Regional Institute of Public Health in Ostrava

Ostrava, Czech Republic

Regional Institute of Public Health in Ostrava

Ostrava, Czech Republic
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Kratky M.,Charles University | Vinsova J.,Charles University | Stolarikova J.,Regional Institute of Public Health in Ostrava
Bioorganic and Medicinal Chemistry | Year: 2017

Twenty-four 2-(4-oxo-2-thioxothiazolidin-3-yl)acetic acid (rhodanine-3-acetic acid)-based amides, esters and 5-arylalkylidene derivatives were synthesized, characterized and evaluated as potential antimicrobial agents against a panel of bacteria, mycobacteria and fungi. All of the derivatives were active against mycobacteria. N-(4-Chlorophenyl)-2-[5-(2-hydroxybenzylidene)-4-oxo-2-thioxothiazolidin-3-yl]acetamide demonstrated the highest activity against Mycobacterium tuberculosis with minimum inhibitory concentrations (MIC) of 8-16. μM. Non-tuberculous mycobacteria were the most susceptible to 2-[5-(2-hydroxybenzylidene)-4-oxo-2-thioxothiazolidin-3-yl]acetic acids (MIC values ≥32. μM). The highest antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus exhibited 4-(trifluoromethyl)phenyl 2-(4-oxo-2-thioxothiazolidin-3-yl)acetate (MIC. ≥. 15.62. μM). Several structure-activity relationships were identified. The activity against Gram-negative and fungal pathogens was marginal. © 2017 Elsevier Ltd.


Kratky M.,Charles University | Vinsova J.,Charles University | Novotna E.,Charles University | Stolarikova J.,Regional Institute of Public Health in Ostrava
European Journal of Pharmaceutical Sciences | Year: 2014

The development of antimicrobial agents represents an up-to-date topic. This study investigated in vitro antimycobacterial activity, mycobacterial isocitrate lyase inhibition and cytotoxicity of salicylanilide pyrazinoates. They may be considered being mutual prodrugs of both antimycobacterial active salicylanilides and pyrazinoic acid (POA), an active metabolite of pyrazinamide, in which these esters are likely hydrolysed without presence of pyrazinamidase/nicotinamidase. Minimum inhibitory concentrations (MICs) of the esters were within the range 0.5-8 μmol/l for Mycobacterium tuberculosis and 1-32 μmol/l for nontuberculous mycobacteria (Mycobacterium avium, Mycobacterium kansasii). All esters showed a weak inhibition (8-17%) of isocitrate lyase at the concentration of 10 μmol/l. The most active pyrazinoates showed MICs for multidrug-resistant tuberculosis strains in the range of 0.125-2 μmol/l and no cross-resistance with clinically used drugs, thus being the most in vitro efficacious salicylanilide esters with 4-chloro-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl pyrazine-2-carboxylate superiority (MICs ≤ 0.25 μmol/l). This promising activity is likely due to an additive or synergistic effect of released POA and salicylanilides. Selectivity indexes for the most active salicylanilide pyrazinoates ranged up to 64, making some derivatives being attractive candidates for the next research; 4-bromo-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl pyrazine-2-carboxylate showed the most convenient toxicity profile. © 2013 Elsevier B.V. All rights reserved.


Kratky M.,Charles University | Stolarikova J.,Regional Institute of Public Health in Ostrava | Vinsova J.,Charles University
Molecules | Year: 2017

Infections caused by Mycobacterium tuberculosis (Mtb.) and nontuberculous mycobacteria (NTM) are considered to be a global health problem; current therapeutic options are limited. Sulfonamides have exhibited a wide range of biological activities including those against mycobacteria. Based on the activity of 4-(3-heptylureido)-N-(5-methylisoxazol-3-yl)benzenesulfonamide against NTM, we designed a series of homologous sulfamethoxazole-based n-Alkyl ureas (C1-C12), as well as several related ureas and an oxalamide. Fifteen ureas and one oxalamide were synthesized by five synthetic procedures and characterized. They were screened for their activity against Mtb. and three NTM strains (M. avium, M. kansasii). All of them share antimycobacterial properties with minimum inhibitory concentration (MIC) values starting from 2 μM. The highest activity showed 4,40-[carbonylbis(azanediyl)]bis[N-(5-methylisoxazol-3-yl)benzenesulfonamide] with MIC of 2-62.5 μM(i.e., 1.07-33.28 μg/mL). Among n-Alkyl ureas, methyl group is optimal for the inhibition of both Mtb. and NTM. Generally, longer alkyls led to increased MIC values, heptyl being an exception for NTM. Some of the novel derivatives are superior to parent sulfamethoxazole. Several urea and oxalamide derivatives are promising antimycobacterial agents with low micromolar MIC values. © 2017 by the authors.


