Tibor Liptaj | Slovak University of Technology (original) (raw)
Papers by Tibor Liptaj
ChemInform, May 24, 2010
ABSTRACT Oxidation of furan-2-carboximidamides 8 by (dicarboxyiodo)benzenes gives N1-acyl-N1-(2-f... more ABSTRACT Oxidation of furan-2-carboximidamides 8 by (dicarboxyiodo)benzenes gives N1-acyl-N1-(2-furyl)ureas 9via rearrangement to a carbodiimide. Thermolysis of eleven ureas 9 gave the corresponding 2-acylaminofurans 10, which cannot be made from the free amines owing to their high instability. When oxidation of the corresponding benzo[b]furan derivatives 12 was investigated a new type of product was isolated, in addition to the expected ureas 14, and these were shown to be benzo[4,5]furo[2,3-d]pyrimidine derivatives 15. The mechanism of formation of these products must involve reaction of the carbodiimide intermediate with the amidine precursor and cyclisation of the resulting guanidine derivatives 19. The corresponding tetraphenylguanidine 21 was prepared and underwent thermal cyclisation but the quinazoline derivative formed 23 was shown to occur via an alternative cyclisation mechanism. The structures of cyclisation products 15 and 23 were confirmed by X-ray crystallography. N-(2-Furyl)acetamide 10a readily undergoes cycloaddition reactions with electron-deficient alkynes to give phenols after spontaneous ring opening. Observed regioselectivity is in agreement with the results of AM1 molecular orbital calculations. Reaction of the amide 10a with Lawesson’s reagent gave the thioamide 26.
Scientific Reports, Apr 23, 2019
A series of 116 small-molecule 1-hydroxynaphthalene-2-carboxanilides was designed based on the fr... more A series of 116 small-molecule 1-hydroxynaphthalene-2-carboxanilides was designed based on the fragment-based approach and was synthesized according to the microwave-assisted protocol. The biological activity of all of the compounds was tested on human colon carcinoma cell lines including a deleted TP53 tumor suppressor gene. The mechanism of activity was studied according to the p53 status in the cell. Several compounds revealed a good to excellent activity that was similar to or better than the standard anticancer drugs. Some of these appeared to be more active against the p53 null cells than their wild-type counterparts. Intercalating the properties of these compounds could be responsible for their mechanism of action. Small-molecule drugs are still most commonly used in the treatment of cancer. However, the cytostatic agents and DNA poisons that were initially developed for clinical use are losing their position today. The particularly offensive, and often even life-threatening and difficult to restrain side effects, significantly degrade the quality of life of patients and are often responsible for the cessation of therapy. This is the result of a non-specific mechanism of action and the low selectivity of these drugs. In fact, some alkylating agents are more toxic on normal cells than on malignant cells. Another problem that is often encountered is the resistance that may emerge after a brief period of a positive reaction to the therapy or may even occur in drug-naïve patients 1. This phenomenon is also an obstacle in so-called targeted therapies that use novel agents such as kinase inhibitors as well as in non-small therapeutics such as monoclonal antibodies 2. Therefore, although novel small-molecule agents are still in demand, newly designed compounds are required to have a specific even multitargeted mechanism of action and a good selectivity over normal cells. Because of their resemblance to biological structures and their great synthetic availability, simple aromatic amides are interesting scaffolds for designing new drugs. However, the majority of the literature data deals with their antimicrobial or anti-infectious activity and relatively few reports focus on their antiproliferative and anticancer potency (Fig. 1) 3,4. Even though salicylanilide has been claimed as privileged structure 5 , these compounds are only being developed as antibacterial 4,6-8 , antimycobacterial 9-14 , antifungal 15,16 and antiprotozoic/antihelmintic 16,17 agents or as photosynthesis inhibitors 18-20. Recently, some appealing reports on simple antihelmintic drugs that have been used for quite some time have been published. For example, mebendazole was found to be
Magnetic Resonance in Chemistry, 1992
The application of a chemical shift selective filter in 1D INADEQUATE a d H-CC relay experiments ... more The application of a chemical shift selective filter in 1D INADEQUATE a d H-CC relay experiments is p r e posed. It is demonstrated that highly selective filtering can be the equivalent of low-power excitations. Applications to the selective detection of carbon-carbon conwctivities are presented.
The aim of this study was to induce a sporadic form of age-related early-stage dementia, such as ... more The aim of this study was to induce a sporadic form of age-related early-stage dementia, such as that in Alzheimer’s disease (AD) by chronic injection of D-galactose and NaNO2 to rats and investigate changes in brain metabolites levels using in vivo proton magnetic resonance spectroscopy. As reference methods behavioral tests were used. Localized proton magnetic resonance spectroscopy measurements in a brain showed a significant decrease in the concentration of N-acetylaspartate + N-acetylaspartylglutamate, glutamine + glutamate, and myo-inositol in the D-gal/NaNO2 group compared to the control group. The dynamics of the learning process represented by the learning index in modified Morris water maze test revealed a reduction in learning in the D-gal/NaNO2. The total motor activity in the Open-field test was also reduced compared to the control. We propose, that our results support the use of D-galactose in combination with NaNO2 to rats to induce earlystage of dementia and could be...
