We report the design, synthesis, and in vitro antimicrobial activity of a series of N-substituted 3-aminopyrazine-2-carboxamides with free amino groups in position 3 on the pyrazine ring. Based on various substituents on the carboxamidic moiety, the series is subdivided into benzyl, alkyl, and phenyl derivatives. The three-dimensional structures of the title compounds were predicted using energy minimization and low mode molecular dynamics under AMBER10:EHT forcefield. Compounds were evaluated for antimycobacterial, antibacterial, and antifungal activities in vitro. The most active compound against Mycobacterium tuberculosis H37Rv (Mtb) was 3-amino-N-(2,4-dimethoxyphenyl)pyrazine-2-carboxamide (17, MIC = 12.5 μg/mL, 46 μM). Antimycobacterial activity against Mtb and M. kansasii along with antibacterial activity increased among the alkyl derivatives with increasing the length of carbon side chain. Antibacterial activity was observed for phenyl and alkyl derivatives, but not for benzyl derivatives. Antifungal activity was observed in all structural subtypes, mainly against Trichophyton interdigitale and Candida albicans. The four most active compounds (compounds 10, 16, 17, 20) were evaluated for their in vitro cytotoxicity in HepG2 cancer cell line; only compound 20 was found to exert some level of cytotoxicity. Compounds belonging to the current series were compared to previously published, structurally related compounds in terms of antimicrobial activity to draw structure activity relationships conclusions.
- MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- antifungální látky farmakologie MeSH
- Bacteria účinky léků MeSH
- buněčná smrt účinky léků MeSH
- buňky Hep G2 MeSH
- houby účinky léků MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární konformace MeSH
- pyraziny chemická syntéza chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
1. Some flavonoids contained in the common diet have been shown to interact with important membrane uptake transporters, including organic anion transporting polypeptides (OATPs). OATP2B1 and OATP1A2 expressed in the apical membrane of human enterocytes may significantly contribute to the intestinal absorption of drugs, e.g. statins. This study is aimed at an evaluation of the inhibitory potency of selected food honey flavonoids (namely galangin, myricetin, pinocembrin, pinobanksin, chrysin and fisetin) toward hOATP2B1 and hOATP1A2 as well as at examining their effect on the cellular uptake of the known OATP substrate rosuvastatin. 2. Cell lines overexpressing the hOATP2B1 or hOATP1A2 transporter were employed as in vitro model to determine the inhibitory potency of the flavonoids toward the OATPs. 3. Chrysin, galangin and pinocembrin were found to inhibit both hOATP2B1 and hOATP1A2 in lower or comparable concentrations as the known flavonoid OATP inhibitor quercetin. Galangin, chrysin and pinocembrin effectively inhibited rosuvastatin uptake by hOATP2B1 with IC50 ∼1-10 μM. The inhibition of the hOATP1A2-mediated transport of rosuvastatin by these flavonoids was weaker. 4. The found data indicate that several of the tested natural compounds could potentially affect drug cellular uptake by hOATP2B1 and/or hOATP1A2 at relative low concentrations, a finding which suggests their potential for food-drug interactions.
- MeSH
- biologické modely MeSH
- buňky MDCK MeSH
- dieta MeSH
- flavonoidy farmakologie MeSH
- HEK293 buňky MeSH
- inhibiční koncentrace 50 MeSH
- lidé MeSH
- med * MeSH
- přenašeče organických aniontů antagonisté a inhibitory metabolismus MeSH
- psi MeSH
- rosuvastatin kalcium metabolismus MeSH
- transfekce MeSH
- transport proteinů účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Membrane organic anion-transporting polypeptides (OATPs) are responsible for the drug transmembrane transport within the human body. The function of OATP2B1 transporter can be inhibited by various natural compounds. Despite increased research interest in soya as a part of human diet, the effect of its active components to interact with hOATP2B1 has not been elucidated in a complex extent. This in vitro study examined the inhibitory effect of main soy isoflavones (daidzin, daidzein, genistin, genistein, glycitin, glycitein, biochanin A, formononetin) and their metabolites formed in vivo (S-equol, O-desmethylangolensin) towards human OATP2B1 transporter. MDCKII cells overexpressing hOATP2B1 were employed to determine quantitative inhibitory parameters of the tested compounds and to analyze mechanism/s of the inhibitory interaction. The study showed that aglycones of soy isoflavones and the main biologically active metabolite S-equol were able to significantly inhibit hOATP2B1-mediated transport. The Ki values for most of aglycones range from 1 to 20 μM. In contrast, glucosides did not exhibit significant inhibitory effect. The kinetic analysis did not indicate a uniform type of inhibition towards the hOATP2B1 although predominant mechanism of inhibition seemed to be competitive. These findings may suggest that tested soy isoflavones and their metabolites might affect transport of xenobiotics including drugs across tissue barriers via hOATP2B1.