Kratky M.,Charles University | Vinsova J.,Charles University | Buchta V.,Charles University | Horvati K.,Eötvös Loránd University | And 2 more authors.
European Journal of Medicinal Chemistry | Year: 2010

Eleven halogenated (S)-2-(phenylcarbamoyl)phenyl 2-acetamido-3- phenylpropanoates (3a-3k) were designed and synthesized as potential antimicrobial agents. They were evaluated in vitro against some mycobacterial, bacterial and fungal strains. These compounds were active against drug-sensitive and atypical mycobacterial strains with general MIC values from 0.25 to 16 μmol/L. The most active compounds were (S)-4-chloro-2-(4-(trifluoromethyl) phenylcarbamoyl)phenyl 2-acetamido-3-phenylpropanoate (3i) and (S)-4-bromo-2-(4-(trifluoromethyl)phenylcarbamoyl)phenyl 2-acetamido-3- phenylpropanoate (3k) which exhibited activity against MDR and XDR-TB strains with MICs from 1 to 2 μmol/L. 3k was shown to be less cytotoxic with higher IC50. Some compounds exhibited low MICs on Gram-positive bacteria (MICs ≥ 0.98 μmol/L) and on fungi (MICs ≥ 3.9 μmol/L). © 2010 Elsevier Masson SAS. All rights reserved.


Kratky M.,Charles University | Vinsova J.,Charles University | Rodriguez N.G.,Charles University | Stolarikova J.,Regional Institute of Public Health in Ostrava
Molecules | Year: 2012

A series of eighteen novel esters of salicylanilides with benzenesulfonic acid were designed, synthesized and characterized by IR, 1H-NMR and 13C-NMR. They were evaluated in vitro as potential antimycobacterial agents towards Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii. In general, the minimum inhibitory concentrations range from 1 to 500 μmol/L. The most active compound against M. tuberculosis was 4-chloro-2-(4-(trifluoromethyl)phenylcarbamoyl)- phenyl benzenesulfonate, with MIC of 1 μmol/L and towards M. kansasii its isomer 5-chloro- 2-(4-(trifluoromethyl)phenylcarbamoyl)phenyl benzenesulfonate (MIC of 2-4 μmol/L). M. avium was the less susceptible strain. However, generally, salicylanilide benzenesulfonates did not surpass the activity of other salicylanilide esters with carboxylic acids. © 2012 by the authors.


Vinsova J.,Charles University | Kozic J.,Charles University | Kratky M.,Charles University | Stolarikova J.,Regional Institute of Public Health in Ostrava | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2014

A series of 27 salicylanilide diethyl phosphates was prepared as a part of our on-going search for new antimicrobial active drugs. All compounds exhibited in vitro activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium strains, with minimum inhibitory concentration (MIC) values of 0.5-62.5 μmol/L. Selected salicylanilide diethyl phosphates also inhibit multidrug-resistant tuberculous strains at the concentration of 1 μmol/L. Salicylanilide diethyl phosphates also exhibited mostly the activity against Gram-positive bacteria (MICs ≥1.95 μmol/L), whereas their antifungal activity is significantly lower. The IC50 values for Hep G2 cells were within the range of 1.56-33.82 μmol/L, but there is no direct correlation with MICs for mycobacteria. © 2013 Elsevier Ltd. All rights reserved.


Kratky M.,Charles University | Vinsova J.,Charles University | Novotna E.,Charles University | Mandikova J.,Charles University | And 2 more authors.
Molecules | Year: 2013

The development of novel antimicrobial agents represents a timely research topic. Eighteen salicylanilide 4-(trifluoromethyl)benzoates were evaluated against Mycobacterium tuberculosis, M. avium and M. kansasii, eight bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA) and for the inhibition of mycobacterial isocitrate lyase. Some compounds were further screened against drug-resistant M. tuberculosis and for their cytotoxicity. Minimum inhibitory concentrations (MICs) for all mycobacterial strains were within 0.5-32 μmol/L, with 4-chloro-2-[4- (trifluoromethyl)phenylcarbamoyl] phenyl 4-(trifluoromethyl)benzoate superiority. Grampositive bacteria including MRSA were inhibited with MICs ≥ 0.49 μmol/L, while Gramnegative ones were much less susceptible. Salicylanilide 4-(trifluoromethyl)benzoates showed significant antibacterial properties, for many strains being comparable to standard drugs (isoniazid, benzylpenicillin) with no cross-resistance. All esters showed mild inhibition of mycobacterial isocitrate lyase and four compounds were comparable to 3-nitropropionic acid without a direct correlation between in vitro MICs and enzyme inhibition. © 2013 by the authors.