Applied and Environmental Microbiology, 1998
We investigated the carbon metabolism of three strains of Fibrobacter succinogenes and one strain... more We investigated the carbon metabolism of three strains of Fibrobacter succinogenes and one strain of Fibrobacter intestinalis . The four strains produced the same amounts of the metabolites succinate, acetate, and formate in approximately the same ratio (3.7/1/0.3). The four strains similarly stored glycogen during all growth phases, and the glycogen-to-protein ratio was close to 0.6 during the exponential growth phase. 13 C nuclear magnetic resonance (NMR) analysis of [1- 13 C]glucose utilization by resting cells of the four strains revealed a reversal of glycolysis at the triose phosphate level and the same metabolic pathways. Glycogen futile cycling was demonstrated by 13 C NMR by following the simultaneous metabolism of labeled [ 13 C]glycogen and exogenous unlabeled glucose. The isotopic dilutions of the CH 2 of succinate and the CH 3 of acetate when the resting cells were metabolizing [1- 13 C]glucose and unlabeled glycogen were precisely quantified by using 13 C-filtered spin...
Proceedings of The 22nd International Electronic Conference on Synthetic Organic Chemistry, 2018
A series of variously methoxylated and methylated N-aryl-1-hydroxynaphthalene-2-carboxanilides wa... more A series of variously methoxylated and methylated N-aryl-1-hydroxynaphthalene-2-carboxanilides was prepared and characterized as potential anti-invasive agents. As it is known that lipophilicity significantly influences the biological activity of compounds, the hydro-lipophilic properties of these mono-, di- and tri-substituted 1-hydroxynaphthalene-2-carboxanilides are investigated in the study. All the discussed hydroxynaphthalene derivatives were analyzed using the reversed-phase, high-performance liquid chromatography method, to measure lipophilicity. The procedure was performed under isocratic conditions with methanol as an organic modifier in the mobile phase, using an end-capped, non-polar C18 stationary reversed-phase column. The present study discusses the correlations between the logarithm of the capacity factor k and log P/Clog P values, calculated in various ways, as well as the relationships between the lipophilicity and the chemical structure of the studied compounds.
Molecules (Basel, Switzerland), Jan 12, 2017
Series of seventeen new multihalogenated 1-hydroxynaphthalene-2-carboxanilides was prepared and c... more Series of seventeen new multihalogenated 1-hydroxynaphthalene-2-carboxanilides was prepared and characterized. All the compounds were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach ( L.) chloroplasts. 1-Hydroxy--phenylnaphthalene-2-carboxamides substituted in the anilide part by 3,5-dichloro-, 4-bromo-3-chloro-, 2,5-dibromo- and 3,4,5-trichloro atoms were the most potent PET inhibitors (IC = 5.2, 6.7, 7.6 and 8.0 µM, respectively). The inhibitory activity of these compounds depends on the position and the type of halogen substituents, i.e., on lipophilicity and electronic properties of individual substituents of the anilide part of the molecule. Interactions of the studied compounds with chlorophyll and aromatic amino acids present in pigment-protein complexes mainly in PS II were documented by fluorescence spectroscopy. The section between P and plastoquinone Q in the PET chain occurring on the acceptor side of PS II can be...
Molecules, 2016
A series of nineteen N-(alkoxyphenyl)-2-hydroxynaphthalene-1-carboxamides and a series of their n... more A series of nineteen N-(alkoxyphenyl)-2-hydroxynaphthalene-1-carboxamides and a series of their nineteen positional isomers N-(alkoxyphenyl)-1-hydroxynaphthalene-2-carboxamides were prepared and characterized. Primary in vitro screening of all the synthesized compounds was performed against Mycobacterium tuberculosis H37Ra, M. kansasii and M. smegmatis. Screening of the cytotoxicity of the compounds was performed using human monocytic leukemia THP-1 cells. Some of the tested compounds showed antimycobacterial activity comparable with or higher than that of rifampicin. For example, 2-hydroxy-N-(4-propoxyphenyl)-naphthalene-1-carboxamide showed the highest activity (MIC = 12 µM) against M. tuberculosis with insignificant cytotoxicity. N-[3-(But-2-yloxy)phenyl]and N-[4-(but-2-yloxy)phenyl]-2-hydroxy-naphthalene-1-carboxamide demonstrated high activity against all tested mycobacterial strains and insignificant cytotoxicity. N-(Alkoxyphenyl)-1-hydroxynaphthalene-2-carboxamides demonstrated rather high effect against M. smegmatis and M. kansasii and strong antiproliferative effect against the human THP-1 cell line. Lipophilicity was found as the main physicochemical parameter influencing the activity. A significant decrease of mycobacterial cell metabolism (viability of M. tuberculosis H37Ra) was observed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) assay. Structure-activity relationships are discussed.
Acta Chimica Slovaca, 2015
The quantification ofThe purpose of this study was to compare the most frequently used algorithms... more The quantification ofThe purpose of this study was to compare the most frequently used algorithms for quantification ofOur analysis revealed that all values determined by QUEST, except for one value, were lower in comparison to values obtained by LCModel. The minimal differences were found in N-acetylaspartate/(phospho) creatine (−0.3 %) and maximal in inositol in both control and VD rats. This underestimation of a metabolite concentration in QUEST may be caused by an overestimation of baseline.Although our study found the different values of metabolite concentrations by these two methods, the quantified metabolite changes in pathological brain were comparable in both analyses.
