Supplementary data for the article: Ciura, K.; Fedorowicz, J.; Andrić, F.; Greber, K. E.; Gurgielewicz, A.; Sawicki, W.; Saczewski, J. Lipophilicity Determination of Quaternary (Fluoro)Quinolones by Chromatographic and Theoretical Approaches. International Journal of Molecular Sciences 2019, 20 (21). https://doi.org/10.3390/ijms20215288

Supplementary material for: [https://doi.org/10.3390/ijms20215288]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/3740

Development of Safirinium dyes for new applications : fluorescent staining of bacteria, human kidney cells, and the horny layer of the epidermis

Low-molecular synthetic fluorophores are convenient tools in bioimaging applications. Several derivatives of Safirinium dyes as well as their reactive N-hydroxysuccinimide (NHS) esters bearing diverse substituents were synthesized and evaluated experimentally in terms of their lipophilicity by means of reverse-phase and immobilized artificial membrane high-performance liquid chromatography. Subsequently, the selected compounds were employed as novel cellular imaging agents for staining Gram-positive and Gram-negative bacteria, human kidney cell line, as well as human skin tissue. The analyzed dyes allowed for visualization of cellular structures such as mitochondria, endoplasmic reticulum, and cellular nuclei. They proved to be useful in fluorescent staining of stratum corneum, especially in the aspect of xenobiotic exposure and its penetration into the skin. The best results were obtained with the use of moderately lipophilic NHS esters of Safirinium Q. The development of Safirinium dyes is a promising alternative for commercially available dyes since the reported molecules have low molecular masses and exhibit efficient staining and remarkable water solubility. Moreover, they are relatively simple and low-cost in synthesis.Peer reviewe

Lipophilicity determination of quaternary (Fluoro)quinolones by chromatographic and theoretical approaches

Lipophilicity is a vital physicochemical parameter of a molecule, which affects several biological processes such as absorption, tissue distribution, and pharmacokinetic properties. In this study, evaluation of lipophilicities of a series of novel fluoroquinolone-Safirinium dye hybrids using chromatographic and computational methods is presented. Fluoroquinolone-Safirinium dye hybrids have been synthesized as new dual-acting hydrophilic antibacterial agents. Reversed phase thin-layer chromatography and micellar electrokinetic chromatography experiments were carried out. Furthermore, logP values of the target structures were predicted by means of different software platforms and algorithms. In order to assess similarities and dissimilarities of the obtained lipophilicity indexes, cluster analysis and sum of ranking differences were performed. The significant differences of calculated logP values (α = 0.05, p < 0.001) indicated that an experimental approach is necessary for lipophilicity prediction of this class of antibiotics. Chromatographic data indicated that the newly synthesized hybrid (fluoro)quinolone-based quaternary ammonium derivatives show less lipophilic character than the parent (fluoro)quinolones. Additionally, the chromatographically obtained lipophilicity indexes were evaluated for possible application in quantitative retention–activity relationships. The established lipophilicity models have the potential to predict antimicrobial activities of a series of quaternary (fluoro)quinolones against Bacillus subtilis, Escherichia coli, and Proteus vulgaris.Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3741

Synthesis and biological evaluation of hybrid quinolone-based quaternary ammonium antibacterial agents

A series of novel fluoroquinolone-Safirinium dye hybrids was synthesized by means of tandem Mannich-electrophilic amination reactions from profluorophoric isoxazolones and antibiotics bearing a secondary amino group at position 7 of the quinoline ring. The obtained fluorescent spiro fused conjugates incorporating quaternary nitrogen atoms were characterized by H-1 NMR, IR, MS, and elemental analysis. All the synthetic analogues (3a-h and 4a-h) were evaluated for their in vitro antimicrobial, bactericidal, and antibiofilm activities against a panel of Gram positive and Gram-negative pathogenic bacteria. The most active Safirinium Q derivatives of lomefloxacin (4d) and ciprofloxacin (4e) exhibited molar-based antibacterial activities comparable to the unmodified drugs and displayed considerable inhibitory potencies in E. coli DNA gyrase supercoiling assays with IC50 values in the low micromolar range. Zwiterionic hybrids were noticeably less lipophilic than the parent quinolones in micellar electrokinetic chromatography (MECK) experiments. The tests performed in the presence of phenylalanine-arginine-beta-naphthylamide (PA beta N) or carbonyl cyanide m-chlorophenylhydrazone (CCCP) revealed that the conjugates are to some extent subject to bacterial efflux and cellular accumulation, respectively. Moreover, the hybrids did not exhibit notable cytotoxicity towards the HEK 293 control cell line and demonstrated low propensity for resistance development, as exemplified for compounds 3g and 4b. Finally, molecular docking experiments revealed that the synthesized compounds were able to bind in the fluoroquinolone-binding mode at S. aureus DNA gyrase and S. pneumoniae topoisomerase IV active sites. (C) 2019 Elsevier Masson SAS. All rights reserved.Peer reviewe

