Combating highly resistant emerging pathogen Mycobacterium abscessus and Mycobacterium tuberculosis with novel salicylanilide esters and carbamates

Zsuzsa Baranyai, Martin Krátký, Jarmila Vinšová, Nóra Szabó, Zsuzsanna Senoner, Kata Horváti, Jiřina Stolaříková, Sándor Dávid, Sz. Bősze

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Abstract In the Mycobacterium genus over one hundred species are already described and new ones are periodically reported. Species that form colonies in a week are classified as rapid growers, those requiring longer periods (up to three months) are the mostly pathogenic slow growers. More recently, new emerging species have been identified to lengthen the list, all rapid growers. Of these, Mycobacterium abscessus is also an intracellular pathogen and it is the most chemotherapy-resistant rapid-growing mycobacterium. In addition, the cases of multidrug-resistant Mycobacterium tuberculosis infection are also increasing. Therefore there is an urgent need to find new active molecules against these threatening strains. Based on previous results, a series of salicylanilides, salicylanilide 5-chloropyrazinoates and carbamates was designed, synthesized and characterised. The compounds were evaluated for their in vitro activity on M. abscessus, susceptible M. tuberculosis H37Rv, multidrug-resistant (MDR) M. tuberculosis MDR A8, M. tuberculosis MDR 9449/2006 and on the extremely-resistant Praha 131 (XDR) strains. All derivatives exhibited a significant activity with minimum inhibitory concentrations (MICs) in the low micromolar range. Eight salicylanilide carbamates and two salicylanilide esters exhibited an excellent in vitro activity on M. abscessus with MICs from 0.2 to 2.1 μM, thus being more effective than ciprofloxacin and gentamicin. This finding is potentially promising, particularly, as M. abscessus is a threateningly chemotherapy-resistant species. M. tuberculosis H37Rv was inhibited with MICs from 0.2 μM, and eleven compounds have lower MICs than isoniazid. Salicylanilide esters and carbamates were found that they were effective also on MDR and XDR M. tuberculosis strains with MICs ≥1.0 μM. The in vitro cytotoxicity (IC50) was also determined on human MonoMac-6 cells, and selectivity index (SI) of the compounds was established. In general, salicylanilide derivatives substituted by halogens on both salicyl and aniline rings showed better activity, than 4-benzoylaniline derivatives. The ester or carbamate bond formation of parent salicylanilides mostly retained or improved antimycobacterial potency with moderate selectivity.

Original languageEnglish
Article number7982
Pages (from-to)692-704
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume101
DOIs
Publication statusPublished - Jul 25 2015

Fingerprint

Carbamates
Microbial Sensitivity Tests
Pathogens
Mycobacterium
Mycobacterium tuberculosis
Esters
Salicylanilides
Multidrug-Resistant Tuberculosis
Chemotherapy
Derivatives
Drug Therapy
Mycobacterium Infections
Halogens
Isoniazid
Cytotoxicity
Ciprofloxacin
Gentamicins
Inhibitory Concentration 50
salicylanilide
Molecules

Keywords

  • Antimycobacterial activity
  • Multidrug-resistant Mycobacterium tuberculosis
  • Mycobacterium abscessus
  • Salicylanilide
  • Salicylanilide 5-chloropyrazinoate
  • Salicylanilide carbamate

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Combating highly resistant emerging pathogen Mycobacterium abscessus and Mycobacterium tuberculosis with novel salicylanilide esters and carbamates. / Baranyai, Zsuzsa; Krátký, Martin; Vinšová, Jarmila; Szabó, Nóra; Senoner, Zsuzsanna; Horváti, Kata; Stolaříková, Jiřina; Dávid, Sándor; Bősze, Sz.

In: European Journal of Medicinal Chemistry, Vol. 101, 7982, 25.07.2015, p. 692-704.