Bioorganic & Medicinal Chemistry, 2015
In this study, a series of twenty-two ring-substituted 8-hydroxyquinoline-2-carboxanilides was pr... more In this study, a series of twenty-two ring-substituted 8-hydroxyquinoline-2-carboxanilides was prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Mycobacterium tuberculosis H37Ra, M. avium complex and M. avium subsp. paratuberculosis. Some of the tested compounds showed the antimycobacterial activity against M. avium subsp. paratuberculosis comparable with or higher than that of rifampicin. 8-Hydroxy-N-[3-(trifluoromethyl)phenyl]-and 8-hydroxy-N-[4-(trifluoromethyl)phenyl]quinoline-2-carboxamide showed MIC = 24 µM against all tested mycobacterial strains. 3-Methoxyphenyl-and 3-methylphenyl derivatives expressed MIC = 27 or 29 µM also against all the tested strains. Their activity against M. avium subsp. paratuberculosis was 4-fold higher than that of rifampicin. 2-Bromophenyl-and 2-(trifluoromethyl)phenyl derivatives had MIC = 23 or 24 µM against M. tuberculosis. A significant decrease of mycobacterial cell metabolism (viability of M. tuberculosis H37Ra) was observed using MTT assay. Screening of cytotoxicity of the compounds was performed using the THP-1 cells, and no significant lethal effect was observed up to tested concentration 30 µM. The structure-activity relationships are discussed.
Magnetic Resonance in Chemistry, 1992
The application of a chemical shift selective filter in 1D INADEQUATE and HCC relay experiments... more The application of a chemical shift selective filter in 1D INADEQUATE and HCC relay experiments is proposed. It is demonstrated that highly selective filtering can be the equivalent of low‐power excitations. Applications to the selective detection of carbon–carbon connectivities are presented.
Bratislavské lekárske listy, 1995
1H-nuclear magnetic resonance spectroscopy was used to study malignant melanoma extract. The aim ... more 1H-nuclear magnetic resonance spectroscopy was used to study malignant melanoma extract. The aim of this work was to study low molecular weight metabolites soluble in water, which can be helpful for a more detailed understanding of tumor metabolism with a view to using this knowledge for diagnosis. The authors found in a well distinguished spectrum the presence of numerous low molecular weight metabolites such as glutamate, glutamine, choline, inositol, creatine, phosphocreatine, phosphocholine, glucose, acetate, alanine, lactate. It is necessary to correlate these in-vitro findings with a study of the above mentioned metabolites in-vivo. Malignant melanoma is appropriate for this investigative and diagnostic technique because of its superficial localization. (Fig. 1, Ref. 18.)
Biomedical Papers, 2005
Creatine kinase (CK) plays a central role in energy transfer in cells with high-energy demands, a... more Creatine kinase (CK) plays a central role in energy transfer in cells with high-energy demands, and the enzyme is rather susceptible to oxidative inactivation. The aim of the present study was to investigate whether the rate constant of forward CK reaction (k for) is a suitable indicator of alterations in cerebral energy metabolism. We monitored k for in the rat brain non-invasively by in vivo phosphorus (31 P) magnetic resonance spectroscopy (MRS). To alter energy metabolism, we applied following experimental models: Huntington's disease, diabetes mellitus, chronic alcohol intoxication and chronic cerebral hypoperfusion (vascular dementia model). Results of our 31 P MRS experiment confirm importance of creatine kinase/phosphocreatinine (CK/PCr) system in the regulation of brain energy metabolism in vivo because a kinetic parameter k for was significantly changed in all above animal models that simulate neurodegenerative diseases or commonly during oxidative stress. Using this method we distinguished vascular dementia (VD) and Huntington disease (HD), because in VD model a kinetic parameter k for decreased and in the case HD increased. Considering the importance of CK for the maintenance of energy homeostasis in the brain, it is conceivable that an alteration of this enzyme activity in the brain may be one of the mechanisms by which various neurodegenerative diseases might be monitored just by means saturation transfer method 31 P MRS.
Proceedings of The 18th International Electronic Conference on Synthetic Organic Chemistry, 2014
In this study a series of twelve n-alkoxy-substituted 2-hydroxynaphthalene-1carboxanilides was pr... more In this study a series of twelve n-alkoxy-substituted 2-hydroxynaphthalene-1carboxanilides was prepared and characterized. The discussed compounds were prepared by microwave-assisted synthesis. The compounds were tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. The highest PET inhibition was observed for meta-substituted compounds, whereas 2-hydroxy-N-(3-propoxyphenyl)naphthalene-1-carboxamide showed the highest PET inhibition within the whole series. In spite of medium or moderate PET-inhibiting activity it was found that the compounds inhibit PET in photosystem II. The activity of all positional isomers is strongly influenced by lipophilicity and the length/bulkiness of the alkoxy chain.
Proceedings of The 17th International Electronic Conference on Synthetic Organic Chemistry, 2013
In this study a series of twelve ring-substituted 8-hydroxyquinoline-2-carboxanilides was prepare... more In this study a series of twelve ring-substituted 8-hydroxyquinoline-2-carboxanilides was prepared and characterized. The discussed compounds were prepared by using microwave-assisted synthesis. The compounds were tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. The compounds were found to inhibit PET in photosystem II. Significant PET-inhibiting activity was observed for meta-substituted compounds showing IC 50 values close to that of photosystem II herbicide DCMU (3-(3,4-dichlorophenyl)-1,1-dimethylurea, IC 50 = 1.9 μmol/L). N-(3-Fluorophenyl)-8-hydroxyquinoline-2-carboxamide showed the highest PET inhibition. The activity of meta-and para-substituted compounds strongly decreased with lipophilicity increase and electron-withdrawing effect. No influence of any of these parameters on PET-inhibiting activity of ortho-substituted compounds was observed.
