František Trejtnar - Academia.edu (original) (raw)
Papers by František Trejtnar
Nuclear Medicine Communications, 2000
The quarterly journal of nuclear medicine : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), 2002
Renal excretion is the preferable elimination pathway of radiopharmaceuticals and/or their metabo... more Renal excretion is the preferable elimination pathway of radiopharmaceuticals and/or their metabolites from the body. The mechanisms of renal excretion involve glomerular filtration, tubular secretion, tubular reabsorption, and kidney metabolism. Radiopharmaceuticals of a molecular weight of up to 60 kDa are ultrafiltrated in the glomeruli at a rate dependent on their protein binding (the rate of glomerular filtration is a product of glomerular filtration rate and free fraction of the agent in plasma). Exclusive excretion by this route is typical for many chelates such us 99mTc-DTPA (diethylenetriaminepentaacetic acid). Some other radiopharmaceuticals are excreted in the renal tubuli into the tubular fluid by carrier-mediated and active processes involving different transport systems. Examples are ortho-iodohippurate and 99mTc-MAG-3 (mercaptoacetyltriglycine). Tubular reabsorption involves either passive diffusion of lipid-soluble radiopharmaceuticals from the glomerular filtrate ba...
Nuclear Medicine and Biology
Introduction Radiolabeled receptor-targeting peptides are a useful tool for the diagnostic imagin... more Introduction Radiolabeled receptor-targeting peptides are a useful tool for the diagnostic imaging and radiotherapy of some malignancies. However, the retention of radioactivity in the kidney may result in renal radiotoxic injury. This study seeks to evaluate the role of endocytic receptor megalin, renal SLC influx transporters and fluid phase endocytosis (FPE) in the cellular accumulation of radiolabeled peptides. Methods In vitro transport cellular studies using megalin ligands (RAP, albumin), fluid phase endocytosis (FPE) inhibitor rottlerin and low temperature were employed to evaluate the transport mechanisms of the peptides. Cells transfected with hOAT1 or hOCT2 were used to analyze the role of these SLC transporters. Somatostatin (177Lu-DOTA-[Tyr3]octreotate, 177Lu-DOTA-[1-Nal3]octreotide), gastrin (177Lu-DOTA-sargastrin) and bombesin (177Lu-DOTA-[Pro1,Tyr4]bombesin, 177Lu-DOTA-[Lys3]bombesin, 177Lu-PCTA-[Lys3]bombesin) analogues were involved in the study. Results RAP, album...
Journal of Nuclear …, 2000
the incorporation of suitablepeptidesequencespermitsthemto exploit efficient routes of renal excr... more the incorporation of suitablepeptidesequencespermitsthemto exploit efficient routes of renal excretion,such as tubular secre tion, therebyoptimizingthe pattem of biodistribution of these radiopharmaceuticals.
Anticancer …, 2010
Background: In this study, two octreotate
European Journal of Drug Metabolism and Pharmacokinetics, 2002
The present study compares distribution and elimination characteristics of 111In-DTPA-D-Phe'-octr... more The present study compares distribution and elimination characteristics of 111In-DTPA-D-Phe'-octreotide and 11IIn-DTPA-L-Phe'-octreotide in rats and evaluated the effect of the replacement of the terminal L-phenylalanine by D-phenylalanine on pharmacokinetic profiles of the radiolabelled peptides. Both agents exhibited rapid radioactivity clearance from the blood and most organs and tissues with no systematic and significant differences in activity accumulation. The long-term retention and high radioactivity concentrations for both compounds under study were found in the kidneys and organs with a high density of somatostatin receptors, such as the pancreas and adrenals. The residence times in these organs were longer for lIIIn-DTPA-D-Phe'-octreotide in comparison with I II In-DTPA-L-Phel-octreotide. The major elimination pathway for both radiolabelled peptides was relatively rapid excretion into the urine. Analysis of the renal handling by an employment of the perfused rat kidney showed that both peptides were eliminated mainly by the mechanism of glomerular filtration. Rat liver perfusion experiments confirmed a very low value of bile clearance of radioactivity for both agents under study.
RSC Advances
A second total synthesis of (+)-hyacinthacine C3 is reported. As a result, structure of the first... more A second total synthesis of (+)-hyacinthacine C3 is reported. As a result, structure of the first synthetically prepared alkaloid is proved to be correct, clearly confirming the inconsistency with the stereochemistry assigned to the natural sample.
