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

Martin Krátký, Ondřej Janďourek, Zsuzsa Baranyai, Eva Novotná, Jiřina Stolaříková, Sz. Bősze, Jarmila Vinšová

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number111578
JournalEuropean Journal of Medicinal Chemistry
Volume181
DOIs
Publication statusPublished - Nov 1 2019

Fingerprint

Carbamates
Salicylanilides
Toxicity
Isocitrate Lyase
Mycobacterium tuberculosis
Nontuberculous Mycobacteria
Hep G2 Cells
Cytostatic Agents
Cytotoxicity
Pharmaceutical Preparations
Mycobacterium kansasii
Derivatives
Mycobacterium smegmatis
Mycobacterium avium
Microbial Sensitivity Tests
Mycobacterium
Scaffolds
Maintenance
Enzymes
Infection

Keywords

  • Antimycobacterial activity
  • Carbamate
  • Cytotoxicity
  • Multi-targeting
  • Mycobacterium tuberculosis
  • Salicylanilide

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Phenolic N-monosubstituted carbamates : Antitubercular and toxicity evaluation of multi-targeting compounds. / Krátký, Martin; Janďourek, Ondřej; Baranyai, Zsuzsa; Novotná, Eva; Stolaříková, Jiřina; Bősze, Sz.; Vinšová, Jarmila.

In: European Journal of Medicinal Chemistry, Vol. 181, 111578, 01.11.2019.

Research output: Contribution to journalArticle

Krátký, Martin ; Janďourek, Ondřej ; Baranyai, Zsuzsa ; Novotná, Eva ; Stolaříková, Jiřina ; Bősze, Sz. ; Vinšová, Jarmila. / Phenolic N-monosubstituted carbamates : Antitubercular and toxicity evaluation of multi-targeting compounds. In: European Journal of Medicinal Chemistry. 2019 ; Vol. 181.
@article{b7af42e670534eb8be59224f88a68c81,
title = "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.",
keywords = "Antimycobacterial activity, Carbamate, Cytotoxicity, Multi-targeting, Mycobacterium tuberculosis, Salicylanilide",
author = "Martin Kr{\'a}tk{\'y} and Ondřej Janďourek and Zsuzsa Baranyai and Eva Novotn{\'a} and Jiřina Stolař{\'i}kov{\'a} and Sz. Bősze and Jarmila Vinšov{\'a}",
year = "2019",
month = "11",
day = "1",
doi = "10.1016/j.ejmech.2019.111578",
language = "English",
volume = "181",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - Phenolic N-monosubstituted carbamates

T2 - Antitubercular and toxicity evaluation of multi-targeting compounds

AU - Krátký, Martin

AU - Janďourek, Ondřej

AU - Baranyai, Zsuzsa

AU - Novotná, Eva

AU - Stolaříková, Jiřina

AU - Bősze, Sz.

AU - Vinšová, Jarmila

PY - 2019/11/1

Y1 - 2019/11/1

N2 - 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.

AB - 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.

KW - Antimycobacterial activity

KW - Carbamate

KW - Cytotoxicity

KW - Multi-targeting

KW - Mycobacterium tuberculosis

KW - Salicylanilide

UR - http://www.scopus.com/inward/record.url?scp=85070191479&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070191479&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2019.111578

DO - 10.1016/j.ejmech.2019.111578

M3 - Article

AN - SCOPUS:85070191479

VL - 181

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

M1 - 111578

ER -