Research output: Contribution to journalArticle

Baranyai, Zsuzsa ; Krátký, Martin ; Vinšová, Jarmila ; Szabó, Nóra ; Senoner, Zsuzsanna ; Horváti, Kata ; Stolaříková, Jiřina ; Dávid, Sándor ; Bősze, Sz. / Combating highly resistant emerging pathogen Mycobacterium abscessus and Mycobacterium tuberculosis with novel salicylanilide esters and carbamates. In: European Journal of Medicinal Chemistry. 2015 ; Vol. 101. pp. 692-704.
@article{4ae22211766344e79485ed10da03cfac,
title = "Combating highly resistant emerging pathogen Mycobacterium abscessus and Mycobacterium tuberculosis with novel salicylanilide esters and carbamates",
abstract = "Abstract In the Mycobacterium genus over one hundred species are already described and new ones are periodically reported. Species that form colonies in a week are classified as rapid growers, those requiring longer periods (up to three months) are the mostly pathogenic slow growers. More recently, new emerging species have been identified to lengthen the list, all rapid growers. Of these, Mycobacterium abscessus is also an intracellular pathogen and it is the most chemotherapy-resistant rapid-growing mycobacterium. In addition, the cases of multidrug-resistant Mycobacterium tuberculosis infection are also increasing. Therefore there is an urgent need to find new active molecules against these threatening strains. Based on previous results, a series of salicylanilides, salicylanilide 5-chloropyrazinoates and carbamates was designed, synthesized and characterised. The compounds were evaluated for their in vitro activity on M. abscessus, susceptible M. tuberculosis H37Rv, multidrug-resistant (MDR) M. tuberculosis MDR A8, M. tuberculosis MDR 9449/2006 and on the extremely-resistant Praha 131 (XDR) strains. All derivatives exhibited a significant activity with minimum inhibitory concentrations (MICs) in the low micromolar range. Eight salicylanilide carbamates and two salicylanilide esters exhibited an excellent in vitro activity on M. abscessus with MICs from 0.2 to 2.1 μM, thus being more effective than ciprofloxacin and gentamicin. This finding is potentially promising, particularly, as M. abscessus is a threateningly chemotherapy-resistant species. M. tuberculosis H37Rv was inhibited with MICs from 0.2 μM, and eleven compounds have lower MICs than isoniazid. Salicylanilide esters and carbamates were found that they were effective also on MDR and XDR M. tuberculosis strains with MICs ≥1.0 μM. The in vitro cytotoxicity (IC50) was also determined on human MonoMac-6 cells, and selectivity index (SI) of the compounds was established. In general, salicylanilide derivatives substituted by halogens on both salicyl and aniline rings showed better activity, than 4-benzoylaniline derivatives. The ester or carbamate bond formation of parent salicylanilides mostly retained or improved antimycobacterial potency with moderate selectivity.",
keywords = "Antimycobacterial activity, Multidrug-resistant Mycobacterium tuberculosis, Mycobacterium abscessus, Salicylanilide, Salicylanilide 5-chloropyrazinoate, Salicylanilide carbamate",
author = "Zsuzsa Baranyai and Martin Kr{\'a}tk{\'y} and Jarmila Vinšov{\'a} and N{\'o}ra Szab{\'o} and Zsuzsanna Senoner and Kata Horv{\'a}ti and Jiřina Stolař{\'i}kov{\'a} and S{\'a}ndor D{\'a}vid and Sz. Bősze",
year = "2015",
month = "7",
day = "25",
doi = "10.1016/j.ejmech.2015.07.001",
language = "English",
volume = "101",
pages = "692--704",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - Combating highly resistant emerging pathogen Mycobacterium abscessus and Mycobacterium tuberculosis with novel salicylanilide esters and carbamates

AU - Baranyai, Zsuzsa

AU - Krátký, Martin

AU - Vinšová, Jarmila

AU - Szabó, Nóra

AU - Senoner, Zsuzsanna

AU - Horváti, Kata

AU - Stolaříková, Jiřina

AU - Dávid, Sándor

AU - Bősze, Sz.