Chemical Papers
A new series of hybrid compounds were designed, consisting of anti-AChE and BuChE activity compon... more A new series of hybrid compounds were designed, consisting of anti-AChE and BuChE activity components with an antiinflammatory component. A series of 9-amino-1,2,3,4-tetrahydroacridine and indomethacin derivatives were synthesized. All compounds were created using alkyldiamine with different chain lengths as a linker. Various biological activities were evaluated, including inhibitory activity against AChE and BuChE. The tested compounds showed high inhibitory activities against cholinesterases. The IC 50 values for all compounds ranging from 10 nM to 7 µM. The potency of inhibition was much higher than well-known AChE and BuChE inhibitors (tacrine and donepezil). Compound 3h had the strongest inhibitory activity; kinetic studies showed it to have a mixed-type of acetylcholinesterase inhibition properties. The cytotoxicity of the newly-synthesized compounds against HepG2 (hepatocarcinoma cells) and EA.hy96 (human vein endothelial cells) cell lines was determined using the MTT and MTS tests. All investigated compounds presented similar cytotoxic activity against HepG2 and EA.hy926 cell line, ranged in micromolar values. Compounds with longer linkers showed higher antioxidant activity. The most active compound was 3h. Docking studies confirmed interactions with important regions of AChE and BuChE. Its multifunctional properties, i.e. high activity against AChE and BuChE, antioxidant activity and low cytotoxicity, highlight 3h as a promising agent for the treatment of AD.
Biomolecules
4-aminobenzoic acid (PABA), an essential nutrient for many human pathogens, but dispensable for h... more 4-aminobenzoic acid (PABA), an essential nutrient for many human pathogens, but dispensable for humans, and its derivatives have exhibited various biological activities. In this study, we combined two pharmacophores using a molecular hybridization approach: this vitamin-like molecule and various aromatic aldehydes, including salicylaldehydes and 5-nitrofurfural, via imine bond in one-step reaction. Resulting Schiff bases were screened as potential antimicrobial and cytotoxic agents. The simple chemical modification of non-toxic PABA resulted in constitution of antibacterial activity including inhibition of methicillin-resistant Staphylococcus aureus (minimum inhibitory concentrations, MIC, from 15.62 µM), moderate antimycobacterial activity (MIC ≥ 62.5 µM) and potent broad-spectrum antifungal properties (MIC of ≥ 7.81 µM). Some of the Schiff bases also exhibited notable cytotoxicity for cancer HepG2 cell line (IC50 ≥ 15.0 µM). Regarding aldehyde used for the derivatization of PABA, ...
Naunyn-Schmiedeberg's Archives of Pharmacology
The presented data "a-g" (Fig. 3), "a-e", (Fig. 4) and "a-b" (Fig. 5) located between the figure ... more The presented data "a-g" (Fig. 3), "a-e", (Fig. 4) and "a-b" (Fig. 5) located between the figure number and the text of the caption are redundant. Such data should be deleted. The original article has been corrected.
Naunyn-Schmiedeberg's Archives of Pharmacology
European Journal of Medicinal Chemistry
Molecules
A series of substituted N-benzyl-3-chloropyrazine-2-carboxamides were prepared as positional isom... more 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-(3,4dichlorobenzyl)-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.
Molecules
The resistance among microbes has brought an urgent need for new drugs. Thus, we synthesized a se... more The resistance among microbes has brought an urgent need for new drugs. Thus, we synthesized a series of Schiff bases derived from the sulfa drug sulfadiazine and various salicylaldehydes. The resulting 4-[(2-hydroxybenzylidene)amino]-N-(pyrimidin-2-yl)benzene-sulfonamides were characterized and evaluated against Gram-positive and Gram-negative bacteria, yeasts, moulds, Mycobacterium tuberculosis, nontuberculous mycobacteria (M. kansasii, M. avium) and their cytotoxicity was determined. Among bacteria, the genus Staphylococcus, including methicillin-resistant S. aureus, showed the highest susceptibility, with minimum inhibitory concentration values from 7.81 µM. The growth of Candida sp. and Trichophyton interdigitale was inhibited at concentrations starting from 1.95 µM. 4-[(2,5-Dihydroxybenzylidene)amino]-N-(pyrimidin-2-yl)-benzenesulfonamide was identified as the most selective Schiff base for these strains with no apparent cytotoxicity and a selectivity index higher than 16. With respect to M. tuberculosis and M. kansasii that were inhibited within the range of 8 to 250 µM, unsubstituted 4-[(2-hydroxy-benzylidene)amino]-N-(pyrimidin-2-yl)benzenesulfonamide meets the selectivity requirement. In general, dihalogenation of the salicylic moiety improved the antibacterial and antifungal activity but also increased the cytotoxicity, especially with an increasing atomic mass. Some derivatives offer more advantageous properties than the parent sulfadiazine, thus constituting promising hits for further antimicrobial drug development.
