Biomedical subjects

Barbara Malawska

Publications and source records attributed to Barbara Malawska.

12 recordsLinked to original sources

PubMed2007

Investigation of lipophilicity of anticancer-active thioquinoline derivatives.

The lipophilicity of a series of anticancer propargylthioquinoline derivatives has been investigated using chromatographic and computational methods. The parameters of relative lipophilicity (R(MO) and logk0) of the tested compounds were determined experimentally both by reversed-phase thin layer (RP-TLC), and high-performance liquid chromatographic methods (RP-HPLC, LiChrospher RP18 column), with mixtures of acetonitrile and water as mobile phases. Their phospholipophilicity (logk(0IAM)) was determined using immobilized artificial membrane HPLC (IAM. PC DD2 Regis column). Mobile phase acetonitrile concentrations were in the ranges 50-90% (RP-TLC), 55-90% (RP-HPLC) and 35-60% (IAM-HPLC). The R(M), logk and logk(IAM) values of the compounds investigated were linearly dependent on acetonitrile concentration. The analysis led to the calculation of R(MO), logk0 and logk(0IAM) parameter values for each of the tested compounds. Their partition coefficients (logP) were also calculated with the Pallas and CAChe programs. The obtained results indicated that, among experimental methods, both RP-TLC and RP-HPLC gave similar results, and these methods enable the determination of lipophilicity of derivatives of thioquinolines. Using the IAM-HPLC technique a simple method of estimation of phospholipoplilicity was described. The CAChe program might better predict calculated lipophilicity logP values, and therefore is a useful tool for the early stage of design of new propargyl thioquinolines.

Acetonitriles↗

PubMed2006

Estimation of phospholipophilicity of 1-[3-(arylpiperazin-1-yl)-propyl]-pyrrolidin-2-one derivatives on immobilized artificial membrane stationary phase and its correlation with biological data.

A molecule library containing 42 1-[3-(arylpiperazin-1-yl)-propyl]-pyrrolidin-2-one derivatives has been designed and synthesized. The phospholipophilicity of the obtained compounds has been determined using immobilized artificial membrane high-performance liquid chromatography (IAM-HPLC). The performed analysis allowed the calculation of log k(we) values for each of the tested compounds. Experimental phospholipophilicity data (log k(we)) has been compared with the affinity of the tested compounds to alpha(2)-adrenoceptors. Performed quantitative structure-activity relationship studies indicated that, for the tested compounds, there are dependences between affinity for alpha(2)-adrenoceptors and their log k(we) values. The obtained results confirmed that the applied chromatographic IAM-HPLC method could be useful in fast characterization of the phosholipophilicity of structurally closely related compounds as well as for larger series of compounds, such as drug candidates. It could also be used as a tool for further research into this group of compounds.

Chromatography, High Pressure Liquid↗

PubMed2006

Trends in the development of new drugs for treatment of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a common condition in aging men that is characterized by nonmalignant enlargement of the prostate gland, and is frequently accompanied by urinary obstruction, and lower urinary tract symptoms (LUST). Currently pharmacotherapy of BPH is based on two classes of drugs: alpha(1)-adrenoceptor (alpha(1)-AR) antagonists and 5alpha-reductase inhibitors. It has been shown that alpha(1)-AR antagonists reduce symptom scores and increase peak urinary flow rates in BPH. Of particular importance for BPH therapy are uroselective alpha(1)-AR antagonists for which the hypotensive related side-effect caused by alpha(1)-AR blockade is reduced. 5alpha-Reductase inhibitors reduce prostate volume and symptom scores, while increasing peak urinary flow rates. This review describes new alpha(1)-AR antagonists and 5alpha-reductase inhibitors in the treatment of BPH. The new alpha(1)-AR antagonists represent various structures such as quinazolines, phenylethylamines, piperidines, and arylpiperazines. 5alpha-Reductase inhibitors are classified into two groups: steroidal and non-steroidal. The newer non-steroidal inhibitors include derivatives of benzo[c]quinolizinones, benzo[f]quinolonones, piperidones and carboxylic acids. Besides the development of new compounds belonging to the above mentioned groups, new agents for BPH treatment are sought among combined 5alpha-reductase/alpha(1)-AR inhibitors, endothelins, androgen receptors antagonists, growth factors, estrogens and phosphodiesterase isoenzymes as well as several phytomedicines, used for prevention and treatment of prostate disorders. These new agents can be used for the design of future targets and development of new drugs in the treatment of BPH. The discovery of a number of active leads may also ultimately help in developing new safe and effective drugs.

