Study of Biological Activities and ADMET-Related Properties of Salicylanilide-Based Peptidomimetics
| Autor: | Dominika Pindjakova, Eliska Pilarova, Karel Pauk, Hana Michnova, Jan Hosek, Pratibha Magar, Alois Cizek, Ales Imramovsky, Josef Jampilek |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Methicillin-Resistant Staphylococcus aureus
Organic Chemistry Microbial Sensitivity Tests Mycobacterium tuberculosis General Medicine Salicylanilides Catalysis Anti-Bacterial Agents Computer Science Applications Inorganic Chemistry Vancomycin Benzamides Isoniazid Humans Ampicillin Anilides Peptidomimetics Physical and Theoretical Chemistry Molecular Biology Spectroscopy salicylamide peptidomimetics antimicrobial activity cytotoxicity lipophilicity structure–activity relationships |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 19; Pages: 11648 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms231911648 |
| Popis: | 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-CF3-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 IC50 ranged from 1.4 to >10 µM and increased with increasing lipophilicity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|