Bioorganic chemistry, 2017
A series of thirty novel N-acetylated fluorophenylalanine-based aromatic amides and esters was sy... more A series of thirty novel N-acetylated fluorophenylalanine-based aromatic amides and esters was synthesized using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or phosphorus trichloride in pyridine. They were characterized by spectral methods and screened against various microbes (Mycobacterium tuberculosis, non-tuberculous mycobacteria, other bacteria, fungi), for their inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and cytotoxicity. All amino acids derivatives revealed a moderate inhibition of both cholinesterases with IC50 values for AChE and BChE of 57.88-130.75µM and 8.25-289.0µM, respectively. Some derivatives were comparable or superior to rivastigmine, an established drug. Phenyl 2-acetamido-3-(4-fluorophenyl)propanoate was identified as the selective and most potent inhibitor of BChE. The esterification and amidation of parent acids led to an improved BChE inhibition. The esters are better inhibitors of BChE than the amides. The introduction ...
Bioorganic & medicinal chemistry, Jan 15, 2017
Bioorganic & medicinal chemistry, Jan 15, 2017
Salicylanilides have proved their activity against tuberculosis (TB). One weak electron-withdrawi... more Salicylanilides have proved their activity against tuberculosis (TB). One weak electron-withdrawing substituent is favored at the salicylic part, specially Cl or Br atoms at positions 4 or 5. On the other hand, the antimycobacterial activity of salicylanilides is negatively affected when a strong electron-withdrawing substituent (NO2) is present at the same positions. Herein we describe the synthesis and characterization of novel salicylanilides possessing two weak electron-withdrawing groups (halogen atoms) at their salicylic part and compare their antitubercular activity with their monohalogenated analogues. All dihalogenated derivatives proved to possess antitubercular activity at a very narrow micromolar range (MIC=1-4μM), similar with their most active monohalogenated analogues. More importantly, the most active final molecules were further screened against multidrug resistant strains and found to inhibit their growth at the range of 0.5-4μM.
Chemical Papers, 2015
N-Phenylpyrazine-2-carboxamides (anilides of pyrazinoic acids with simple substituents in various... more N-Phenylpyrazine-2-carboxamides (anilides of pyrazinoic acids with simple substituents in various positions) were previously shown to possess significant biological activities in vitro, markedly anti-mycobacterial and photosynthesis-inhibiting activity. Based on structure-activity relationships (SAR) extracted from previously published series, 25 new anilides of non-substituted pyrazinoic acid (POA), 5-CH
Frontiers in Pharmacology, 2016
Entecavir (ETV) is one of the most potent agents for the treatment of the hepatitis B viral infec... more Entecavir (ETV) is one of the most potent agents for the treatment of the hepatitis B viral infection. The drug is principally eliminated by the kidney. The goal of this study was to investigate the potential of ETV to interact in vitro with the renal SLC transporters hOAT1, hOCT2, hCNT2 and hCNT3. Potential drug-drug interactions of ETV at the renal transporters with antiviral drugs known to be excreted by the kidney (adefovir, tenofovir, cidofovir) as well as transporter-dependent cytotoxicity were also examined. Interactions with the selected transporters along with cytotoxicity were studied in several transiently transfected cellular models using specific substrates and inhibitors. ETV was found to be both a substrate and inhibitor of hOAT1 (IC 50 = 175.3 μM), hCNT2 (IC 50 = 241.9 μM) and hCNT3 (IC 50 = 278.4 μM) transporters, although it interacted with the transporters with relatively low affinities. ETV inhibited the cellular uptake of adefovir, tenofovir, and cidofovir by hOAT1; however, effective inhibition was shown at ETV concentrations exceeding therapeutic levels. In comparison with adefovir, tenofovir, and cidofovir, ETV displayed no transporter-mediated cytotoxicity in cells transfected with hOAT1, hCNT2, and hCNT3. No significant interaction of ETV with hOCT2 was detected. The study demonstrates interactions of ETV with several human renal transporters. For the first time, an interaction of ETV with the hCNTs was proved. We show that the potency of ETV to cause nephrotoxicity and/or clinically significant drug-drug interactions related to the tested transporters is considerably lower than that of adefovir, tenofovir, and cidofovir.
