatives of aryloxyaminopropanol.

The preparation of pure individual enantiomers represents a topical problem from the standpoint of efficacy and safety of drugs. This paper continues in the preceeding review of the blockers of beta-adrenergic receptors as a group of chiral drugs, which is concerned with different pharmacodynamic, pharmacokinetic, and toxicological effects of individual enantiomers of this group. The review paper pays attention to the problems of enantioseparation of this group of chiral drugs, listing individual examples of the methods of enantioseparation, such as crystallization, biocatalysis, chromatographic methods (HPLC, GC, TLC), capillary electrophoresis, and the method of nuclear magnetic resonance (NMR). The individual methods of enantioseparation including enantioseparation in biological material (urine, serum) are illustrated on examples on beta-blockers used in clinical practice (e.g., propranolol, atenolol, metoprolol) as well as potential agents of this group of drugs.

Following our previous structure-activity relationship studies, some novel compounds of the aryloxyaminopropanol type, derived from 2- or 4-hydroxyphenylalkanones, with phenethyl or 3,4-dimethoxyphenethyl groups in the hydrophilic part of the molecule were synthesized and pharmacologically evaluated. The compounds were prepared by means of two methods and their structures were confirmed by the interpretation of their IR, UV and 1H NMR spectra. The enantiomers were separated by HPLC on vancomycin (Chirobiotic V) and teicoplanin (Chirobiotic T) chiral stationary phases. The affinity of the prepared racemic compounds to beta1- and beta2-adrenergic receptors was pre-determined on isolated guinea pig atria and trachea. The assumed cardioselectivity was expressed as the beta1/beta2 ratio. Reciprocal changes in the position of the phenoxysubstituents did not influence the antiisoprenaline activity of the compounds. On the other hand, the increase of the N-substituent size in the hydrophilic part of molecule (3,4-dimethoxyphenethyl moietyled to a substantially higher affinity for cardiac (beta1) than for tracheal (beta2) tissue.

The present review of beta-adrenergic receptor blockers deals with different pharmacodynamic, pharmacokinetic and toxicological effects of individual enantiomers in the group of arylaminoethanols and aryloxyaminopropanols. From the viewpoint of beta-adrenolytic activity, (-)-enantiomers in both groups are several times more effective and in many beta-blockers both enantiomers show different therapeutic indications. The absolute configuration in the sense of Cahn-Ingold-Prelog system exists in (-)-enantiomers in the group of arylaminoethanols (R) and in the group of aryloxyaminopropanols (S). Of the beta-blockers hitherto used in therapeutic practice, pure enantiomers are (S)-(-)-penbutolol, (S)-(-)-timolol, and (S)-(-)-levobunolol. The hitherto research in this field, however, does not unambiguously answer, as the experience with labetalol, sotalol, and timolol shows, the question of the advantages of therapeutic use of pure enantiomeric forms.

The paper investigates the effect of two potential beta-adrenolytical agents, 1-[4-(3-isopropylamino-2-hydroxypropoxy)-3-(propoxymethyl)phenyl]etan on (FA33) and 1-[4-(3-isopropylamino-2-hydroxypropoxy)-3-(propoxymethyl)phenyl]prop anan-1-on (FP33), in the form of salts with fumaric acid on the enzymatic activities of the markers of subcellular fractions of the rabbit cardiac muscle (in vitro). In the mitochondria, both substances inhibit the specific activity of cytochromoxidase (FA33 by 37.14% and FP33 by 35.88%). In the sarcolemma, substance FA33 inhibits the specific activity of Na(+)-K(+)-ATPase by 23.02%, while substance FP33 possesses an activating effect increased by 23.24%. In the sarcoplasmatic reticule both substances inhibit the specific activity of Ca(2+)-Mg(2+)-ATPase (FA33 by 14.96% and FP33 by 8.79%). The different effects of substances FA33 and FP33 on the activities of the markers of the subcellular fractions of the cardiac muscle can be connected with different inotropism of both substances.

The effect of 18 compounds of the aryloxyaminopropanol type--potential beta-adrenolytics (differing each from other by modifications in the hydrophilic and lipophilic part of the molecule) on the inhibition of oxygen evolution rate in spinach chloroplasts has been investigated. The compounds with n-octyloxymethyl and n-nonyloxymethyl group in position 3 of aromatic ring were found to exhibit the highest inhibitory activity (IC50 = 67, resp. 120 mumol dm-3). The compounds containing a heterocycle or the dimethylamino group in the hydrophilic part of the molecule and with propoxymethyl group on the aromatic ring were not active. Using EPR spectroscopy it was found that the studied compounds interact with Z+/D+ intermediates, i.e. tyrosine radicals TyrZ and TyrD situated in D1 and D2 proteins on the donor side of photosystem 2. Higher concentrations of the studied inhibitors cause release of Mn2+ ions from the oxygen evolving complex which is situated in photosystem 2. The interaction of the tested compounds with chlorophyll occurring in the photosynthetic centres has been confirmed by fluorescence measurements as well.

Within the framework of a structure-effect relationships study in a group of new beta-adrenoreceptor blockers, a series of new derivatives derived from p-hydroxyacetophenone with modifications in the basic moiety of the side chain was prepared. The initial p-hydroxyacetophenone prepared by Fries rearrangement of phenylacetate in a reaction with 2-(chloromethyl)oxirane yields 1-[4-(2-oxiranylmetoxy)phenyl]-1-etanone, which combines with the appropriate amines to produce final substances. They were isolated either in the form of free bases, or salts with fumaric acid. Their structure was confirmed by interpretations of the IR, 1H-NMR and 13C-NMR-spectra. Within the framework of pharmacological evaluation of the prepared agents, the anticonvulsive effect as a protective effect against pentetrazole spasms was examined. The results of the evaluation were compared with the values of their distribution coefficients.

