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 /
Authors Bertašiūtė, Monika ; Kavaliauskas, Povilas ; Vaickelionienė, Rita ; Grybaitė, Birutė ; Petraitis, Vidmantas ; Petraitienė, Rūta ; Naing, Ethan ; Garcia, Andrew ; Šiugždaitė, Jūratė ; Lelešius, Raimundas ; Mickevičius, Vytautas
DOI 10.3390/ijms24097966
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Is Part of International journal of molecular sciences.. Basel : MDPI. 2023, vol. 24, iss. 9, art. no. 7966, p. 1-23.. ISSN 1422-0067
Keywords [eng] pyrrolidinone ; hydrazone ; azole ; gram-positive bacteria ; antimicrobial activity ; anticancer activity
Abstract [eng] 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.
Published Basel : MDPI
Type Journal article
Language English
Publication date 2023
CC license CC license description