5-alpha Reductase Inhibitors↗

PubMed2005

Synthesis and development of new 2-substituted 1-[3-(4-arylpiperazin-1-yl)propyl]-pyrrolidin-2-one derivatives with antiarrhythmic, hypotensive, and alpha-adrenolytic activity.

A series of new 1-[3-(4-arylpiperazinyl-1-yl)-2-(N-alkylcarbamoyloxy)propyl]-pyrrolidin-2-one derivatives (4a-12a) were synthesised and tested for their electrocardiographic, antiarrhythmic and antihypertensive activity, as well as for the alpha1- and alpha2-adrenoceptor binding affinities. Of the newly synthesised derivatives, 1-{2-(N-2-methylethylcarbamoiloxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl)]propyl}pyrrolidin-2-one dihydrochloride (10a) was the most active in prophylactic antiarrhythmic tests, its ED50 value equalling 2.7 mg kg(-1), and the therapeutic index being 75.2; moreover, compound 10a was also found to possess hypotensive activity. A preliminary molecular modelling study suggested that the selected alpha1-AR antagonist distances and angles between pharmacophoric features, estimated for the tested compounds, were in good agreement with the parameters evaluated for ligands.

Adrenergic alpha-Agonists↗

PubMed2005

New anticonvulsant agents.

The search for antiepileptic compounds with more selective activity and lower toxicity continues to be an area of intensive investigation in medicinal chemistry. This review describes new anticonvulsant agents representing various structures for which the precise mechanism of action is still not known. Many of the compounds presented in this review have been tested according to the procedure established by the Antiepileptic Drug Development Program of the Epilepsy Branch of the National Institute of Neurological Disorders and Stroke, National Institute of Health, USA. The newer agents include sulfonamides, amino acids, amides (analogs of gamma-vinyl GABA, N-benzylamides, 2,6-dimethylanilides, carboxyamides, hydroxyamides, alkanoamides); heterocyclic agents ((arylalkyl)imidazoles, pyrrolidin-2,5-diones, lactams, semi- thiosemicarbazones, thiadiazoles, quinazolin-4(3H)-ones, 2,5-disubstituted 1,2,4-thadiazoles, xanthones, derivatives of isatin) and enaminones. These new structural classes of compounds can prove useful for the design of future targets and development of new drugs.

Animals↗

PubMed2005

Brivaracetam UCB.

Brivaracetam (UCB-34714), an orally active, high-affinity synaptic vesicle protein 2A ligand, is being developed by UCB for the potential treatment of neurological disorders, namely epilepsy and neuropathic pain. By December 2003, UCB reported that phase II epilepsy trials had begun [517569].

Animals↗

PubMed2004

Investigation into new anticonvulsant derivatives of alpha-substituted N-benzylamides of gamma-hydroxy- and gamma-acetoxybutyric acid. Part 5: search for new anticonvulsant compounds.

A series of four N-benzylamides of gamma-hydroxybutyric acid (GHB), that contain N-(4-phenylpiperazine)-, N-(4-benzylpiperazine)rings, N-benzylamino-, or N-(2-phenylethylamine)-groups in the alpha-position of GHB were selected as model compounds, for determining the structural elements responsible for their potential anticonvulsant action. Based on the results of pharmacological, physicochemical, and molecular modelling investigations, the pharmacophore model for anticonvulsant N-substituted amides of GHB was defined. In this model, the presence of the N-benzylamide fragment is essential for activity. In addition, all of the amides contained another hydrophobic unit (aryl ring) as a distal binding site and H-bond donor. In consideration of these model parameters, a number of N-substituted amides of GHB, containing a hydrophobic moiety such as: N-benzylamino or N-(4-chlorobenzylamino) group in the alpha-position of GHB, and a lipophilic substituent in the amide portion, were prepared. It has been shown that the anticonvulsant activities of the newly synthesized compounds might partially be explained on the basis of their lipophilicity (calculated log P values) and the presence of a hydroxyl group in the molecule.

Amides↗

PubMed2004

Synthesis of novel N-alkyl carbamates of a-substituted amides of g-hydroxybutyric acid as potential acetylcholinesterase inhibitors.

