• MeSH
• dýchání účinky léků   MeSH
• kočky MeSH
• neurony účinky léků   MeSH
• piperaziny MeSH
• Check Tag
• kočky MeSH

Práca nadväzuje na štúdium základných farmakologických účinkov u novosyntetizovaných aryloxyaminopropanolov substituovaných v hydrofilnej časti molekuly derivátmi 1,4-piperazínu.b-adrenolyticky a vazodilatačne najúčinnejšia látka s pracovným označením IIIv bola podrobenáďalším farmakologickým hodnoteniam so snahou prispieť k objasneniu jej mechanizmu pôsobenia.Po 7dňovej aplikácii tejto látky v dvoch dávkach (5 a 50 mg.kg -1 ) boli na troch modeloch kontrakcieizolovanej aorty potkanov (KCl, noradrenalín a PGF2a ) kvalitatívne i kvantitatívne sledovanézmeny reaktibility aortálnych preparátov. Výsledky sú doplnené aj o organometrické štúdie vplyvulátky u potkanov.

The present paper links up with the study of principal pharmacological effects of newly synthesizedaryloxyaminopropanols substituted with 1,4-piperazine derivatives in the hydrophilic moiety of themolecule. The substance with the working name IIIv showing the highest b-adrenolytical andvasodilating effect underwent further pharmacological evaluations with the aim of contributing tothe elucidation of the mechanism of its action. After 7-day administration of the substance in twodoses (5 and 50 mg.kg -1 ), the changes in the reactibility of arterial preparations were investigatedon three models of the contraction of the isolated rat aorta (KCl, noradrenaline, and PGF2a) fromboth qualitative and quantitative views. The results were also supplemented with organometricstudies of the effect of the substance in rats.

• MeSH
• aorta účinky léků   MeSH
• kardiovaskulární systém účinky léků   MeSH
• krysa rodu rattus MeSH
• piperazin MeSH
• piperaziny MeSH
• sympatolytika MeSH
• vazodilatancia MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

• MeSH
• biologické modely MeSH
• ileum MeSH
• piperazin MeSH
• piperaziny MeSH
• propanolaminy analogy a deriváty   chemická syntéza   MeSH
• sympatolytika MeSH
• techniky in vitro MeSH

Transdermal administration of drugs that penetrate, in this case directly into the blood circulation, has many advantages and is promising for many drugs thanks to its easy application and good patient compliance. (S)-8-Methyl-6,9-diazaspiro[4.5]decan-7,10-dione (alaptide), has been studied as a potential chemical permeation enhancer. Based on its structure, four selected piperazine-2,5-diones were synthesized by means of multi-step synthetic pathways. All the compounds were investigated on their ability to enhance the permeation of the model drug theophylline from the hydrophilic medium propylene glycol:water (1:1). In vitro experiments were performed using vertical Franz diffusion cells at constant temperature 34 ± 0.5 °C and using full-thickness pig (Sus scrofa f. domestica) ear skin. Withdrawn samples were analyzed by RP-HPLC for determination of the permeated amount of theophylline. All the compounds were applied in ratio 1:10 (w/w) relative to the amount of theophylline. One hour after application, the permeated amount of theophylline from formulations with alaptide and (3S,6S)-3,6-dimethylpiperazine-2,5-dione, was ca. 15- and 12-fold higher, respectively, than from the formulation without the tested compounds. Despite the enhancement ratio of both enhancers in a steady state was ca. 2.3, the pseudo-enhancement ratio in the time range from 1 to 3 h was 4.4. These enhancement ratios indicate that the compounds are able to enhance the permeation of agents through the skin; however, the short-term application of both compound formulations seems to be more advantageous. In addition, the screening of the cytotoxicity of all the prepared compounds was performed using three cell lines, and the compounds did not show any significant toxic effect.

• MeSH
• kožní absorpce * MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• permeabilita MeSH
• piperazin chemie   farmakokinetika   MeSH
• theofylin chemie   farmakokinetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• piperazin MeSH
• piperaziny chemická syntéza   MeSH
• preklinické hodnocení léčiv MeSH