Behavioural Brain Research, 2015
h i g h l i g h t s • We report results of in vivo magnetic resonance study of dementia on rat br... more h i g h l i g h t s • We report results of in vivo magnetic resonance study of dementia on rat brain. • Dementia was induced by d-galactose and treated by Simvastatin. • We found decrease of N-acetylaspartate in a group of dementia. • Simvastatin restored the level of N-acetylaspartate. • Simvastatin improved behavioral test and biochemical results.
Cellular and Molecular Neurobiology, 2000
1. In vivo 1 H and 31 P magnetic resonance spectroscopy techniques were applied to reveal biochem... more 1. In vivo 1 H and 31 P magnetic resonance spectroscopy techniques were applied to reveal biochemical changes in the rat brain caused by prolonged ethanol consumption. 2. Three models of ethanol intoxication were used. 3. 1 H MRS showed a significant decrease in the concentration of myo-inositol in the brain of rats fed with 20% ethanol for 8 weeks. This change is consistent with perturbances in astrocytes. On the other hand, N-acetyl aspartate and choline content did not differ from controls. 4. 31 P MRS did not reveal any significant changes in the high-energy phosphates or intracellular free Mg 2ϩ content in the brain of rats after 14 weeks of 20% ethanol drinking. The intracellular pH was diminished. 5. By means of a 31 P saturation transfer technique, a significant decrease was observed for the pseudo first-order rate constant k for of the creatine kinase reaction in the brain of rats administered 30% ethanol for 3 weeks using a gastric tube. 6. The 1 H MRS results may indicate that myo-inositol loss, reflecting a disorder in astrocytes, might be one of the first changes associated with alcoholism, which could be detected in the brain by means of in vivo 1 H MRS. 7. The results from 31 P MRS experiments suggest that alcoholism is associated with decreased brain energy metabolism. 8. 31 P saturation transfer, which provides insight into the turnover of high-energy phosphates, could be a more suitable technique for studying the brain energetics in chronic pathological states than conventional 31 P MRS.
Neurochemistry International, 2005
A multiple analysis of the cerebral oxidative stress was performed on a physiological model of de... more A multiple analysis of the cerebral oxidative stress was performed on a physiological model of dementia accomplished by three-vessel occlusion in aged rats. The forward rate constant of creatine kinase, k for , was studied by saturation transfer 31 P magnetic resonance spectroscopy in adult and aged rat brain during chronic hypoperfusion. In addition, free radicals in aging rat brain homogenates before and/or after occlusion were investigated by spin-trapping electron paramagnetic resonance spectroscopy (EPR). Finally, biochemical measurements of oxidative phosphorylation parameters in the above physiological model were performed. The significant reduction of k for in rat brain compared to controls 2 and 10 weeks after occlusion indicates a disorder in brain energy metabolism. This result is consistent with the decrease of the coefficient of oxidative phosphorylation (ADP:O), and the oxidative phosphorylation rate measured in vitro on brain mitochondria. The EPR study showed a significant increase of the ascorbyl free radical concentration in this animal model. Application of aphenyl-N-tert-butylnitrone (PBN) and 5,5-dimethyl-1-pyrroline N-oxide (DMPO) spin traps revealed formation of highly reactive hydroxyl radical (OH) trapped in DMSO as the CH 3 adduct. It was concluded that the ascorbate as a major antioxidant in brain seems to be useful in monitoring chronic cerebral hypoperfusion.
Neurochemistry International, 2006
The neuropathological and clinical symptoms of Huntington&amp;amp;amp;amp;amp;amp;amp;amp... more The neuropathological and clinical symptoms of Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (HD) can be simulated in animal model with systemic administration of 3-nitropropionic acid (3-NP). Energy defects in HD could be ameliorated by administration of coenzyme Q(10) (CoQ(10)), creatine, or nicotinamid. We studied the activity of creatine kinase (CK) and the function of mitochondrial respiratory chain in the brain of aged rats administered with 3-NP with and without previous application of antioxidants CoQ(10)+vitamin E. We used dynamic and steady-state methods of in vivo phosphorus magnetic resonance spectroscopy ((31)P MRS) for determination of the pseudo-first order rate constant (k(for)) of the forward CK reaction, the phosphocreatine (PCr) to adenosinetriphosphate (ATP) ratio, intracellular pH(i) and Mg(i)(2+) content in the brain. The respiratory chain function of isolated mitochondria was assessed polarographically; the concentration of CoQ(10) and alpha-tocopherol by HPLC. We found significant elevation of k(for) in brains of 3-NP rats, reflecting increased rate of CK reaction in cytosol. The function of respiratory chain in the presence of succinate was severely diminished. The activity of cytochromeoxidase and mitochondrial concentration of CoQ(10) was unaltered; tissue content of CoQ(10) was decreased in 3-NP rats. Antioxidants CoQ(10)+vitamin E prevented increase of k(for) and the decrease of CoQ(10) content in brain tissue, but were ineffective to prevent the decline of respiratory chain function. We suppose that increased activity of CK system could be compensatory to decreased mitochondrial ATP production, and CoQ(10)+vitamin E could prevent the increase of k(for) after 3-NP treatment likely by activity of CoQ(10) outside the mitochondria. Results of our experiments contributed to elucidation of mechanism of beneficial effect of CoQ(10) administration in HD and showed that the rate constant of CK is a sensitive indicator of brain energy disorder reflecting therapeutic effect of drugs that could be used as a new in vivo biomarker of neurodegenerative diseases.
