Cargando…

Study of Biological Activities and ADMET-Related Properties of Salicylanilide-Based Peptidomimetics

A series of eleven benzylated intermediates and eleven target compounds derived from salicylanilide were tested against Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 as reference strains and against three clinical isolates of methicillin-resistant S. aureus (MRSA) and three i...

Descripción completa

Detalles Bibliográficos
Autores principales: Pindjakova, Dominika, Pilarova, Eliska, Pauk, Karel, Michnova, Hana, Hosek, Jan, Magar, Pratibha, Cizek, Alois, Imramovsky, Ales, Jampilek, Josef
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9569995/
https://www.ncbi.nlm.nih.gov/pubmed/36232947
http://dx.doi.org/10.3390/ijms231911648
_version_ 1784809996246056960
author Pindjakova, Dominika
Pilarova, Eliska
Pauk, Karel
Michnova, Hana
Hosek, Jan
Magar, Pratibha
Cizek, Alois
Imramovsky, Ales
Jampilek, Josef
author_facet Pindjakova, Dominika
Pilarova, Eliska
Pauk, Karel
Michnova, Hana
Hosek, Jan
Magar, Pratibha
Cizek, Alois
Imramovsky, Ales
Jampilek, Josef
author_sort Pindjakova, Dominika
collection PubMed
description A series of eleven benzylated intermediates and eleven target compounds derived from salicylanilide were tested against Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 as reference strains and against three clinical isolates of methicillin-resistant S. aureus (MRSA) and three isolates of vancomycin-resistant E. faecalis. In addition, the compounds were evaluated against Mycobacterium tuberculosis H37Ra and M. smegmatis ATCC 700084. The in vitro cytotoxicity of the compounds was assessed using the human monocytic leukemia cell line THP-1. The lipophilicity of the prepared compounds was experimentally determined and correlated with biological activity. The benzylated intermediates were found to be completely biologically inactive. Of the final eleven compounds, according to the number of amide groups in the molecule, eight are diamides, and three are triamides that were inactive. 5-Chloro-2-hydroxy-N-[(2S)- 4-(methylsulfanyl)-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino}butan-2-yl]benzamide (3e) and 5-chloro-2-hydroxy-N-[(2S)-(4-methyl-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino)pentan-2-yl)benzamide (3f) showed the broadest spectrum of activity against all tested species/isolates comparable to the used standards (ampicillin and isoniazid). Six diamides showed high antistaphylococcal activity with MICs ranging from 0.070 to 8.95 μM. Three diamides showed anti-enterococcal activity with MICs ranging from 4.66 to 35.8 μM, and the activities of 3f and 3e against M. tuberculosis and M. smegmatis were MICs of 18.7 and 35.8 μM, respectively. All the active compounds were microbicidal. It was observed that the connecting linker between the chlorsalicylic and 4-CF(3)-anilide cores must be substituted with a bulky and/or lipophilic chain such as isopropyl, isobutyl, or thiabutyl chain. Anticancer activity on THP-1 cells IC(50) ranged from 1.4 to >10 µM and increased with increasing lipophilicity.
format Online
Article
Text
id pubmed-9569995
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-95699952022-10-17 Study of Biological Activities and ADMET-Related Properties of Salicylanilide-Based Peptidomimetics Pindjakova, Dominika Pilarova, Eliska Pauk, Karel Michnova, Hana Hosek, Jan Magar, Pratibha Cizek, Alois Imramovsky, Ales Jampilek, Josef Int J Mol Sci Article A series of eleven benzylated intermediates and eleven target compounds derived from salicylanilide were tested against Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 as reference strains and against three clinical isolates of methicillin-resistant S. aureus (MRSA) and three isolates of vancomycin-resistant E. faecalis. In