Phenolic N-monosubstituted carbamates: Antitubercular and toxicity evaluation of multi-targeting compounds
Language English Country France Media print-electronic
Document type Journal Article
PubMed
31401536
DOI
10.1016/j.ejmech.2019.111578
PII: S0223-5234(19)30712-3
Knihovny.cz E-resources
- Keywords
- Antimycobacterial activity, Carbamate, Cytotoxicity, Multi-targeting, Mycobacterium tuberculosis, Salicylanilide,
- MeSH
- Antitubercular Agents chemical synthesis chemistry pharmacology MeSH
- Hep G2 Cells MeSH
- Phenols chemical synthesis chemistry pharmacology MeSH
- Isocitrate Lyase antagonists & inhibitors metabolism MeSH
- Carbamates chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Mycobacterium tuberculosis drug effects enzymology MeSH
- Salicylanilides chemical synthesis chemistry pharmacology MeSH
- Tuberculosis drug therapy MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Antitubercular Agents MeSH
- Phenols MeSH
- Isocitrate Lyase MeSH
- Carbamates MeSH
- salicylanilide MeSH Browser
- Salicylanilides 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.
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