Repurposing of monocyclic β-lactams as anti-inflammatory agents - The case of new ferrocene-azetidin-2-one hybrids.

Autor: Genčić MS; Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia. Electronic address: denijum@yahoo.com., Stojanović NM; Department of Physiology, Faculty of Medicine, University of Niš, Bulevar Zorana Đinđića 81, 18000, Niš, Serbia., Denić JM; Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia., Stojanović-Radić ZZ; Department of Biology and Ecology, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia., Stojanović P; National Reference Laboratory for Anaerobic Infections - Clostridium difficile, Center of Microbiology, Institute for Public Health Niš, Bulevar Zorana Đinđića 50, 18000, Niš, Serbia., Van Hecke K; XStruct, Department of Chemistry, Faculty of Science, Ghent University, Krijgslaan 281-S3, B-9000, Ghent, Belgium., Jovanović LS; Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000, Novi Sad, Serbia., Nikolić MV; Department of Biology and Human Genetics, Faculty of Medicine, University of Niš, Bulevar Zorana Đinđića 81, 18000, Niš, Serbia., Jevtović-Stoimenov T; Department of Biochemistry, Faculty of Medicine, University of Niš, Bulevar Zorana Đinđića 81, 18000, Niš, Serbia., Radulović NS; Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia. Electronic address: nikoradulovic@yahoo.com., D'hooghe M; SynBioC Research Group, Department of Green Chemistry and Technology, Ghent University, Coupure Links 653, B-9000, Gent, Belgium. Electronic address: Matthias.Dhooghe@UGent.be.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Dec 15; Vol. 280, pp. 116910. Date of Electronic Publication: 2024 Oct 01.
DOI: 10.1016/j.ejmech.2024.116910
Abstrakt: There is growing interest in developing monotherapy drugs that treat inflammation caused by microbial infections, focusing on dual antimicrobial and anti-inflammatory agents with minimal side effects and high safety margins. This study synthesized and characterized a library of novel cis-4-ferrocenylazetidin-2-ones, evaluating their antimicrobial and anti-inflammatory activities. These organometallic monocyclic β-lactams showed moderate in vitro antimicrobial activity against various standard microbial strains, including yeasts and Gram-negative and Gram-positive bacteria. Some compounds overcame the resistance of clinical Staphylococcus aureus isolates. Traditionally, monocyclic β-lactams target Gram-negative bacilli, but adding a ferrocene moiety and substituting the COOH group near the N-1 position with a non-ionizable ester group (COOR) extended their activity spectrum. The anti-inflammatory properties were assessed in macrophage-based models, revealing non-cytotoxicity below 10 μM. Two compounds were shown to be strong and selective arginase inhibitors, while five others effectively suppressed excessive NO formation without affecting basal NO production. The presence of a phenoxy group at C-3 of the β-lactam ring appeared to be crucial for selective NO inhibition. These hybrids did not scavenge NO but inhibited NO synthesis by suppressing iNOS expression. Overall, two novel hybrids were identified as promising hit candidates for treating infection-induced inflammatory reactions.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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