- MeSH
- buňky MDCK MeSH
- Glycine max * MeSH
- isoflavony farmakologie MeSH
- kinetika MeSH
- přenašeče organických aniontů antagonisté a inhibitory genetika metabolismus MeSH
- psi MeSH
- transfekce MeSH
- zvířata MeSH
- Check Tag
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
A series of amphiphilic derivatives of (3β,17β)-3-hydroxyandrost-5-ene-17-carboxylic acid (1) with the polyamine spermine and three other diamines, 1,2-diaminoethane, piperazine and cadaverine, were synthesized and their antimicrobial activity and cytotoxicity were investigated. Among the target compounds, several ones showed antimicrobial activity on Gram positive and Gram negative microorganisms. The most active compounds were 20 (Streptococcus mutans CCM 7409, 3.125 µM), 16 (Streptococcus mutans CCM 7409, 12.5 µM) and 10d (Escherichia coli CCM 3954, 12.5 µM). In addition, compounds 5d, 10d, 13 and 20 displayed cytotoxicity on CEM (12.1 ± 2.1 µM, 7.6 ± 1.0 µM, 19.0 ± 0.4 µM and 5.9 ± 0.7 µM, respectively). Two additional compounds displayed medium cytotoxicity on CEM, 5a (34.6 ± 5.2 µM) and 5c (37.7 ± 5.9 µM). The compound 13 and 20 displayed high toxicity also on normal fibroblasts.
- MeSH
- androsteny chemická syntéza chemie farmakologie MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- Escherichia coli účinky léků patogenita MeSH
- kyseliny karboxylové chemická syntéza chemie farmakologie MeSH
- mikrobiální testy citlivosti MeSH
- polyaminy chemická syntéza chemie farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Streptococcus milleri group (SMG) is a group of three streptococcal species (S. anginosus, intermedius and constellatus) that act as opportunist pathogens, among others in cystic fibrosis. Due to their fastidious character, they are both difficult to cultivate and to differentiate from less pathogenic streptococcal species, therefore being most probably underdiagnosed. Semi-selective McKay agar and NAS agar were developed to facilitate SMG recovery from clinical samples; however, direct comparison of recovery rates has not been published yet. We tested the performance of both media on 123 patient samples and demonstrated general superiority of NAS agar for SMG recovery during primary cultivation convincingly. This observation was also confirmed by quantitative drop tests during subculture. Despite the undisputed overall superiority of NAS agar over McKay agar, a smaller fraction of strains grew better on McKay agar. Inter-strain differences were the most probable explanation. Therefore, when economic conditions are not limiting and maximum recovery rate is desirable, both plates are advised to be used in parallel for primary cultivation of clinical samples.
Pyrazinamide, the first-line antitubercular drug, has been regarded the basic component of tuberculosis treatment for over sixty years. Researchers have investigated its effect on Mycobacterium tuberculosis for this long time, and as a result, new potential targets of pyrazinamide or its active form, pyrazinoic acid, have been found. We have designed and prepared 3-(phenyl-carbamoyl)pyrazine-2-carboxylic acids as more lipophilic derivatives of pyrazinoic acid. We also prepared methyl and propyl derivatives as prodrugs with further increased lipophilicity. Antimycobacterial, antibacterial and antifungal growth inhibiting activity was investigated in all prepared compounds. 3-[(4-Nitrophenyl)carbamoyl]pyrazine-2-carboxylic acid (16) exerted high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 1.56 μg·mL-1 (5 μM). Propyl 3-{[4-(trifluoromethyl)phenyl]carbamoyl}pyrazine-2-carboxylate (18a) showed also high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 3.13 μg·mL-1. In vitro cytotoxicity of the active compounds was investigated and no significant cytotoxic effect was observed. Based to structural similarity to known inhibitors of decaprenylphosphoryl-β-d-ribose oxidase, DprE1, we performed molecular docking of the prepared acids to DprE1. These in silico experiments indicate that modification of the linker connecting aromatic parts of molecule does not have any negative influence on the binding.