ChemInform, May 24, 2010
ABSTRACT Oxidation of furan-2-carboximidamides 8 by (dicarboxyiodo)benzenes gives N1-acyl-N1-(2-f... more ABSTRACT Oxidation of furan-2-carboximidamides 8 by (dicarboxyiodo)benzenes gives N1-acyl-N1-(2-furyl)ureas 9via rearrangement to a carbodiimide. Thermolysis of eleven ureas 9 gave the corresponding 2-acylaminofurans 10, which cannot be made from the free amines owing to their high instability. When oxidation of the corresponding benzo[b]furan derivatives 12 was investigated a new type of product was isolated, in addition to the expected ureas 14, and these were shown to be benzo[4,5]furo[2,3-d]pyrimidine derivatives 15. The mechanism of formation of these products must involve reaction of the carbodiimide intermediate with the amidine precursor and cyclisation of the resulting guanidine derivatives 19. The corresponding tetraphenylguanidine 21 was prepared and underwent thermal cyclisation but the quinazoline derivative formed 23 was shown to occur via an alternative cyclisation mechanism. The structures of cyclisation products 15 and 23 were confirmed by X-ray crystallography. N-(2-Furyl)acetamide 10a readily undergoes cycloaddition reactions with electron-deficient alkynes to give phenols after spontaneous ring opening. Observed regioselectivity is in agreement with the results of AM1 molecular orbital calculations. Reaction of the amide 10a with Lawesson’s reagent gave the thioamide 26.
Scientific Reports, Apr 23, 2019
A series of 116 small-molecule 1-hydroxynaphthalene-2-carboxanilides was designed based on the fr... more A series of 116 small-molecule 1-hydroxynaphthalene-2-carboxanilides was designed based on the fragment-based approach and was synthesized according to the microwave-assisted protocol. The biological activity of all of the compounds was tested on human colon carcinoma cell lines including a deleted TP53 tumor suppressor gene. The mechanism of activity was studied according to the p53 status in the cell. Several compounds revealed a good to excellent activity that was similar to or better than the standard anticancer drugs. Some of these appeared to be more active against the p53 null cells than their wild-type counterparts. Intercalating the properties of these compounds could be responsible for their mechanism of action. Small-molecule drugs are still most commonly used in the treatment of cancer. However, the cytostatic agents and DNA poisons that were initially developed for clinical use are losing their position today. The particularly offensive, and often even life-threatening and difficult to restrain side effects, significantly degrade the quality of life of patients and are often responsible for the cessation of therapy. This is the result of a non-specific mechanism of action and the low selectivity of these drugs. In fact, some alkylating agents are more toxic on normal cells than on malignant cells. Another problem that is often encountered is the resistance that may emerge after a brief period of a positive reaction to the therapy or may even occur in drug-naïve patients 1. This phenomenon is also an obstacle in so-called targeted therapies that use novel agents such as kinase inhibitors as well as in non-small therapeutics such as monoclonal antibodies 2. Therefore, although novel small-molecule agents are still in demand, newly designed compounds are required to have a specific even multitargeted mechanism of action and a good selectivity over normal cells. Because of their resemblance to biological structures and their great synthetic availability, simple aromatic amides are interesting scaffolds for designing new drugs. However, the majority of the literature data deals with their antimicrobial or anti-infectious activity and relatively few reports focus on their antiproliferative and anticancer potency (Fig. 1) 3,4. Even though salicylanilide has been claimed as privileged structure 5 , these compounds are only being developed as antibacterial 4,6-8 , antimycobacterial 9-14 , antifungal 15,16 and antiprotozoic/antihelmintic 16,17 agents or as photosynthesis inhibitors 18-20. Recently, some appealing reports on simple antihelmintic drugs that have been used for quite some time have been published. For example, mebendazole was found to be
Magnetic Resonance in Chemistry, 1992
The application of a chemical shift selective filter in 1D INADEQUATE a d H-CC relay experiments ... more The application of a chemical shift selective filter in 1D INADEQUATE a d H-CC relay experiments is p r e posed. It is demonstrated that highly selective filtering can be the equivalent of low-power excitations. Applications to the selective detection of carbon-carbon conwctivities are presented.
The aim of this study was to induce a sporadic form of age-related early-stage dementia, such as ... more The aim of this study was to induce a sporadic form of age-related early-stage dementia, such as that in Alzheimer’s disease (AD) by chronic injection of D-galactose and NaNO2 to rats and investigate changes in brain metabolites levels using in vivo proton magnetic resonance spectroscopy. As reference methods behavioral tests were used. Localized proton magnetic resonance spectroscopy measurements in a brain showed a significant decrease in the concentration of N-acetylaspartate + N-acetylaspartylglutamate, glutamine + glutamate, and myo-inositol in the D-gal/NaNO2 group compared to the control group. The dynamics of the learning process represented by the learning index in modified Morris water maze test revealed a reduction in learning in the D-gal/NaNO2. The total motor activity in the Open-field test was also reduced compared to the control. We propose, that our results support the use of D-galactose in combination with NaNO2 to rats to induce earlystage of dementia and could be...