The present paper evaluated the effect of the potential beta-adrenoreceptor blocker 2-(3-isopropylamino-2-hydroxypropoxy)-5-(propoxymethyl) acetophenone (FoA33) on the oxidative and phosphorylating processes of the cardiac muscle influenced by small doses of isoprenaline (2 mg.kg-1). Under selected experimental conditions, the consumption of oxygen by the mitochondria of the cardiac muscle in states S3 and S4, rate of production of energy by mitochondria (OPR), coefficient of oxidative phosphorylyzation (ADP:O), respiratory control index (RCI) as well as the effect on the specific activity of the cytochromoxidase marker of mitochondria (COX) were examined. It follows from the obtained results that in contrast to large doses of isoprenaline (10-50 mg.kg-1) producing necrosis and affecting metabolic processes, small doses of isoprenaline (2 mg.kg-1) in many parameters activate the bioenergetic activity of the cardiac mitochondria, which is only minimally changed in combination with the beta-adrenoreceptor blocker (FoA33).

The present paper carries out the pharmacological evaluation of 4-(2-hydroxy-3-isopropylaminopropoxy)-3-(alkoxymethyl) propiophenones with an ethoxy, propoxy and butoxy-group, whose structures are typical of the blockers of beta-adrenergic receptors. In the above-mentioned compounds the anticalcium effect on the frequency and the amplitude and the negative chronotropic and the negative inotropic effects were evaluated by means of the method of spontaneously pulsing guinea-pig atria within a concentration range of 4-16 microgram.cm-3. The obtained results confirmed a significant anticalcium effect on the heart rate in the compounds with a propoxy and a butoxy group, and in the standard verapamil. In all three compounds as well as in the standard verapamil, no anticalcium effect on the amplitude was found. The results of this membrane efficacy are in agreement with the preceding evaluation of the antidysrhythmic and anti-isoprenaline activity with the most marked effect in the compound with a propoxy group. On the basis of these results it is possible to conclude that in these derivatives of 4-hydroxypropiophenone also the anticalcium effect can participate, besides the beta-adrenolytic and the membranostabilizing effects, in the antidysrhythmic activity.

Within the relationship of the structure and effect of new beta-adrenolytic agents derivatived from p-hydroxyacetophenone and p-hydroxypropiophenone with a propoxymethyl group in the lipophilic part of the molecule and with a propanamine, a butanamine and a pyrrolidine in the side-chain were studied. In order to prepare these substances, a procedure was selected from several tested ones, in which 4-hydroxy-3propoxymethylphenylketone were treated with chloromethyloxirane and subsequent reaction a hydrobromic acid were prepared 4-(3-brom-2-hydroxypropoxy)-3-propoxymethylalkylketone. Final substances were prepared reaction with amine. The structure of prepared compounds was confirmed on the basic interpretation of the IR, UV and 1H NMR spectra. The results of pharmacological evaluation of selected compounds showed a significant beta 1-blocking activity lower than acebutolol. Their local anesthetic activity is low according with their partition coefficients. The characteristic of the prepared compounds was supplemented by the determination of their partition coefficients, surface tension, dissociation constants and acute toxicity.

The present paper investigated histological changes in the myocardium in two potential beta-adrenolytic agents, 4-[3-isopropylamino-2-hydroxypropoxy]-3-[propoxymethyl]acetophenone and 4-[3-isopropylamino-hydroxypropoxy]-3-[pentyloxymethyl]acetophenon e after intravenous administration in doses of 8 mg/kg and 24 mg/kg. It results from the found data that in both agents in the doses used there are no necrotic changes in the myocardium and the values of the impairment range within the 1st degree of Zbinden's classification, comparable to the standard metipranolol.

Concentrations ranging from 1-9 x 10(-7) mol.dm-3 were employed for in vitro studies. Under the selected experimental conditions, both agents markedly decreased the stimulated consumption of oxygen by the cardiac muscle mitochondria in the condition S3, the rate of the formation of energy by mitochondria as well as the respiratory control index. The coefficient of oxidative phosphorylation was not markedly changed due to the effect of the added agents. The results of the present paper suggest possible integration of the cardiac muscle mitochondria in the oxidative metabolism of the potential beta-adrenolytic agents FA33 and FP33, which requires further in vivo studies.

Within the framework of the study of the structure-effect relationship, a series of novel potential beta-adrenolytic agents derived from p-hydroxyacetophenone and p-hydroxypropiophenone with an alyloxymethyl and a cycloalkyloxymethyl group in the lipophilic part of the molecule and an isopropyl and a tert-butyl group in the hydrophilic part on the basic nitrogen were prepared by means of a well-tried method. The structure of the prepared drugs was confirmed on the basis of interpretation of the IR, UV, 1H-NMR and mass spectra. The results of pharmacological evaluation of selected drugs show that the agents poses beta-adrenolytic and antiarrhythmic activity. From the viewpoint of comparison of the individual drugs subjected to testing the presence of an alyl seems more advantageous than that of a cyclohexyl. The characteristic of the prepared drugs was supplemented by the determination of their partition coefficients, surface tension and acute toxicity.