Novel antimycobacterial drugs are needed, especially those with dual activity against both actively growing and non-replicating subpopulations of mycobacteria. Isocitrate lyase (ICL) is one of proposed targets and this enzyme is inhibited by itaconic acid. That is why we have designed and prepared sixteen amides of itaconic acid and various anilines and amine antimicrobial drugs to evaluate them as potential inhibitors of ICL and antimycobacterial agents. N-Phenylitaconamides were prepared from itaconic anhydride and substituted anilines (yields 57-99%). They were characterized and evaluated against mycobacterial ICL and against actively growing mycobacteria (M. tuberculosis H37Rv, M. avium, two strains of M. kansasii). All derivatives showed antimycobacterial efficacy with minimum inhibitory concentrations starting from 125 µM. M. kansasii was the most susceptible species. Itaconamides derived from sulfonamides or p-aminosalicylic acid were optimal for activity against extracellular mycobacteria. ICL1 was significantly inhibited by two compounds, with 2-methylene-4-[(4-nitrophenyl)amino]-4-oxobutanoic acid 1k being the most potent (36% inhibition at 10 µM), which was also more efficient than two comparators. Molecular docking revealed its mode of binding to the enzyme. Using in silico tools, physicochemical properties and structural features for drug-likeness and gastrointestinal absorption were evaluated.

• Klíčová slova
• Amides, Antimycobacterial activity, Enzyme inhibition, Isocitrate lyase, Itaconic acid, Molecular docking,
• MeSH
• aniliny MeSH
• antibakteriální látky farmakologie   MeSH
• isocitrátlyasa * chemie   metabolismus   MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium tuberculosis * metabolismus   MeSH
• simulace molekulového dockingu MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aniliny MeSH
• antibakteriální látky MeSH
• isocitrátlyasa * MeSH

The research of novel antimycobacterial drugs represents a cutting-edge topic. Thirty phenolic N-monosubstituted carbamates, derivatives of salicylanilides and 4-chlorophenol, were investigated against Mycobacterium tuberculosis H37Ra, H37Rv including multidrug- and extensively drug-resistant strains, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium aurum and Mycobacterium smegmatis as representatives of nontuberculous mycobacteria (NTM) and for their cytotoxic and cytostatic properties in HepG2 cells. Since salicylanilides are multi-targeting compounds, we determined also inhibition of mycobacterial isocitrate lyase, an enzyme involved in the maintenance of persistent tuberculous infection. The minimum inhibitory concentrations were from ≤0.5 μM for both drug-susceptible and resistant M. tuberculosis and from ≤0.79 μM for NTM with no cross-resistance to established drugs. The presence of halogenated salicylanilide scaffold results into an improved activity. We have verified that isocitrate lyase is not a key target, presented carbamates showed only moderate inhibitory activity (up to 18% at a concentration of 10 μM). Most of the compounds showed no cytotoxicity for HepG2 cells and some of them were without cytostatic activity. Cytotoxicity-based selectivity indexes of several carbamates for M. tuberculosis, including resistant strains, were higher than 125, thus favouring some derivatives as promising features for future development.

• Klíčová slova
• Antimycobacterial activity, Carbamate, Cytotoxicity, Multi-targeting, Mycobacterium tuberculosis, Salicylanilide,
• MeSH
• antituberkulotika chemická syntéza   chemie   farmakologie   MeSH
• buňky Hep G2 MeSH
• fenoly chemická syntéza   chemie   farmakologie   MeSH
• isocitrátlyasa antagonisté a inhibitory   metabolismus   MeSH
• karbamáty chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• Mycobacterium tuberculosis účinky léků   enzymologie   MeSH
• salicylanilidy chemická syntéza   chemie   farmakologie   MeSH
• tuberkulóza farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antituberkulotika MeSH
• fenoly MeSH
• isocitrátlyasa MeSH
• karbamáty MeSH
• salicylanilide MeSH Prohlížeč
• salicylanilidy MeSH

The development of novel antimicrobial drugs represents a cutting edge research topic. In this study, 20 salicylanilide N,N-disubstituted carbamates and thiocarbamates were designed, synthesised and characterised by IR, (1)H NMR and (13)C NMR. The compounds were evaluated in vitro as potential antimicrobial agents against Mycobacterium tuberculosis and nontuberculous mycobacteria (Mycobacterium avium and Mycobacterium kansasii) as well as against eight bacterial and fungal strains. Additionally, we investigated the inhibitory effect of these compounds on mycobacterial isocitrate lyase and cellular toxicity. The minimum inhibitory concentrations (MICs) against mycobacteria were from 4 μM for thiocarbamates and from 16 μM for carbamates. Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, were inhibited with MICs from 0.49 μM by thiocarbamates, whilst Gram-negative bacteria and most of the fungi did not display any significant susceptibility. All (thio)carbamates mildly inhibited isocitrate lyase (up to 22%) at a concentration of 10 μM. The (thio)carbamoylation of the parent salicylanilides led to considerably decreased cytotoxicity and thus improved the selectivity indices (up to 175). These values indicate that some derivatives are attractive candidates for future research.