Nuclear Medicine Communications, 2000
The quarterly journal of nuclear medicine : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), 2002
Renal excretion is the preferable elimination pathway of radiopharmaceuticals and/or their metabo... more Renal excretion is the preferable elimination pathway of radiopharmaceuticals and/or their metabolites from the body. The mechanisms of renal excretion involve glomerular filtration, tubular secretion, tubular reabsorption, and kidney metabolism. Radiopharmaceuticals of a molecular weight of up to 60 kDa are ultrafiltrated in the glomeruli at a rate dependent on their protein binding (the rate of glomerular filtration is a product of glomerular filtration rate and free fraction of the agent in plasma). Exclusive excretion by this route is typical for many chelates such us 99mTc-DTPA (diethylenetriaminepentaacetic acid). Some other radiopharmaceuticals are excreted in the renal tubuli into the tubular fluid by carrier-mediated and active processes involving different transport systems. Examples are ortho-iodohippurate and 99mTc-MAG-3 (mercaptoacetyltriglycine). Tubular reabsorption involves either passive diffusion of lipid-soluble radiopharmaceuticals from the glomerular filtrate ba...
Nuclear Medicine and Biology
Introduction Radiolabeled receptor-targeting peptides are a useful tool for the diagnostic imagin... more Introduction Radiolabeled receptor-targeting peptides are a useful tool for the diagnostic imaging and radiotherapy of some malignancies. However, the retention of radioactivity in the kidney may result in renal radiotoxic injury. This study seeks to evaluate the role of endocytic receptor megalin, renal SLC influx transporters and fluid phase endocytosis (FPE) in the cellular accumulation of radiolabeled peptides. Methods In vitro transport cellular studies using megalin ligands (RAP, albumin), fluid phase endocytosis (FPE) inhibitor rottlerin and low temperature were employed to evaluate the transport mechanisms of the peptides. Cells transfected with hOAT1 or hOCT2 were used to analyze the role of these SLC transporters. Somatostatin (177Lu-DOTA-[Tyr3]octreotate, 177Lu-DOTA-[1-Nal3]octreotide), gastrin (177Lu-DOTA-sargastrin) and bombesin (177Lu-DOTA-[Pro1,Tyr4]bombesin, 177Lu-DOTA-[Lys3]bombesin, 177Lu-PCTA-[Lys3]bombesin) analogues were involved in the study. Results RAP, album...
Journal of Nuclear …, 2000
the incorporation of suitablepeptidesequencespermitsthemto exploit efficient routes of renal excr... more the incorporation of suitablepeptidesequencespermitsthemto exploit efficient routes of renal excretion,such as tubular secre tion, therebyoptimizingthe pattem of biodistribution of these radiopharmaceuticals.
Anticancer …, 2010
Background: In this study, two octreotate
European Journal of Drug Metabolism and Pharmacokinetics, 2002
The present study compares distribution and elimination characteristics of 111In-DTPA-D-Phe'-octr... more The present study compares distribution and elimination characteristics of 111In-DTPA-D-Phe'-octreotide and 11IIn-DTPA-L-Phe'-octreotide in rats and evaluated the effect of the replacement of the terminal L-phenylalanine by D-phenylalanine on pharmacokinetic profiles of the radiolabelled peptides. Both agents exhibited rapid radioactivity clearance from the blood and most organs and tissues with no systematic and significant differences in activity accumulation. The long-term retention and high radioactivity concentrations for both compounds under study were found in the kidneys and organs with a high density of somatostatin receptors, such as the pancreas and adrenals. The residence times in these organs were longer for lIIIn-DTPA-D-Phe'-octreotide in comparison with I II In-DTPA-L-Phel-octreotide. The major elimination pathway for both radiolabelled peptides was relatively rapid excretion into the urine. Analysis of the renal handling by an employment of the perfused rat kidney showed that both peptides were eliminated mainly by the mechanism of glomerular filtration. Rat liver perfusion experiments confirmed a very low value of bile clearance of radioactivity for both agents under study.
RSC Advances
A second total synthesis of (+)-hyacinthacine C3 is reported. As a result, structure of the first... more A second total synthesis of (+)-hyacinthacine C3 is reported. As a result, structure of the first synthetically prepared alkaloid is proved to be correct, clearly confirming the inconsistency with the stereochemistry assigned to the natural sample.