Applied and Environmental Microbiology, 1998
We investigated the carbon metabolism of three strains of Fibrobacter succinogenes and one strain... more We investigated the carbon metabolism of three strains of Fibrobacter succinogenes and one strain of Fibrobacter intestinalis . The four strains produced the same amounts of the metabolites succinate, acetate, and formate in approximately the same ratio (3.7/1/0.3). The four strains similarly stored glycogen during all growth phases, and the glycogen-to-protein ratio was close to 0.6 during the exponential growth phase. 13 C nuclear magnetic resonance (NMR) analysis of [1- 13 C]glucose utilization by resting cells of the four strains revealed a reversal of glycolysis at the triose phosphate level and the same metabolic pathways. Glycogen futile cycling was demonstrated by 13 C NMR by following the simultaneous metabolism of labeled [ 13 C]glycogen and exogenous unlabeled glucose. The isotopic dilutions of the CH 2 of succinate and the CH 3 of acetate when the resting cells were metabolizing [1- 13 C]glucose and unlabeled glycogen were precisely quantified by using 13 C-filtered spin...
Proceedings of The 22nd International Electronic Conference on Synthetic Organic Chemistry, 2018
A series of variously methoxylated and methylated N-aryl-1-hydroxynaphthalene-2-carboxanilides wa... more A series of variously methoxylated and methylated N-aryl-1-hydroxynaphthalene-2-carboxanilides was prepared and characterized as potential anti-invasive agents. As it is known that lipophilicity significantly influences the biological activity of compounds, the hydro-lipophilic properties of these mono-, di- and tri-substituted 1-hydroxynaphthalene-2-carboxanilides are investigated in the study. All the discussed hydroxynaphthalene derivatives were analyzed using the reversed-phase, high-performance liquid chromatography method, to measure lipophilicity. The procedure was performed under isocratic conditions with methanol as an organic modifier in the mobile phase, using an end-capped, non-polar C18 stationary reversed-phase column. The present study discusses the correlations between the logarithm of the capacity factor k and log P/Clog P values, calculated in various ways, as well as the relationships between the lipophilicity and the chemical structure of the studied compounds.
Molecules (Basel, Switzerland), Jan 12, 2017
Series of seventeen new multihalogenated 1-hydroxynaphthalene-2-carboxanilides was prepared and c... more Series of seventeen new multihalogenated 1-hydroxynaphthalene-2-carboxanilides was prepared and characterized. All the compounds were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach ( L.) chloroplasts. 1-Hydroxy--phenylnaphthalene-2-carboxamides substituted in the anilide part by 3,5-dichloro-, 4-bromo-3-chloro-, 2,5-dibromo- and 3,4,5-trichloro atoms were the most potent PET inhibitors (IC = 5.2, 6.7, 7.6 and 8.0 µM, respectively). The inhibitory activity of these compounds depends on the position and the type of halogen substituents, i.e., on lipophilicity and electronic properties of individual substituents of the anilide part of the molecule. Interactions of the studied compounds with chlorophyll and aromatic amino acids present in pigment-protein complexes mainly in PS II were documented by fluorescence spectroscopy. The section between P and plastoquinone Q in the PET chain occurring on the acceptor side of PS II can be...
Molecules, 2016
A series of nineteen N-(alkoxyphenyl)-2-hydroxynaphthalene-1-carboxamides and a series of their n... more A series of nineteen N-(alkoxyphenyl)-2-hydroxynaphthalene-1-carboxamides and a series of their nineteen positional isomers N-(alkoxyphenyl)-1-hydroxynaphthalene-2-carboxamides were prepared and characterized. Primary in vitro screening of all the synthesized compounds was performed against Mycobacterium tuberculosis H37Ra, M. kansasii and M. smegmatis. Screening of the cytotoxicity of the compounds was performed using human monocytic leukemia THP-1 cells. Some of the tested compounds showed antimycobacterial activity comparable with or higher than that of rifampicin. For example, 2-hydroxy-N-(4-propoxyphenyl)-naphthalene-1-carboxamide showed the highest activity (MIC = 12 µM) against M. tuberculosis with insignificant cytotoxicity. N-[3-(But-2-yloxy)phenyl]and N-[4-(but-2-yloxy)phenyl]-2-hydroxy-naphthalene-1-carboxamide demonstrated high activity against all tested mycobacterial strains and insignificant cytotoxicity. N-(Alkoxyphenyl)-1-hydroxynaphthalene-2-carboxamides demonstrated rather high effect against M. smegmatis and M. kansasii and strong antiproliferative effect against the human THP-1 cell line. Lipophilicity was found as the main physicochemical parameter influencing the activity. A significant decrease of mycobacterial cell metabolism (viability of M. tuberculosis H37Ra) was observed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) assay. Structure-activity relationships are discussed.
Acta Chimica Slovaca, 2015
The quantification ofThe purpose of this study was to compare the most frequently used algorithms... more The quantification ofThe purpose of this study was to compare the most frequently used algorithms for quantification ofOur analysis revealed that all values determined by QUEST, except for one value, were lower in comparison to values obtained by LCModel. The minimal differences were found in N-acetylaspartate/(phospho) creatine (−0.3 %) and maximal in inositol in both control and VD rats. This underestimation of a metabolite concentration in QUEST may be caused by an overestimation of baseline.Although our study found the different values of metabolite concentrations by these two methods, the quantified metabolite changes in pathological brain were comparable in both analyses.