• Klíčová slova
• Antimicrobial activity, Antimycobacterial activity, Cytotoxicity, Isocitrate lyase inhibition, Salicylanilide carbamate, Salicylanilide thiocarbamate,
• MeSH
• antiinfekční látky chemická syntéza   chemie   farmakologie   MeSH
• buňky Hep G2 MeSH
• grampozitivní bakterie účinky léků   MeSH
• houby účinky léků   MeSH
• isocitrátlyasa antagonisté a inhibitory   metabolismus   MeSH
• karbamáty chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• methicilin rezistentní Staphylococcus aureus účinky léků   MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium avium účinky léků   MeSH
• Mycobacterium kansasii účinky léků   MeSH
• salicylanilidy chemie   MeSH
• thiokarbamáty chemická syntéza   chemie   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiinfekční látky MeSH
• isocitrátlyasa MeSH
• karbamáty MeSH
• salicylanilide MeSH Prohlížeč
• salicylanilidy MeSH
• thiokarbamáty MeSH

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. Gram-positive bacteria including MRSA were inhibited with MICs ³ 0.49 μmol/L, while Gram-negative 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.

• MeSH
• antibakteriální látky farmakologie   MeSH
• benzoáty farmakologie   MeSH
• dusíkaté sloučeniny farmakologie   MeSH
• isocitrátlyasa antagonisté a inhibitory   metabolismus   MeSH
• methicilin rezistentní Staphylococcus aureus účinky léků   MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium avium účinky léků   MeSH
• Mycobacterium kansasii účinky léků   MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• propionáty farmakologie   MeSH
• salicylanilidy farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3-nitropropionic acid MeSH Prohlížeč
• antibakteriální látky MeSH
• benzoáty MeSH
• dusíkaté sloučeniny MeSH
• isocitrátlyasa MeSH
• propionáty MeSH
• salicylanilide MeSH Prohlížeč
• salicylanilidy MeSH

A new series of N-(3/4-substituted phenyl) 4/5-chloro-2-methoxybenzamides and their thioxo analogues have been synthesised and evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv, as well as the two atypical strains Mycobacterium kansasii and Mycobacterium avium. Five of the most active compounds were evaluated for cytotoxicity and their ability to inhibit mycobacterial isocitrate lyase, which is responsible for latent survival of Mycobacterium. The results showed that benzthioanilides were more active than the corresponding benzanilides. The most active compound, 4-chloro-2-methoxy-N-(3,4-dichlorophenyl)benzothioamide (4e), had a minimal inhibition concentration (MIC) against M. tuberculosis of 2 μmol L(-1), which was better than the activity of the previously published corresponding salicylanilide.

• MeSH
• anilidy chemická syntéza   chemie   farmakologie   MeSH
• antibakteriální látky chemická syntéza   chemie   farmakologie   MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• buňky Hep G2 MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• isocitrátlyasa antagonisté a inhibitory   metabolismus   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium avium účinky léků   MeSH
• Mycobacterium kansasii účinky léků   MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anilidy MeSH
• antibakteriální látky MeSH
• antitumorózní látky MeSH
• inhibitory enzymů MeSH
• isocitrátlyasa MeSH

A new series of 2-methoxy-2'-hydroxybenzanilide derivatives and their thioxo analogues have been synthesised and characterised by IR, NMR and elemental analysis. These compounds were investigated for their in vitro antimycobacterial activities against Mycobacterium tuberculosis 331/88, Mycobacterium avium 330/88, Mycobacterium kansasii 235/80, clinically isolated M. kansasii 6509/96 and the ability to act as in vitro isocitrate lyase inhibitors. The best ICL inhibitors were two compounds from the thiobenzanilide group (8f, 8m), which exhibited an inhibition potential that was equal to the standard compound, 3-nitropropionic acid. In addition, the best antimycobacterial properties were exhibited by benzanilide derivatives 6h, 6k and 6l with 5-Cl and 4' or 5' Cl/Br substitution. For all the thiobenzanilide derivatives tested, two conformers were observed in the NMR spectra, which is most likely due to the hindered rotation of the C-N bond.