Chemical Papers
A new series of hybrid compounds were designed, consisting of anti-AChE and BuChE activity compon... more A new series of hybrid compounds were designed, consisting of anti-AChE and BuChE activity components with an antiinflammatory component. A series of 9-amino-1,2,3,4-tetrahydroacridine and indomethacin derivatives were synthesized. All compounds were created using alkyldiamine with different chain lengths as a linker. Various biological activities were evaluated, including inhibitory activity against AChE and BuChE. The tested compounds showed high inhibitory activities against cholinesterases. The IC 50 values for all compounds ranging from 10 nM to 7 µM. The potency of inhibition was much higher than well-known AChE and BuChE inhibitors (tacrine and donepezil). Compound 3h had the strongest inhibitory activity; kinetic studies showed it to have a mixed-type of acetylcholinesterase inhibition properties. The cytotoxicity of the newly-synthesized compounds against HepG2 (hepatocarcinoma cells) and EA.hy96 (human vein endothelial cells) cell lines was determined using the MTT and MTS tests. All investigated compounds presented similar cytotoxic activity against HepG2 and EA.hy926 cell line, ranged in micromolar values. Compounds with longer linkers showed higher antioxidant activity. The most active compound was 3h. Docking studies confirmed interactions with important regions of AChE and BuChE. Its multifunctional properties, i.e. high activity against AChE and BuChE, antioxidant activity and low cytotoxicity, highlight 3h as a promising agent for the treatment of AD.
Biomolecules
4-aminobenzoic acid (PABA), an essential nutrient for many human pathogens, but dispensable for h... more 4-aminobenzoic acid (PABA), an essential nutrient for many human pathogens, but dispensable for humans, and its derivatives have exhibited various biological activities. In this study, we combined two pharmacophores using a molecular hybridization approach: this vitamin-like molecule and various aromatic aldehydes, including salicylaldehydes and 5-nitrofurfural, via imine bond in one-step reaction. Resulting Schiff bases were screened as potential antimicrobial and cytotoxic agents. The simple chemical modification of non-toxic PABA resulted in constitution of antibacterial activity including inhibition of methicillin-resistant Staphylococcus aureus (minimum inhibitory concentrations, MIC, from 15.62 µM), moderate antimycobacterial activity (MIC ≥ 62.5 µM) and potent broad-spectrum antifungal properties (MIC of ≥ 7.81 µM). Some of the Schiff bases also exhibited notable cytotoxicity for cancer HepG2 cell line (IC50 ≥ 15.0 µM). Regarding aldehyde used for the derivatization of PABA, ...
Naunyn-Schmiedeberg's Archives of Pharmacology
The presented data "a-g" (Fig. 3), "a-e", (Fig. 4) and "a-b" (Fig. 5) located between the figure ... more The presented data "a-g" (Fig. 3), "a-e", (Fig. 4) and "a-b" (Fig. 5) located between the figure number and the text of the caption are redundant. Such data should be deleted. The original article has been corrected.
Naunyn-Schmiedeberg's Archives of Pharmacology
European Journal of Medicinal Chemistry
Molecules
A series of substituted N-benzyl-3-chloropyrazine-2-carboxamides were prepared as positional isom... more 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-(3,4dichlorobenzyl)-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.
Molecules
The resistance among microbes has brought an urgent need for new drugs. Thus, we synthesized a se... more The resistance among microbes has brought an urgent need for new drugs. Thus, we synthesized a series of Schiff bases derived from the sulfa drug sulfadiazine and various salicylaldehydes. The resulting 4-[(2-hydroxybenzylidene)amino]-N-(pyrimidin-2-yl)benzene-sulfonamides were characterized and evaluated against Gram-positive and Gram-negative bacteria, yeasts, moulds, Mycobacterium tuberculosis, nontuberculous mycobacteria (M. kansasii, M. avium) and their cytotoxicity was determined. Among bacteria, the genus Staphylococcus, including methicillin-resistant S. aureus, showed the highest susceptibility, with minimum inhibitory concentration values from 7.81 µM. The growth of Candida sp. and Trichophyton interdigitale was inhibited at concentrations starting from 1.95 µM. 4-[(2,5-Dihydroxybenzylidene)amino]-N-(pyrimidin-2-yl)-benzenesulfonamide was identified as the most selective Schiff base for these strains with no apparent cytotoxicity and a selectivity index higher than 16. With respect to M. tuberculosis and M. kansasii that were inhibited within the range of 8 to 250 µM, unsubstituted 4-[(2-hydroxy-benzylidene)amino]-N-(pyrimidin-2-yl)benzenesulfonamide meets the selectivity requirement. In general, dihalogenation of the salicylic moiety improved the antibacterial and antifungal activity but also increased the cytotoxicity, especially with an increasing atomic mass. Some derivatives offer more advantageous properties than the parent sulfadiazine, thus constituting promising hits for further antimicrobial drug development.