addition, the compounds were evaluated against Mycobacterium tuberculosis H37Ra and M. smegmatis ATCC 700084. The in vitro cytotoxicity of the compounds was assessed using the human monocytic leukemia cell line THP-1. The lipophilicity of the prepared compounds was experimentally determined and correlated with biological activity. The benzylated intermediates were found to be completely biologically inactive. Of the final eleven compounds, according to the number of amide groups in the molecule, eight are diamides, and three are triamides that were inactive. 5-Chloro-2-hydroxy-N-[(2S)- 4-(methylsulfanyl)-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino}butan-2-yl]benzamide (3e) and 5-chloro-2-hydroxy-N-[(2S)-(4-methyl-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino)pentan-2-yl)benzamide (3f) showed the broadest spectrum of activity against all tested species/isolates comparable to the used standards (ampicillin and isoniazid). Six diamides showed high antistaphylococcal activity with MICs ranging from 0.070 to 8.95 μM. Three diamides showed anti-enterococcal activity with MICs ranging from 4.66 to 35.8 μM, and the activities of 3f and 3e against M. tuberculosis and M. smegmatis were MICs of 18.7 and 35.8 μM, respectively. All the active compounds were microbicidal. It was observed that the connecting linker between the chlorsalicylic and 4-CF(3)-anilide cores must be substituted with a bulky and/or lipophilic chain such as isopropyl, isobutyl, or thiabutyl chain. Anticancer activity on THP-1 cells IC(50) ranged from 1.4 to >10 µM and increased with increasing lipophilicity. MDPI 2022-10-01 /pmc/articles/PMC9569995/ /pubmed/36232947 http://dx.doi.org/10.3390/ijms231911648 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pindjakova, Dominika
Pilarova, Eliska
Pauk, Karel
Michnova, Hana
Hosek, Jan
Magar, Pratibha
Cizek, Alois
Imramovsky, Ales
Jampilek, Josef
Study of Biological Activities and ADMET-Related Properties of Salicylanilide-Based Peptidomimetics
title Study of Biological Activities and ADMET-Related Properties of Salicylanilide-Based Peptidomimetics
title_full Study of Biological Activities and ADMET-Related Properties of Salicylanilide-Based Peptidomimetics
title_fullStr Study of Biological Activities and ADMET-Related Properties of Salicylanilide-Based Peptidomimetics
title_full_unstemmed Study of Biological Activities and ADMET-Related Properties of Salicylanilide-Based Peptidomimetics
title_short Study of Biological Activities and ADMET-Related Properties of Salicylanilide-Based Peptidomimetics
title_sort study of biological activities and admet-related properties of salicylanilide-based peptidomimetics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9569995/
https://www.ncbi.nlm.nih.gov/pubmed/36232947
http://dx.doi.org/10.3390/ijms231911648
work_keys_str_mv AT pindjakovadominika studyofbiologicalactivitiesandadmetrelatedpropertiesofsalicylanilidebasedpeptidomimetics
AT pilarovaeliska studyofbiologicalactivitiesandadmetrelatedpropertiesofsalicylanilidebasedpeptidomimetics
AT paukkarel studyofbiologicalactivitiesandadmetrelatedpropertiesofsalicylanilidebasedpeptidomimetics
AT michnovahana studyofbiologicalactivitiesandadmetrelatedpropertiesofsalicylanilidebasedpeptidomimetics
AT hosekjan studyofbiologicalactivitiesandadmetrelatedpropertiesofsalicylanilidebasedpeptidomimetics
AT magarpratibha studyofbiologicalactivitiesandadmetrelatedpropertiesofsalicylanilidebasedpeptidomimetics
AT cizekalois studyofbiologicalactivitiesandadmetrelatedpropertiesofsalicylanilidebasedpeptidomimetics
AT imramovskyales studyofbiologicalactivitiesandadmetrelatedpropertiesofsalicylanilidebasedpeptidomimetics
AT jampilekjosef studyofbiologicalactivitiesandadmetrelatedpropertiesofsalicylanilidebasedpeptidomimetics