PY - 2015/7/25

Y1 - 2015/7/25

N2 - Abstract In the Mycobacterium genus over one hundred species are already described and new ones are periodically reported. Species that form colonies in a week are classified as rapid growers, those requiring longer periods (up to three months) are the mostly pathogenic slow growers. More recently, new emerging species have been identified to lengthen the list, all rapid growers. Of these, Mycobacterium abscessus is also an intracellular pathogen and it is the most chemotherapy-resistant rapid-growing mycobacterium. In addition, the cases of multidrug-resistant Mycobacterium tuberculosis infection are also increasing. Therefore there is an urgent need to find new active molecules against these threatening strains. Based on previous results, a series of salicylanilides, salicylanilide 5-chloropyrazinoates and carbamates was designed, synthesized and characterised. The compounds were evaluated for their in vitro activity on M. abscessus, susceptible M. tuberculosis H37Rv, multidrug-resistant (MDR) M. tuberculosis MDR A8, M. tuberculosis MDR 9449/2006 and on the extremely-resistant Praha 131 (XDR) strains. All derivatives exhibited a significant activity with minimum inhibitory concentrations (MICs) in the low micromolar range. Eight salicylanilide carbamates and two salicylanilide esters exhibited an excellent in vitro activity on M. abscessus with MICs from 0.2 to 2.1 μM, thus being more effective than ciprofloxacin and gentamicin. This finding is potentially promising, particularly, as M. abscessus is a threateningly chemotherapy-resistant species. M. tuberculosis H37Rv was inhibited with MICs from 0.2 μM, and eleven compounds have lower MICs than isoniazid. Salicylanilide esters and carbamates were found that they were effective also on MDR and XDR M. tuberculosis strains with MICs ≥1.0 μM. The in vitro cytotoxicity (IC50) was also determined on human MonoMac-6 cells, and selectivity index (SI) of the compounds was established. In general, salicylanilide derivatives substituted by halogens on both salicyl and aniline rings showed better activity, than 4-benzoylaniline derivatives. The ester or carbamate bond formation of parent salicylanilides mostly retained or improved antimycobacterial potency with moderate selectivity.

AB - Abstract In the Mycobacterium genus over one hundred species are already described and new ones are periodically reported. Species that form colonies in a week are classified as rapid growers, those requiring longer periods (up to three months) are the mostly pathogenic slow growers. More recently, new emerging species have been identified to lengthen the list, all rapid growers. Of these, Mycobacterium abscessus is also an intracellular pathogen and it is the most chemotherapy-resistant rapid-growing mycobacterium. In addition, the cases of multidrug-resistant Mycobacterium tuberculosis infection are also increasing. Therefore there is an urgent need to find new active molecules against these threatening strains. Based on previous results, a series of salicylanilides, salicylanilide 5-chloropyrazinoates and carbamates was designed, synthesized and characterised. The compounds were evaluated for their in vitro activity on M. abscessus, susceptible M. tuberculosis H37Rv, multidrug-resistant (MDR) M. tuberculosis MDR A8, M. tuberculosis MDR 9449/2006 and on the extremely-resistant Praha 131 (XDR) strains. All derivatives exhibited a significant activity with minimum inhibitory concentrations (MICs) in the low micromolar range. Eight salicylanilide carbamates and two salicylanilide esters exhibited an excellent in vitro activity on M. abscessus with MICs from 0.2 to 2.1 μM, thus being more effective than ciprofloxacin and gentamicin. This finding is potentially promising, particularly, as M. abscessus is a threateningly chemotherapy-resistant species. M. tuberculosis H37Rv was inhibited with MICs from 0.2 μM, and eleven compounds have lower MICs than isoniazid. Salicylanilide esters and carbamates were found that they were effective also on MDR and XDR M. tuberculosis strains with MICs ≥1.0 μM. The in vitro cytotoxicity (IC50) was also determined on human MonoMac-6 cells, and selectivity index (SI) of the compounds was established. In general, salicylanilide derivatives substituted by halogens on both salicyl and aniline rings showed better activity, than 4-benzoylaniline derivatives. The ester or carbamate bond formation of parent salicylanilides mostly retained or improved antimycobacterial potency with moderate selectivity.

KW - Antimycobacterial activity

KW - Multidrug-resistant Mycobacterium tuberculosis

KW - Mycobacterium abscessus

KW - Salicylanilide

KW - Salicylanilide 5-chloropyrazinoate

KW - Salicylanilide carbamate

UR - http://www.scopus.com/inward/record.url?scp=84937925828&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84937925828&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2015.07.001

DO - 10.1016/j.ejmech.2015.07.001

M3 - Article

VL - 101

SP - 692

EP - 704

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

M1 - 7982

ER -