Bioorganic chemistry, 2017
A series of thirty novel N-acetylated fluorophenylalanine-based aromatic amides and esters was sy... more A series of thirty novel N-acetylated fluorophenylalanine-based aromatic amides and esters was synthesized using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or phosphorus trichloride in pyridine. They were characterized by spectral methods and screened against various microbes (Mycobacterium tuberculosis, non-tuberculous mycobacteria, other bacteria, fungi), for their inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and cytotoxicity. All amino acids derivatives revealed a moderate inhibition of both cholinesterases with IC50 values for AChE and BChE of 57.88-130.75µM and 8.25-289.0µM, respectively. Some derivatives were comparable or superior to rivastigmine, an established drug. Phenyl 2-acetamido-3-(4-fluorophenyl)propanoate was identified as the selective and most potent inhibitor of BChE. The esterification and amidation of parent acids led to an improved BChE inhibition. The esters are better inhibitors of BChE than the amides. The introduction ...
Bioorganic & medicinal chemistry, Jan 15, 2017
Bioorganic & medicinal chemistry, Jan 15, 2017
Salicylanilides have proved their activity against tuberculosis (TB). One weak electron-withdrawi... more Salicylanilides have proved their activity against tuberculosis (TB). One weak electron-withdrawing substituent is favored at the salicylic part, specially Cl or Br atoms at positions 4 or 5. On the other hand, the antimycobacterial activity of salicylanilides is negatively affected when a strong electron-withdrawing substituent (NO2) is present at the same positions. Herein we describe the synthesis and characterization of novel salicylanilides possessing two weak electron-withdrawing groups (halogen atoms) at their salicylic part and compare their antitubercular activity with their monohalogenated analogues. All dihalogenated derivatives proved to possess antitubercular activity at a very narrow micromolar range (MIC=1-4μM), similar with their most active monohalogenated analogues. More importantly, the most active final molecules were further screened against multidrug resistant strains and found to inhibit their growth at the range of 0.5-4μM.
Chemical Papers, 2015
N-Phenylpyrazine-2-carboxamides (anilides of pyrazinoic acids with simple substituents in various... more N-Phenylpyrazine-2-carboxamides (anilides of pyrazinoic acids with simple substituents in various positions) were previously shown to possess significant biological activities in vitro, markedly anti-mycobacterial and photosynthesis-inhibiting activity. Based on structure-activity relationships (SAR) extracted from previously published series, 25 new anilides of non-substituted pyrazinoic acid (POA), 5-CH
Frontiers in Pharmacology, 2016
Entecavir (ETV) is one of the most potent agents for the treatment of the hepatitis B viral infec... more Entecavir (ETV) is one of the most potent agents for the treatment of the hepatitis B viral infection. The drug is principally eliminated by the kidney. The goal of this study was to investigate the potential of ETV to interact in vitro with the renal SLC transporters hOAT1, hOCT2, hCNT2 and hCNT3. Potential drug-drug interactions of ETV at the renal transporters with antiviral drugs known to be excreted by the kidney (adefovir, tenofovir, cidofovir) as well as transporter-dependent cytotoxicity were also examined. Interactions with the selected transporters along with cytotoxicity were studied in several transiently transfected cellular models using specific substrates and inhibitors. ETV was found to be both a substrate and inhibitor of hOAT1 (IC 50 = 175.3 μM), hCNT2 (IC 50 = 241.9 μM) and hCNT3 (IC 50 = 278.4 μM) transporters, although it interacted with the transporters with relatively low affinities. ETV inhibited the cellular uptake of adefovir, tenofovir, and cidofovir by hOAT1; however, effective inhibition was shown at ETV concentrations exceeding therapeutic levels. In comparison with adefovir, tenofovir, and cidofovir, ETV displayed no transporter-mediated cytotoxicity in cells transfected with hOAT1, hCNT2, and hCNT3. No significant interaction of ETV with hOCT2 was detected. The study demonstrates interactions of ETV with several human renal transporters. For the first time, an interaction of ETV with the hCNTs was proved. We show that the potency of ETV to cause nephrotoxicity and/or clinically significant drug-drug interactions related to the tested transporters is considerably lower than that of adefovir, tenofovir, and cidofovir.