- MeSH
- alkoholoxidoreduktasy antagonisté a inhibitory chemie MeSH
- antibakteriální látky chemie farmakologie MeSH
- antifungální látky chemie farmakologie MeSH
- bakteriální proteiny antagonisté a inhibitory chemie MeSH
- lidé MeSH
- mikrobiální testy citlivosti metody MeSH
- molekulární struktura MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- počítačová simulace MeSH
- pyraziny chemie farmakologie MeSH
- racionální návrh léčiv MeSH
- simulace molekulového dockingu metody MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The increasing number of infections caused by multidrug-resistant and pandrug-resistant bacteria represents a serious worlwide problem. Drug resistance limits available antimicrobials and can lead to suboptimal treatment of bacterial infections. It can be predicted that resistance to more antimicrobial drugs will be acquired by even more bacteria in the future. Among the distinct resistance strategies, preventing drug entrance to intracellular compartment through modification of membrane permeability (bacterial influx) and active export of compounds to the external environment (bacterial efflux) are of particular importance as they limit the interaction of the drug with its intracellular targets and, consequently, its deleterious effects on the cell. Several current studies have extended our understanding of drug resistance mechanisms associated with altered membrane permeability in gram-negative bacteria. In this study, we propose a summary of resistance mechanisms associated with transport of drugs across bacterial cell envelope exploited by Klebsiella pneumoniae, one of the most common nosocomial infection-causing pathogens. The better understanding of molecular bases of drug transport in/out of the single cell may have consequence for success in antimicrobial therapy of infection caused by drug-resistant Klebsiella.
- MeSH
- antibakteriální látky farmakologie MeSH
- bakteriální proteiny genetika metabolismus MeSH
- biologický transport MeSH
- buněčná membrána účinky léků MeSH
- fenotyp MeSH
- geny MDR * MeSH
- infekce bakteriemi rodu Klebsiella farmakoterapie mikrobiologie přenos MeSH
- infekce spojené se zdravotní péčí farmakoterapie mikrobiologie přenos MeSH
- Klebsiella pneumoniae účinky léků genetika metabolismus MeSH
- lidé MeSH
- mnohočetná bakteriální léková rezistence genetika MeSH
- permeabilita buněčné membrány genetika MeSH
- poriny genetika metabolismus MeSH
- regulace genové exprese u bakterií * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
A series of substituted N-benzyl-3-chloropyrazine-2-carboxamides were prepared as positional isomers of 5-chloro and 6-chloro derivatives, prepared previously. During the aminolysis of the acyl chloride, the simultaneous substitution of chlorine with benzylamino moiety gave rise to N-benzyl-3-(benzylamino)pyrazine-2-carboxamides as side products, in some cases. Although not initially planned, the reaction conditions were modified to populate this double substituted series. The final compounds were tested against four mycobacterial strains. N-(2-methylbenzyl)-3-((2-methylbenzyl)amino)pyrazine-2-carboxamide (1a) and N-(3,4-dichlorobenzyl)-3-((3,4-dichlorobenzyl)amino)pyrazine-2-carboxamide (9a) proved to be the most effective against Mycobacterium tuberculosis H37Rv, with MIC = 12.5 μg·mL(-1). Compounds were screened for antibacterial activity. The most active compound was 3-chloro-N-(2-chlorobenzyl)pyrazine-2-carboxamide (5) against Staphylococcus aureus with MIC = 7.81 μM, and Staphylococcus epidermidis with MIC = 15.62 μM. HepG2 in vitro cytotoxicity was evaluated for the most active compounds; however, no significant toxicity was detected. Compound 9a was docked to several conformations of the enoyl-ACP-reductase of Mycobacterium tuberculosis. In some cases, it was capable of H-bond interactions, typical for most of the known inhibitors.
- MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- buňky Hep G2 MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- pyraziny chemická syntéza chemie farmakologie MeSH
- simulace molekulového dockingu MeSH
- Staphylococcus aureus účinky léků MeSH
- Staphylococcus epidermidis účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Východiska: Tradiční fyzioterapeutické přístupy u pacientů po cévní mozkové příhodě jsou v posledních letech doplňovány novými technikami na bázi robotiky i virtuální reality a přináší možnost aktivně a intenzivně trénovat komplexní pohyby v závislosti na potřebách pacienta. Cíl: Zhodnotit efekt fyzioterapie na přístroji s využitím virtuální reality u pacientů po cévní mozkové příhodě a porovnat jej s konvenční fyzioterapií. Metody: 16 probandů po ischemické cévní mozkové příhodě bylo rozděleno do dvou skupin – experimentální (využití virtuální reality) a kontrolní (konvenční fyzioterapie), u nichž probíhala terapie horní končetiny po dobu 2 týdnů (10 terapií po 30min). Pomocí klinických testů, dynamometrie a přístrojových testů zkoumané- ho přístroje jsme hodnotili rozdíly měřených parametrů. Pro zhodnocení dat jsme použili Wilcoxonův párový a Mann-Whitneyův test, hladina statistické významnosti byla stanovena na hodnotě p ≤ 0,05. Výsledky: U experimentální skupiny jsme zjistili signifikantní zlepšení u 6 z 6 parametrů, u kontrolní skupiny jsme dosáhli zlepšení u 2 z 6 sledovaných parametrů. Při porovnávání efektů terapií, tedy hodnot parametrů jednotlivých skupin navzájem jsme našli signifikantní změnu pouze u 1 parametru. Závěr: Z výsledků experimentu je možné usuzovat, že terapie ve virtuálním prostředí se zdá být oproti konvenč- ní terapii efektivnější, zlepšuje konkrétní dovednosti a funkce horní končetiny. Komparace obou terapií mezi sebou však nebyla statisticky významná.
