Salicylanilide pyrazinoates inhibit in vitro multidrug-resistant Mycobacterium tuberculosis strains, atypical mycobacteria and isocitrate lyase
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24333643
DOI
10.1016/j.ejps.2013.12.001
PII: S0928-0987(13)00458-2
Knihovny.cz E-resources
- Keywords
- Antimycobacterial activity, In vitro activity, Isocitrate lyase inhibition, Multidrug-resistant tuberculosis, Pyrazine-2-carboxylic acid ester, Salicylanilide ester,
- MeSH
- Anti-Bacterial Agents pharmacology MeSH
- Isocitrate Lyase antagonists & inhibitors MeSH
- Microbial Sensitivity Tests MeSH
- Drug Resistance, Multiple, Bacterial MeSH
- Mycobacterium tuberculosis drug effects genetics MeSH
- Nontuberculous Mycobacteria drug effects growth & development MeSH
- Pyrazinamide analogs & derivatives pharmacology MeSH
- Salicylanilides pharmacology MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Anti-Bacterial Agents MeSH
- Isocitrate Lyase MeSH
- Pyrazinamide MeSH
- pyrazinoic acid MeSH Browser
- salicylanilide MeSH Browser
- Salicylanilides MeSH
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.
References provided by Crossref.org
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