Bioorganic & Medicinal Chemistry, 2015
In this study, a series of twenty-two ring-substituted 8-hydroxyquinoline-2-carboxanilides was pr... more In this study, a series of twenty-two ring-substituted 8-hydroxyquinoline-2-carboxanilides was prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Mycobacterium tuberculosis H37Ra, M. avium complex and M. avium subsp. paratuberculosis. Some of the tested compounds showed the antimycobacterial activity against M. avium subsp. paratuberculosis comparable with or higher than that of rifampicin. 8-Hydroxy-N-[3-(trifluoromethyl)phenyl]-and 8-hydroxy-N-[4-(trifluoromethyl)phenyl]quinoline-2-carboxamide showed MIC = 24 µM against all tested mycobacterial strains. 3-Methoxyphenyl-and 3-methylphenyl derivatives expressed MIC = 27 or 29 µM also against all the tested strains. Their activity against M. avium subsp. paratuberculosis was 4-fold higher than that of rifampicin. 2-Bromophenyl-and 2-(trifluoromethyl)phenyl derivatives had MIC = 23 or 24 µM against M. tuberculosis. A significant decrease of mycobacterial cell metabolism (viability of M. tuberculosis H37Ra) was observed using MTT assay. Screening of cytotoxicity of the compounds was performed using the THP-1 cells, and no significant lethal effect was observed up to tested concentration 30 µM. The structure-activity relationships are discussed.
Magnetic Resonance in Chemistry, 1992
The application of a chemical shift selective filter in 1D INADEQUATE and HCC relay experiments... more The application of a chemical shift selective filter in 1D INADEQUATE and HCC relay experiments is proposed. It is demonstrated that highly selective filtering can be the equivalent of low‐power excitations. Applications to the selective detection of carbon–carbon connectivities are presented.
Bratislavské lekárske listy, 1995
1H-nuclear magnetic resonance spectroscopy was used to study malignant melanoma extract. The aim ... more 1H-nuclear magnetic resonance spectroscopy was used to study malignant melanoma extract. The aim of this work was to study low molecular weight metabolites soluble in water, which can be helpful for a more detailed understanding of tumor metabolism with a view to using this knowledge for diagnosis. The authors found in a well distinguished spectrum the presence of numerous low molecular weight metabolites such as glutamate, glutamine, choline, inositol, creatine, phosphocreatine, phosphocholine, glucose, acetate, alanine, lactate. It is necessary to correlate these in-vitro findings with a study of the above mentioned metabolites in-vivo. Malignant melanoma is appropriate for this investigative and diagnostic technique because of its superficial localization. (Fig. 1, Ref. 18.)
Biomedical Papers, 2005
Creatine kinase (CK) plays a central role in energy transfer in cells with high-energy demands, a... more Creatine kinase (CK) plays a central role in energy transfer in cells with high-energy demands, and the enzyme is rather susceptible to oxidative inactivation. The aim of the present study was to investigate whether the rate constant of forward CK reaction (k for) is a suitable indicator of alterations in cerebral energy metabolism. We monitored k for in the rat brain non-invasively by in vivo phosphorus (31 P) magnetic resonance spectroscopy (MRS). To alter energy metabolism, we applied following experimental models: Huntington's disease, diabetes mellitus, chronic alcohol intoxication and chronic cerebral hypoperfusion (vascular dementia model). Results of our 31 P MRS experiment confirm importance of creatine kinase/phosphocreatinine (CK/PCr) system in the regulation of brain energy metabolism in vivo because a kinetic parameter k for was significantly changed in all above animal models that simulate neurodegenerative diseases or commonly during oxidative stress. Using this method we distinguished vascular dementia (VD) and Huntington disease (HD), because in VD model a kinetic parameter k for decreased and in the case HD increased. Considering the importance of CK for the maintenance of energy homeostasis in the brain, it is conceivable that an alteration of this enzyme activity in the brain may be one of the mechanisms by which various neurodegenerative diseases might be monitored just by means saturation transfer method 31 P MRS.
Proceedings of The 18th International Electronic Conference on Synthetic Organic Chemistry, 2014
In this study a series of twelve n-alkoxy-substituted 2-hydroxynaphthalene-1carboxanilides was pr... more In this study a series of twelve n-alkoxy-substituted 2-hydroxynaphthalene-1carboxanilides was prepared and characterized. The discussed compounds were prepared by microwave-assisted synthesis. The compounds were tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. The highest PET inhibition was observed for meta-substituted compounds, whereas 2-hydroxy-N-(3-propoxyphenyl)naphthalene-1-carboxamide showed the highest PET inhibition within the whole series. In spite of medium or moderate PET-inhibiting activity it was found that the compounds inhibit PET in photosystem II. The activity of all positional isomers is strongly influenced by lipophilicity and the length/bulkiness of the alkoxy chain.
Proceedings of The 17th International Electronic Conference on Synthetic Organic Chemistry, 2013
In this study a series of twelve ring-substituted 8-hydroxyquinoline-2-carboxanilides was prepare... more In this study a series of twelve ring-substituted 8-hydroxyquinoline-2-carboxanilides was prepared and characterized. The discussed compounds were prepared by using microwave-assisted synthesis. The compounds were tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. The compounds were found to inhibit PET in photosystem II. Significant PET-inhibiting activity was observed for meta-substituted compounds showing IC 50 values close to that of photosystem II herbicide DCMU (3-(3,4-dichlorophenyl)-1,1-dimethylurea, IC 50 = 1.9 μmol/L). N-(3-Fluorophenyl)-8-hydroxyquinoline-2-carboxamide showed the highest PET inhibition. The activity of meta-and para-substituted compounds strongly decreased with lipophilicity increase and electron-withdrawing effect. No influence of any of these parameters on PET-inhibiting activity of ortho-substituted compounds was observed.