Supplementary data for the article: Ciura, K.; Fedorowicz, J.; Andrić, F.; Greber, K. E.; Gurgielewicz, A.; Sawicki, W.; Saczewski, J. Lipophilicity Determination of Quaternary (Fluoro)Quinolones by Chromatographic and Theoretical Approaches. International Journal of Molecular Sciences 2019, 20 (21). https://doi.org/10.3390/ijms20215288

Supplementary material for: [https://doi.org/10.3390/ijms20215288]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/3740

Lipophilicity determination of antifungal isoxazolo[3,4-b]pyridin-3(1h)-ones and their n1-substituted derivatives with chromatographic and computational methods

The lipophilicity of a molecule is a well-recognized as a crucial physicochemical factor that conditions the biological activity of a drug candidate. This study was aimed to evaluate the lipophilicity of isoxazolo[3,4-b]pyridine-3(1H)-ones and their N1-substituted derivatives, which demonstrated pronounced antifungal activities. Several methods, including reversed-phase thin layer chromatography (RP-TLC), reversed phase high-performance liquid chromatography (RP-HPLC), and micellar electrokinetic chromatography (MEKC), were employed. Furthermore, the calculated logP values were estimated using various freely and commercially available software packages and online platforms, as well as density functional theory computations (DFT). Similarities and dissimilarities between the determined lipophilicity indices were assessed using several chemometric approaches. Principal component analysis (PCA) indicated that other features beside lipophilicity affect antifungal activities of the investigated derivatives. Quantitative-structure-retention-relationship (QSRR) analysis by means of genetic algorithm - partial least squares (GA-PLS) - was implemented to rationalize the link between the physicochemical descriptors and lipophilicity. Among the studied compounds, structure 16 should be considered as the best starting structure for further studies, since it demonstrated the lowest lipophilic character within the series while retaining biological activity. Sum of ranking differences (SRD) analysis indicated that the chromatographic approach, regardless of the technique employed, should be considered as the best approach for lipophilicity assessment of isoxazolones

an untargeted metabolomics approach to characterize metabolic changes during E-waste recycling

Funding Information: HBM4EU E-Waste Study Team: The HBM4EU e-waste study team consists of Kukka Aimonen l, Lasma Akulova m, Radia Bousoumah n, Argelia Casta\u00F1o o, Adam Clarke p, Adrian Covaci q, Maurice van Dael c, Marta Esteban L\u00F3pez o, Thomas G\u00F6eno c, Martien Graumans c, Ogier Hanser n, Beata Janasik r, Kate Jones p, Laura Komarovska m, Sirpa Laitinen l, Henriqueta Louro s, Carla Martins b, Linda Matisane m, Inese Martinsone m, Rodrigo Moreira u, Darren Musgrove p, Maria-Mirela Ani d, Maria Torres Toda f, Ana Nogueira s, Linda Paegle m, Herm\u00EDnia Pinhal s, Tiina Rantio l, S\u00EDlvia Reis Santos s, Edna Ribeiro t, Joanna R\u00F3g a, Anita Seile m, Marina Silva t, S\u00EDlvia Reis Santos s, Marjo V\u00E4nsk\u00E4 l, Riitta Velin l, C\u00E9lia Ventura j,u and Wojciech Wasowicz r., Affiliations of these authors can be found in Supplementary material S3. Funding Information: This work has received external funding from the European Union\u2019s Horizon 2020 research and innovation program under grant agreement No. 733032 and received co-funding from the author\u2019s organizations and/or Ministries. In addition, the Finnish Work Environment fund provided funding (grant no. 200345). The publication was financed by the Science Development Fund of the Warsaw University of Life Sciences \u2013 SGGW. Publisher Copyright: © 2025 The Author(s)E-waste contains hazardous chemicals that may be a direct health risk for workers involved in recycling. We conducted an untargeted metabolomics analysis of urine samples collected from male e-waste processing workers to explore metabolic changes associated with chemical exposures in e-waste recycling in Belgium, Finland, Latvia, Luxembourg, the Netherlands, Poland, and Portugal. Questionnaire data and urine samples were obtained from workers involved in the processing of e-waste (sorting, dismantling, shredding, pre-processing, metal, and non-metal processing), as well as from controls with no known occupational exposure. Pre- and post-shift urine samples were collected and analysed using ultrahigh-performance liquid chromatography-mass spectrometry (UPLC-MS). A total of 32 endogenous urinary metabolites were annotated with a Variable Importance in Projection (VIP) above 2, indicating that e-waste recycling is mainly associated with changes in steroid hormone and neurotransmitter metabolism, energy metabolism, bile acid biosynthesis, and inflammation. The highest VIP was observed for dopamine-o-quinone, which is linked to Parkinson's disease. These and other changes in metabolism in workers employed in the processing of e-waste need further verification in targeted studies.publishersversionpublishe

<i>In vitro</i> to <i>in vivo</i> extrapolation to support the development of the next generation risk assessment (NGRA) strategy for nanomaterials

The in vitro to in vivo extrapolation models (IVIVE) can support the development of the Next Generation Risk Assessment through integration the AOP-anchored strategy for in vitro assays selection with the PBPK models.</jats:p