• MeSH
• anilidy chemická syntéza   chemie   farmakologie   MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• benzoxazoly chemická syntéza   chemie   farmakologie   MeSH
• buňky Hep G2 MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• isocitrátlyasa antagonisté a inhibitory   metabolismus   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• Mycobacterium účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2-methoxy-2'-hydroxybenzanilide MeSH Prohlížeč
• anilidy MeSH
• antitumorózní látky MeSH
• benzoxazoly MeSH
• inhibitory enzymů MeSH
• isocitrátlyasa MeSH

Isocitrate lyase plays a key role for survival of Mycobacterium tuberculosis in the latent form during a chronic stage of infection. This enzyme is important for M. tuberculosis during steady stage growth when it converts isocitrate to succinate and glyoxylate. Then, the glyoxylate is condensed with acetyl-CoA to form malate by malate synthase. The carbon conserving glyoxylate pathway has not been observed in mammals; therefore, it has been determined as a potential drug target for discovery of a new antituberculosis agent. Novel active molecules should shorten the duration of therapy, prevent resistance development and eliminate latent disease. The review summarizes recent progresses in isocitrate lyase inhibitors, overviews structural analogues of several metabolic intermediates (3-nitropropionate, 3-bromopyruvate, itaconate, itaconic anhydride), peptide inhibitors, and recently developed inhibitors with various chemical structures. The largest inhibitory activity against isocitrate lyase (IC(50) of 0.10 ± 0.01 μM) and concomitantly a significant antimycobacterial activity has been presented by fluoroquinolone derivative 1-cyclopropyl-7-[3,5-dimethyl-4-(3-nitropropanoyl)piperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which has incorporated 3-nitropropionyl group as one of the structural analogue of succinate, a metabolic intermediate.

• MeSH
• antituberkulotika chemická syntéza   chemie   metabolismus   MeSH
• bakteriální proteiny antagonisté a inhibitory   metabolismus   MeSH
• fluorochinolony chemická syntéza   chemie   metabolismus   MeSH
• inhibitory enzymů chemická syntéza   chemie   metabolismus   MeSH
• isocitrátlyasa antagonisté a inhibitory   metabolismus   MeSH
• Mycobacterium tuberculosis enzymologie   MeSH
• nukleotidy chemie   metabolismus   MeSH
• peptidy chemie   metabolismus   MeSH
• vazba proteinů MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antituberkulotika MeSH
• bakteriální proteiny MeSH
• fluorochinolony MeSH
• inhibitory enzymů MeSH
• isocitrátlyasa MeSH
• nukleotidy MeSH
• peptidy MeSH

An increase in Brestan concentration in nutrient media decreased the content of protein, phosphorus, total ribonucleic acid, activity of pyruvate carboxylase and isocitrate lyase in cells of Saccharomyces cerevisiae parent strain and respiratory deficient (RD) mutant while the trehalose content increased. The respiration quotient value for the RD mutant was higher than for the parent strain. The RD mutant lacked cytochrome aa3; cytochrome c and b contents were lower than those of the parent strain.

• MeSH
• cytochromy metabolismus   MeSH
• fermentace MeSH
• fosfor metabolismus   MeSH
• fungální RNA metabolismus   MeSH
• fungicidy průmyslové farmakologie   MeSH
• isocitrátlyasa metabolismus   MeSH
• organocínové sloučeniny farmakologie   MeSH
• pyruvátkarboxylasa metabolismus   MeSH
• Saccharomyces cerevisiae - proteiny metabolismus   MeSH
• Saccharomyces cerevisiae účinky léků   genetika   růst a vývoj   MeSH
• spotřeba kyslíku účinky léků   MeSH
• trehalosa metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytochromy MeSH
• fosfor MeSH
• fungální RNA MeSH
• fungicidy průmyslové MeSH
• isocitrátlyasa MeSH
• organocínové sloučeniny MeSH
• phentin acetate MeSH Prohlížeč
• pyruvátkarboxylasa MeSH
• Saccharomyces cerevisiae - proteiny MeSH
• trehalosa MeSH

Methylotrophic bacteria, Gram-positive, with the serine pathway, were shown to have their growth inhibited by 0.5% glycine. The effects of this amino acid on individual enzyme activities were studied in wild and mutant strains of Micrococcus varians and Bacillus licheniformis. The enzymes studied were glycerate dehydrogenase (EC 1.1.1.29), isocitrate lyase (EC 4.1.3.1), serine hydroxymethyltransferase (EC 2.1.2.1) and glycine--oxaloacetate aminotransferase (EC 2.6.1.35). The last-named enzyme was found to be inhibited, the kinetic constants having been determined for two strain types.

• MeSH
• Bacillus genetika   metabolismus   MeSH
• glycin farmakologie   MeSH
• glycinhydroxymethyltransferasa metabolismus   MeSH
• isocitrátlyasa metabolismus   MeSH
• karbohydrátdehydrogenasy metabolismus   MeSH
• kyseliny glycerové metabolismus   MeSH
• methanol metabolismus   MeSH
• Micrococcus genetika   metabolismus   MeSH
• mutace * MeSH
• serin metabolismus   MeSH
• transaminasy metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Glycerate dehydrogenase MeSH Prohlížeč
• glycin MeSH
• glycine-oxaloacetate aminotransferase MeSH Prohlížeč
• glycinhydroxymethyltransferasa MeSH
• isocitrátlyasa MeSH
• karbohydrátdehydrogenasy MeSH
• kyseliny glycerové MeSH
• methanol MeSH
• serin MeSH
• transaminasy MeSH