Phenolic N-monosubstituted carbamates: Antitubercular and toxicity evaluation of multi-targeting compounds.

Abstract

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.

• Authors: Martin Krátký, Ondřej Janďourek, Zsuzsa Baranyai, Eva Novotná, Jiřina Stolaříková, Szilvia Bősze, Jarmila Vinšová
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 181 Pg. 111578 (Nov 01 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 31401536 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antitubercular Agents
• Carbamates
• Phenols
• Salicylanilides
• Isocitrate Lyase
• salicylanilide

Topics

• Antitubercular Agents (chemical synthesis, chemistry, pharmacology)
• Carbamates (chemical synthesis, chemistry, pharmacology)
• Hep G2 Cells
• Humans
• Isocitrate Lyase (antagonists & inhibitors, metabolism)
• Mycobacterium tuberculosis (drug effects, enzymology)
• Phenols (chemical synthesis, chemistry, pharmacology)
• Salicylanilides (chemical synthesis, chemistry, pharmacology)
• Tuberculosis (drug therapy)