Background: The importance of robotics and virtual reality has recently grown and complement traditional physiotherapeutic approaches. These new techniques offer the ability to train weakened movements only by adjusting to individual patient ́s needs. Ain: To evaluate the effect of therapy using virtual reality on physiotherapy device in stroke patients and compare it to a conventional therapy. Methods: We enrolled 16 post-stroke patients in our study and divided them into 2 groups – experimental (using virtual reality) and control group (using conventional therapy). We made a 10 sessions of upper limb therapy, each for 30 minutes, and then we evaluated the differences in the measured parameters using common clinical tests, dynamometry and tested device assessment. Wilcoxon pair and Mann-Whitney test was applied to evaluate the data. The significance level was set to 0.05. Results: We found significant improvement in 6 of the 6 parameters in the experimental group and another significant improvement in 2 of the 6 parameters in the control group. Only one parameter has significant changed when statistical comparing the effects of those two interventions. Conclusion: Findings of our study indicate that therapy in virtual reality seems to be more effective than conventional therapy, it improves the specific skills and functions of the upper limb. However, there were no statistically significant differences between the two therapies.
- MeSH
- cévní mozková příhoda terapie MeSH
- fyzioterapie (techniky) přístrojové vybavení trendy využití MeSH
- horní končetina MeSH
- kognitivně behaviorální terapie metody trendy MeSH
- paréza rehabilitace MeSH
- rehabilitace metody přístrojové vybavení trendy MeSH
- robotika metody využití MeSH
- virtuální realita MeSH
Východiska: Tradiční fyzioterapeutické přístupy u pacientů po cévní mozkové příhodě jsou v posledních letech doplňovány novými technikami na bázi robotiky i virtuální reality a přináší možnost aktivně a intenzivně trénovat komplexní pohyby v závislosti na potřebách pacienta. Cíl: Zhodnotit efekt fyzioterapie na přístroji s využitím virtuální reality u pacientů po cévní mozkové příhodě a porovnat jej s konvenční fyzioterapií. Metody: 16 probandů po ischemické cévní mozkové příhodě bylo rozděleno do dvou skupin – experimentální (využití virtuální reality) a kontrolní (konvenční fyzioterapie), u nichž probíhala terapie horní končetiny po dobu 2 týdnů (10 terapií po 30min). Pomocí klinických testů, dynamometrie a přístrojových testů zkoumané- ho přístroje jsme hodnotili rozdíly měřených parametrů. Pro zhodnocení dat jsme použili Wilcoxonův párový a Mann-Whitneyův test, hladina statistické významnosti byla stanovena na hodnotě p ≤ 0,05. Výsledky: U experimentální skupiny jsme zjistili signifikantní zlepšení u 6 z 6 parametrů, u kontrolní skupiny jsme dosáhli zlepšení u 2 z 6 sledovaných parametrů. Při porovnávání efektů terapií, tedy hodnot parametrů jednotlivých skupin navzájem jsme našli signifikantní změnu pouze u 1 parametru. Závěr: Z výsledků experimentu je možné usuzovat, že terapie ve virtuálním prostředí se zdá být oproti konvenč- ní terapii efektivnější, zlepšuje konkrétní dovednosti a funkce horní končetiny. Komparace obou terapií mezi sebou však nebyla statisticky významná.
Background: The importance of robotics and virtual reality has recently grown and complement traditional physiotherapeutic approaches. These new techniques offer the ability to train weakened movements only by adjusting to individual patient´s needs. Ain: To evaluate the effect of therapy using virtual reality on physiotherapy device in stroke patients and compare it to a conventional therapy. Methods: We enrolled 16 post-stroke patients in our study and divided them into 2 groups – experimental (using virtual reality) and control group (using conventional therapy). We made a 10 sessions of upper limb therapy, each for 30 minutes, and then we evaluated the differences in the measured parameters using common clinical tests, dynamometry and tested device assessment. Wilcoxon pair and Mann-Whitney test was applied to evaluate the data. The significance level was set to 0.05. Results: We found significant improvement in 6 of the 6 parameters in the experimental group and another significant improvement in 2 of the 6 parameters in the control group. Only one parameter has significant changed when statistical comparing the effects of those two interventions. Conclusion: Findings of our study indicate that therapy in virtual reality seems to be more effective than conventional therapy, it improves the specific skills and functions of the upper limb. However, there were no statistically significant differences between the two therapies.