In a search for new acetylcholinesterase (AChE) inhibitors, derivatives of N-alkyl carbamates of a-substituted N-benzylamides of g-hydroxybutyric acid (GHB) 2(a-d); 3(a-d); 4(a-d) were obtained. Starting from 3-bromo-tetrahydrofuran-2-one, and N-phenylpiperazine 3-(4-phenylpiperazin-1-yl) tetrahydrofuran-2-one (1) was obtained. The aminolysis of lactone 1 with 4-substituted derivatives of benzylamine yielded N-substituted benzylamides of a-(4-phenylpiperazin-1-yl)-g-hydroxy-butyric acid (2-4). The target compounds were prepared by refluxing N-substituted benzyl-amides of a-(4-phenylpiperazinyl-1-)-GHB with ethyl-, i-propyl-, n-propyl- or n-butyl-isocyanate in dry acetonitrile. The inhibitory potency of AChE was evaluated by means of Ellman's in vitro test.

Animals↗

PubMed2003

Estimation of the lipophilicity of antiarrhythmic and antihypertensive active 1-substituted pyrrolidin-2-one and pyrrolidine derivatives.

The lipophilicity of some antiarrhythmic and antihypertensive active 1-[2-hydroxy- or 1-[2-acetoxy-3-(4-aryl-1-piperazinyl)propyl]pyrrolidin-2-one derivatives (1-12) has been investigated. Their lipophilicity (R(MO) and log k') was determined by reversed-phase thin-layer chromatography and reversed-phase high-performance liquid chromatography with mixtures of acetonitrile and Tris buffer as mobile phases. The partition coefficients of compounds 1-12 (log P(ScilogP)) were also calculated with the ScilogP program. Comparison of R(MO), log k' and calculated log D(7.0 ScilogP) values enabled calculation of clog D(7.0 TLC) and clog D(7.0 HPLC) values. Preliminary quantitative structure-activity relationship studies indicated that for active compounds there is a dependence between affinity for alpha(2)-adrenoceptors and their clog D(7.0 HPLC) values.

Acetonitriles↗

PubMed2003

Application of pharmacophore models for the design and synthesis of new anticonvulsant drugs.

The chemical diversity and various mechanisms of action of anticonvulsants make it difficult to identify a common pharmacophore. The present review outlines different pharmacophore models for anticonvulsant activity with emphasis on the development of new drugs. Some of them represent models for structurally different classes of compounds with similar mechanisms of action. Others represent pharmacophore models for similar chemical classes of compounds for which the mechanism of anticonvulsant action is not clear. A pharmacophore model for sodium channel blocking compounds, anticonvulsants with the phthalimide pharmacophore, a model for anticonvulsant semicarbazones, and a model for GABA uptake inhibitors are presented.

Animals↗

PubMed2002

Synthesis, antiarrhythmic, and antihypertensive effects of novel 1-substituted pyrrolidin-2-one and pyrrolidine derivatives with adrenolytic activity.

A series of 1-substituted pyrrolidin-2-one and pyrrolidine derivatives were synthesised and tested for electrocardiographic, antiarrhythmic, and antihypertensive activity as well as for alpha(1)- and alpha(2)-adrenoceptors binding affinities. Among the newly synthesised derivatives several compounds with 3-(4-arylpiperazin-1-yl)propyl moiety displayed strong antiarrhythmic (7a-12a) and antihypertensive (7a-11a) activities. Compound 11a, 1-[2-acetoxy-3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one, was the most potent in this series. The pharmacological results and binding studies suggest that their antiarrhythmic and hypotensive effects may be related to their alpha-adrenolytic properties, and that those properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or chloro- substituent in the ortho position in the phenyl ring.

Adrenergic alpha-Antagonists↗

PubMedDate not supplied

Influence of new gamma-hydroxybutyric acid amide analogues on the central nervous system activity in mice.

The present study investigates the activity of four gamma-hydroxybutyric acid amide analogues (BM-68, BM-74, BM-75 and BM-76) in two models of chemically induced seizures, i.e. picrotoxin- and pentetrazole-induced seizures and in the thiopental-induced sleep test. The results of pharmacological in vivo experiments with the gamma-hydroxybutyric acid amide analogues presented below show that the compounds possess variable influence on the central nervous system in mice.

Animals↗