We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting N-chloroacetylamiridine with piperazines. The compounds displayed mixed-type reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Conjugates were moderate inhibitors of equine and human BChE with negligible fluctuation in anti-BChE activity, whereas anti-AChE activity was substantially dependent on N4-substitution of the piperazine ring. Compounds with para-substituted aromatic moieties (5g, 5h, and bis-amiridine 7) had the highest anti-AChE activity in the low micromolar range. Top-ranked compound 5h, N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-yl)-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-acetamide, had an IC50 for AChE = 1.83 ± 0.03 μM (Ki = 1.50 ± 0.12 and αKi = 2.58 ± 0.23 μM). The conjugates possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. In agreement with analysis of inhibition kinetics and molecular modeling studies, the lead compounds were found to bind effectively to the peripheral anionic site of AChE and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation. Similar propidium displacement activity was first shown for amiridine. Two compounds, 5c (R = cyclohexyl) and 5e (R = 2-MeO-Ph), exhibited appreciable antioxidant capability with Trolox equivalent antioxidant capacity values of 0.47 ± 0.03 and 0.39 ± 0.02, respectively. Molecular docking and molecular dynamics simulations provided insights into the structure-activity relationships for AChE and BChE inhibition, including the observation that inhibitory potencies and computed pKa values of hybrids were generally lower than those of the parent molecules. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters comparable to those of amiridine and therefore acceptable for potential lead compounds at the early stages of anti-AD drug development.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• aminochinoliny chemie   farmakologie   MeSH
• antioxidancia chemická syntéza   chemie   farmakologie   MeSH
• benzothiazoly antagonisté a inhibitory   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• koně MeSH
• kyseliny sulfonové antagonisté a inhibitory   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• neuroprotektivní látky chemická syntéza   chemie   farmakologie   MeSH
• oxidační stres účinky léků   MeSH
• piperazin chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• beta blokátory chemie   MeSH
• chemie farmaceutická MeSH
• piperazin MeSH
• piperaziny farmakologie   chemie   MeSH
• techniky in vitro MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH

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.

• MeSH
• aminoalkoholy chemie   farmakologie   MeSH
• antigeny nádorové metabolismus   MeSH
• inhibitory karboanhydras chemická syntéza   chemie   farmakologie   MeSH
• karboanhydrasa I antagonisté a inhibitory   metabolismus   MeSH
• karboanhydrasa II antagonisté a inhibitory   metabolismus   MeSH
• karboanhydrasa IX antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• molekulární struktura MeSH
• piperazin chemie   farmakologie   MeSH
• sulfonamidy chemie   farmakologie   MeSH
• triaziny chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• ischemie prevence a kontrola   MeSH
• krysa rodu rattus MeSH
• piperaziny farmakologie   chemie   MeSH
• propanolaminy farmakologie   chemie   MeSH
• reperfuzní poškození komplikace   MeSH
• srdeční arytmie prevence a kontrola   MeSH
• verapamil farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH

Parasites of the Plasmodium genus are unable to produce purine nucleotides de novo and depend completely on the salvage pathway. This fact makes plasmodial hypoxanthine-guanine-(xanthine) phosphoribosyltransferase [HG(X)PRT] a valuable target for development of antimalarial agents. A series of nucleotide analogues was designed, synthesized and evaluated as potential inhibitors of Plasmodium falciparum HGXPRT, P. vivax HGPRT and human HGPRT. These novel nucleoside phosphonates have a pyrrolidine, piperidine or piperazine ring incorporated into the linker connecting the purine base to a phosphonate group(s) and exhibited a broad range of Ki values between 0.15 and 72 μM. The corresponding phosphoramidate prodrugs, able to cross cell membranes, have been synthesized and evaluated in a P. falciparum infected human erythrocyte assay. Of the eight prodrugs evaluated seven exhibited in vitro antimalarial activity with IC50 values within the range of 2.5-12.1 μM. The bis-phosphoramidate prodrug 13a with a mean (SD) IC50 of 2.5 ± 0.7 μM against the chloroquine-resistant P. falciparum W2 strain exhibited low cytotoxicity in the human hepatocellular liver carcinoma (HepG2) and normal human dermal fibroblasts (NHDF) cell lines at a concentration of 100 μM suggesting good selectivity for further structure-activity relationship investigations.

• MeSH
• antimalarika chemická syntéza   metabolismus   farmakologie   MeSH
• buněčné linie MeSH
• erytrocyty cytologie   metabolismus   parazitologie   MeSH
• inhibitory enzymů chemie   metabolismus   MeSH
• léková rezistence účinky léků   MeSH
• lidé MeSH
• nukleotidy chemie   metabolismus   MeSH
• pentosyltransferasy antagonisté a inhibitory   metabolismus   MeSH
• piperazin chemie   MeSH
• piperidiny chemie   MeSH
• Plasmodium falciparum účinky léků   enzymologie   MeSH
• Plasmodium vivax enzymologie   MeSH
• preklinické hodnocení léčiv MeSH
• prekurzory léčiv chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• protozoální proteiny antagonisté a inhibitory   metabolismus   MeSH
• pyrrolidiny chemie   MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH