Cargando…
Synthesis of 1-(2-Hydroxyphenyl)- and (3,5-Dichloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic Acid Derivatives as Promising Scaffolds for the Development of Novel Antimicrobial and Anticancer Agents
Increasing antimicrobial resistance among Gram-positive pathogens and pathogenic fungi remains one of the major public healthcare threats. Therefore, novel antimicrobial candidates and scaffolds are critically needed to overcome resistance in Gram-positive pathogens and drug-resistant fungal pathoge...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10178429/ https://www.ncbi.nlm.nih.gov/pubmed/37175673 http://dx.doi.org/10.3390/ijms24097966 |
_version_ | 1785040860450127872 |
---|---|
author | Bertašiūtė, Monika Kavaliauskas, Povilas Vaickelionienė, Rita Grybaitė, Birutė Petraitis, Vidmantas Petraitienė, Rūta Naing, Ethan Garcia, Andrew Šiugždaitė, Jūratė Lelešius, Raimundas Mickevičius, Vytautas |
author_facet | Bertašiūtė, Monika Kavaliauskas, Povilas Vaickelionienė, Rita Grybaitė, Birutė Petraitis, Vidmantas Petraitienė, Rūta Naing, Ethan Garcia, Andrew Šiugždaitė, Jūratė Lelešius, Raimundas Mickevičius, Vytautas |
author_sort | Bertašiūtė, Monika |
collection | PubMed |
description | Increasing antimicrobial resistance among Gram-positive pathogens and pathogenic fungi remains one of the major public healthcare threats. Therefore, novel antimicrobial candidates and scaffolds are critically needed to overcome resistance in Gram-positive pathogens and drug-resistant fungal pathogens. In this study, we explored 1-(2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic acid and its 3,5-dichloro-2-hydroxyphenyl analogue for their in vitro antimicrobial activity against multidrug-resistant pathogens. The compounds showed structure-dependent antimicrobial activity against Gram-positive pathogens (S. aureus, E. faecalis, C. difficile). Compounds 14 and 24b showed promising activity against vancomycin-intermediate S. aureus strains, and favorable cytotoxic profiles in HSAEC-1 cells, making them attractive scaffolds for further development. 5-Fluorobenzimidazole, having a 3,5-dichloro-2-hydroxyphenyl substituent, was found to be four-fold, and hydrazone, with a thien-2-yl fragment, was two-fold stronger than clindamycin against methicillin resistant S. aureus TCH 1516. Moreover, hydrazone, bearing a 5-nitrothien-2-yl moiety, showed promising activity against three tested multidrug-resistant C. auris isolates representing major genetic lineages (MIC 16 µg/mL) and azole-resistant A. fumigatus strains harboring TR34/L98H mutations in the CYP51A gene. The anticancer activity characterization demonstrated that the 5-fluorobenzimidazole derivative with a 3,5-dichloro-2-hydroxyphenyl substituent showed the highest anticancer activity in an A549 human pulmonary cancer cell culture model. Collectively these results demonstrate that 1-(2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic acid derivatives could be further explored for the development of novel candidates targeting Gram-positive pathogens and drug-resistant fungi. |
format | Online Article Text |
id | pubmed-10178429 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-101784292023-05-13 Synthesis of 1-(2-Hydroxyphenyl)- and (3,5-Dichloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic Acid Derivatives as Promising Scaffolds for the Development of Novel Antimicrobial and Anticancer Agents Bertašiūtė, Monika Kavaliauskas, Povilas Vaickelionienė, Rita Grybaitė, Birutė Petraitis, Vidmantas Petraitienė, Rūta Naing, Ethan Garcia, Andrew Šiugždaitė, Jūratė Lelešius, Raimundas Mickevičius, Vytautas Int J Mol Sci Article Increasing antimicrobial resistance among Gram-positive pathogens and pathogenic fungi remains one of the major public healthcare threats. Therefore, novel antimicrobial candidates and scaffolds are critically needed to overcome resistance in Gram-positive pathogens and drug-resistant fungal pathogens. In this study, we explored 1-(2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic acid and its 3,5-dichloro-2-hydroxyphenyl analogue for their in vitro antimicrobial activity against multidrug-resistant pathogens. The compounds showed structure-dependent antimicrobial activity against Gram-positive pathogens (S. aureus, E. faecalis, C. difficile). Compounds 14 and 24b showed promising activity against vancomycin-intermediate S. aureus strains, and favorable cytotoxic profiles in HSAEC-1 cells, making them attractive scaffolds for further development. 5-Fluorobenzimidazole, having a 3,5-dichloro-2-hydroxyphenyl substituent, was found to be four-fold, and hydrazone, with a thien-2-yl fragment, was two-fold stronger than clindamycin against methicillin resistant S. aureus TCH 1516. Moreover, hydrazone, bearing a 5-nitrothien-2-yl moiety, showed promising activity against three tested multidrug-resistant C. auris isolates representing major genetic lineages (MIC 16 µg/mL) and azole-resistant A. fumigatus strains harboring TR34/L98H mutations in the CYP51A gene. The anticancer activity characterization demonstrated that the 5-fluorobenzimidazole derivative with a 3,5-dichloro-2-hydroxyphenyl substituent showed the highest anticancer activity in an A549 human pulmonary cancer cell culture model. Collectively these results demonstrate that 1-(2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic acid derivatives could be further explored for the development of novel candidates targeting Gram-positive pathogens and drug-resistant fungi. MDPI 2023-04-27 /pmc/articles/PMC10178429/ /pubmed/37175673 http://dx.doi.org/10.3390/ijms24097966 Text en © 2023 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 Bertašiūtė, Monika Kavaliauskas, Povilas Vaickelionienė, Rita Grybaitė, Birutė Petraitis, Vidmantas Petraitienė, Rūta Naing, Ethan Garcia, Andrew Šiugždaitė, Jūratė Lelešius, Raimundas Mickevičius, Vytautas Synthesis of 1-(2-Hydroxyphenyl)- and (3,5-Dichloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic Acid Derivatives as Promising Scaffolds for the Development of Novel Antimicrobial and Anticancer Agents |
title | Synthesis of 1-(2-Hydroxyphenyl)- and (3,5-Dichloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic Acid Derivatives as Promising Scaffolds for the Development of Novel Antimicrobial and Anticancer Agents |
title_full | Synthesis of 1-(2-Hydroxyphenyl)- and (3,5-Dichloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic Acid Derivatives as Promising Scaffolds for the Development of Novel Antimicrobial and Anticancer Agents |
title_fullStr | Synthesis of 1-(2-Hydroxyphenyl)- and (3,5-Dichloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic Acid Derivatives as Promising Scaffolds for the Development of Novel Antimicrobial and Anticancer Agents |
title_full_unstemmed | Synthesis of 1-(2-Hydroxyphenyl)- and (3,5-Dichloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic Acid Derivatives as Promising Scaffolds for the Development of Novel Antimicrobial and Anticancer Agents |
title_short | Synthesis of 1-(2-Hydroxyphenyl)- and (3,5-Dichloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic Acid Derivatives as Promising Scaffolds for the Development of Novel Antimicrobial and Anticancer Agents |
title_sort | synthesis of 1-(2-hydroxyphenyl)- and (3,5-dichloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic acid derivatives as promising scaffolds for the development of novel antimicrobial and anticancer agents |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10178429/ https://www.ncbi.nlm.nih.gov/pubmed/37175673 http://dx.doi.org/10.3390/ijms24097966 |
work_keys_str_mv | AT bertasiutemonika synthesisof12hydroxyphenyland35dichloro2hydroxyphenyl5oxopyrrolidine3carboxylicacidderivativesaspromisingscaffoldsforthedevelopmentofnovelantimicrobialandanticanceragents AT kavaliauskaspovilas synthesisof12hydroxyphenyland35dichloro2hydroxyphenyl5oxopyrrolidine3carboxylicacidderivativesaspromisingscaffoldsforthedevelopmentofnovelantimicrobialandanticanceragents AT vaickelionienerita synthesisof12hydroxyphenyland35dichloro2hydroxyphenyl5oxopyrrolidine3carboxylicacidderivativesaspromisingscaffoldsforthedevelopmentofnovelantimicrobialandanticanceragents AT grybaitebirute synthesisof12hydroxyphenyland35dichloro2hydroxyphenyl5oxopyrrolidine3carboxylicacidderivativesaspromisingscaffoldsforthedevelopmentofnovelantimicrobialandanticanceragents AT petraitisvidmantas synthesisof12hydroxyphenyland35dichloro2hydroxyphenyl5oxopyrrolidine3carboxylicacidderivativesaspromisingscaffoldsforthedevelopmentofnovelantimicrobialandanticanceragents AT petraitieneruta synthesisof12hydroxyphenyland35dichloro2hydroxyphenyl5oxopyrrolidine3carboxylicacidderivativesaspromisingscaffoldsforthedevelopmentofnovelantimicrobialandanticanceragents AT naingethan synthesisof12hydroxyphenyland35dichloro2hydroxyphenyl5oxopyrrolidine3carboxylicacidderivativesaspromisingscaffoldsforthedevelopmentofnovelantimicrobialandanticanceragents AT garciaandrew synthesisof12hydroxyphenyland35dichloro2hydroxyphenyl5oxopyrrolidine3carboxylicacidderivativesaspromisingscaffoldsforthedevelopmentofnovelantimicrobialandanticanceragents AT siugzdaitejurate synthesisof12hydroxyphenyland35dichloro2hydroxyphenyl5oxopyrrolidine3carboxylicacidderivativesaspromisingscaffoldsforthedevelopmentofnovelantimicrobialandanticanceragents AT lelesiusraimundas synthesisof12hydroxyphenyland35dichloro2hydroxyphenyl5oxopyrrolidine3carboxylicacidderivativesaspromisingscaffoldsforthedevelopmentofnovelantimicrobialandanticanceragents AT mickeviciusvytautas synthesisof12hydroxyphenyland35dichloro2hydroxyphenyl5oxopyrrolidine3carboxylicacidderivativesaspromisingscaffoldsforthedevelopmentofnovelantimicrobialandanticanceragents |