Kratky M.,Charles University | Vinova J.,Charles University | Novotna E.,Charles University | Mandikova J.,Charles University | And 7 more authors.
Tuberculosis | Year: 2012

The global burden of tuberculosis, its health and socio-economic impacts, the presence of drug-resistant forms and a potential threat of latent tuberculosis should serve as a strong impetus for the development of novel antituberculosis agents. We reported the in vitro activity of salicylanilide benzoates and pyrazine-2-carboxylates against Mycobacterium tuberculosis (minimum inhibitory concentrations as low as 0.5 μmol/L). Nineteen salicylanilide derivatives with mostly good antimycobacterial activity were evaluated for the inhibition of two essential mycobacterial enzymes, methionine aminopeptidase and isocitrate lyase, which are necessary for the maintenance of the latent tuberculosis infection. Salicylanilide derivatives act as moderate inhibitors of both mycobacterial and human methionine aminopeptidase and they also affect the function of mycobacterial isocitrate lyase. 4-Bromo-2-[4- (trifluoromethyl)phenylcarbamoyl]phenyl pyrazine-2-carboxylate was the most potent inhibitor of mycobacterial methionine aminopeptidase (41% inhibition at 10 μmol/L) and exhibited the highest selectivity. 5-Chloro-2-hydroxy-N-[4- (trifluoromethyl)phenyl]benzamide and 4-chloro-2-[4-(trifluoromethyl) phenylcarbamoyl]phenyl pyrazine-2-carboxylate caused 59% inhibition of isocitrate lyase at 100 μmol/L concentration and (S)-4-bromo-2-[4- (trifluoromethyl)phenylcarbamoyl]phenyl 2-acetamido-3-phenylpropanoate produced 22% inhibition at 10 μmol/L; this rate is approximately comparable to 3-nitropropionic acid. Inhibition of those enzymes contributes at least in part to the antimicrobial activity of the compounds. © 2012 Elsevier Ltd. All rights reserved.


Kratky M.,Charles University | Vinsova J.,Charles University | Volkova M.,Charles University | Buchta V.,Charles University | And 2 more authors.
European Journal of Medicinal Chemistry | Year: 2012

A series of novel sulfonamides containing 5-chloro-2-hydroxybenzaldehyde or 5-chloro-2-hydroxybenzoic acid scaffolds were designed, synthesized and characterized by IR, 1H NMR and 13C NMR. All ten target synthesized derivatives and starting sulfonamides were evaluated in vitro for the activity against Gram-positive and Gram-negative bacteria, fungi, Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium kansasii. The most active compound against methicillin-sensitive and methicillin-resistant Staphyloccoccus aureus was 5-chloro-N-{4-[N-(4,6-dimethylpyrimidin-2-yl) sulfamoyl]phenyl}-2-hydroxybenzamide with MIC 15.62-31.25 μmol/L. 4-Amino-N-(thiazol-2-yl)benzenesulfonamide and 4-(5-chloro-2- hydroxybenzylideneamino)-N-(thiazol-2-yl)benzenesulfonamide have shown the best activity against M. kansasii at the concentrations of 1-4 μmol/L. The efficacy against other strains was weaker and the studied derivatives exhibited almost none antifungal potency. © 2012 Elsevier Masson SAS. All rights reserved.


Kratky M.,Charles University | Vinsova J.,Charles University | Stolarikova J.,Regional Institute of Public Health in Ostrava
Molecules | Year: 2012

The increasing emergence especially of drug-resistant tuberculosis has led to a strong demand for new anti-tuberculosis drugs. Eighteen salicylanilide benzoates were evaluated for their inhibition potential against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii; minimum inhibitory concentration values ranged from 0.5 to 16 μmol/L. The most active esters underwent additional biological assays. Four benzoates inhibited effectively the growth of five multidrug-resistant strains and one extensively drug-resistant strain of M. tuberculosis at low concentrations (0.25-2 μmol/L) regardless of the resistance patterns. The highest rate of multidrug-resistant mycobacteria inhibition expressed 4-chloro-2-[4- (trifluoromethyl)-phenylcarbamoyl]phenyl benzoate (0.25-1 μmol/L). Unfortunately, the most potent esters were still considerably cytotoxic, although mostly less than their parent salicylanilides. © 2012 by the authors.

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