Behavioural Brain Research, 2015
h i g h l i g h t s • We report results of in vivo magnetic resonance study of dementia on rat br... more h i g h l i g h t s • We report results of in vivo magnetic resonance study of dementia on rat brain. • Dementia was induced by d-galactose and treated by Simvastatin. • We found decrease of N-acetylaspartate in a group of dementia. • Simvastatin restored the level of N-acetylaspartate. • Simvastatin improved behavioral test and biochemical results.
Cellular and Molecular Neurobiology, 2000
1. In vivo 1 H and 31 P magnetic resonance spectroscopy techniques were applied to reveal biochem... more 1. In vivo 1 H and 31 P magnetic resonance spectroscopy techniques were applied to reveal biochemical changes in the rat brain caused by prolonged ethanol consumption. 2. Three models of ethanol intoxication were used. 3. 1 H MRS showed a significant decrease in the concentration of myo-inositol in the brain of rats fed with 20% ethanol for 8 weeks. This change is consistent with perturbances in astrocytes. On the other hand, N-acetyl aspartate and choline content did not differ from controls. 4. 31 P MRS did not reveal any significant changes in the high-energy phosphates or intracellular free Mg 2ϩ content in the brain of rats after 14 weeks of 20% ethanol drinking. The intracellular pH was diminished. 5. By means of a 31 P saturation transfer technique, a significant decrease was observed for the pseudo first-order rate constant k for of the creatine kinase reaction in the brain of rats administered 30% ethanol for 3 weeks using a gastric tube. 6. The 1 H MRS results may indicate that myo-inositol loss, reflecting a disorder in astrocytes, might be one of the first changes associated with alcoholism, which could be detected in the brain by means of in vivo 1 H MRS. 7. The results from 31 P MRS experiments suggest that alcoholism is associated with decreased brain energy metabolism. 8. 31 P saturation transfer, which provides insight into the turnover of high-energy phosphates, could be a more suitable technique for studying the brain energetics in chronic pathological states than conventional 31 P MRS.
Neurochemistry International, 2005
A multiple analysis of the cerebral oxidative stress was performed on a physiological model of de... more A multiple analysis of the cerebral oxidative stress was performed on a physiological model of dementia accomplished by three-vessel occlusion in aged rats. The forward rate constant of creatine kinase, k for , was studied by saturation transfer 31 P magnetic resonance spectroscopy in adult and aged rat brain during chronic hypoperfusion. In addition, free radicals in aging rat brain homogenates before and/or after occlusion were investigated by spin-trapping electron paramagnetic resonance spectroscopy (EPR). Finally, biochemical measurements of oxidative phosphorylation parameters in the above physiological model were performed. The significant reduction of k for in rat brain compared to controls 2 and 10 weeks after occlusion indicates a disorder in brain energy metabolism. This result is consistent with the decrease of the coefficient of oxidative phosphorylation (ADP:O), and the oxidative phosphorylation rate measured in vitro on brain mitochondria. The EPR study showed a significant increase of the ascorbyl free radical concentration in this animal model. Application of aphenyl-N-tert-butylnitrone (PBN) and 5,5-dimethyl-1-pyrroline N-oxide (DMPO) spin traps revealed formation of highly reactive hydroxyl radical (OH) trapped in DMSO as the CH 3 adduct. It was concluded that the ascorbate as a major antioxidant in brain seems to be useful in monitoring chronic cerebral hypoperfusion.
Neurochemistry International, 2006
The neuropathological and clinical symptoms of Huntington&amp;amp;amp;amp;amp;amp;amp;amp... more The neuropathological and clinical symptoms of Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (HD) can be simulated in animal model with systemic administration of 3-nitropropionic acid (3-NP). Energy defects in HD could be ameliorated by administration of coenzyme Q(10) (CoQ(10)), creatine, or nicotinamid. We studied the activity of creatine kinase (CK) and the function of mitochondrial respiratory chain in the brain of aged rats administered with 3-NP with and without previous application of antioxidants CoQ(10)+vitamin E. We used dynamic and steady-state methods of in vivo phosphorus magnetic resonance spectroscopy ((31)P MRS) for determination of the pseudo-first order rate constant (k(for)) of the forward CK reaction, the phosphocreatine (PCr) to adenosinetriphosphate (ATP) ratio, intracellular pH(i) and Mg(i)(2+) content in the brain. The respiratory chain function of isolated mitochondria was assessed polarographically; the concentration of CoQ(10) and alpha-tocopherol by HPLC. We found significant elevation of k(for) in brains of 3-NP rats, reflecting increased rate of CK reaction in cytosol. The function of respiratory chain in the presence of succinate was severely diminished. The activity of cytochromeoxidase and mitochondrial concentration of CoQ(10) was unaltered; tissue content of CoQ(10) was decreased in 3-NP rats. Antioxidants CoQ(10)+vitamin E prevented increase of k(for) and the decrease of CoQ(10) content in brain tissue, but were ineffective to prevent the decline of respiratory chain function. We suppose that increased activity of CK system could be compensatory to decreased mitochondrial ATP production, and CoQ(10)+vitamin E could prevent the increase of k(for) after 3-NP treatment likely by activity of CoQ(10) outside the mitochondria. Results of our experiments contributed to elucidation of mechanism of beneficial effect of CoQ(10) administration in HD and showed that the rate constant of CK is a sensitive indicator of brain energy disorder reflecting therapeutic effect of drugs that could be used as a new in vivo biomarker of neurodegenerative diseases.