<abstract xmlns="http://www.w3.org/1999/xhtml">In the present study we investigated the <italic>in vitro</italic> hepatotoxicity of a set of rhodamine-labelled 3-hydroxy-4-pyridinones (3,4-HPO) that had previously demonstrated significant inhibitory effect in the intramacrophagic growth of <italic>Mycobacterium avium</italic>. Our aim was to establish a correspondence between the molecular structure and the <italic>in vitro</italic> toxicological activity of these compounds.The impact of a set of bidentate (MRB2, MRB7, MRB8, and MRB9) and hexadentate (MRH7, MRH8, and MRH10) chelators on cellular metabolic competence and membrane integrity was investigated in HepG2 cells.Our findings indicate that: a) hexadentate chelators are more cytotoxic than parent bidentate ligands; b) disruption of cell membrane and metabolic competence only occurred after 5 days, at the highest concentrations tested; c) strict correlation between bacteriostatic activity and <italic>in vitro</italic> toxicity was observed, which seems to be directly dependent on the size of the molecule and on the hydrophilic/lipophilic balance; d) among the set of bidentate ligands, carboxyrhodamine derivatives (amide linker) presented lower detrimental effects, when compared with rhodamine B isothiocyanate chelators (thiourea linker); e) contrarily, for the hexadentate series, rhodamine B isothiocyanate derivatives are less cytotoxic to HepG2 cells than carboxyrhodamine molecules; and f) for all compounds tested, when the substituents of the nitrogen atom were switched from ethyl to methyl, an increment of toxicity was observed.Overall, all chelators seem to display suitable in vitro toxicological potential to combat fast grow bacteria. According to their <italic>in vitro</italic> pharmacological: toxicological potential ratio, MRH7 and MRH8 may be considered as the most suitable compounds to undergo further pre-clinical development studies.</abstract>

In the present study we investigated the in vitro hepatotoxicity of a set of rhodamine-labelled 3-hydroxy-4-pyridinones (3,4-HPO) that had previously demonstrated significant inhibitory effect in the intramacrophagic growth of Mycobacterium avium. Our aim was to establish a correspondence between the molecular structure and the in vitro toxicological activity of these compounds.The impact of a set of bidentate (MRB2, MRB7, MRB8, and MRB9) and hexadentate (MRH7, MRH8, and MRH10) chelators on cellular metabolic competence and membrane integrity was investigated in HepG2 cells.Our findings indicate that: a) hexadentate chelators are more cytotoxic than parent bidentate ligands; b) disruption of cell membrane and metabolic competence only occurred after 5 days, at the highest concentrations tested; c) strict correlation between bacteriostatic activity and in vitro toxicity was observed, which seems to be directly dependent on the size of the molecule and on the hydrophilic/lipophilic balance; d) among the set of bidentate ligands, carboxyrhodamine derivatives (amide linker) presented lower detrimental effects, when compared with rhodamine B isothiocyanate chelators (thiourea linker); e) contrarily, for the hexadentate series, rhodamine B isothiocyanate derivatives are less cytotoxic to HepG2 cells than carboxyrhodamine molecules; and f) for all compounds tested, when the substituents of the nitrogen atom were switched from ethyl to methyl, an increment of toxicity was observed.Overall, all chelators seem to display suitable in vitro toxicological potential to combat fast grow bacteria. According to their in vitro pharmacological: toxicological potential ratio, MRH7 and MRH8 may be considered as the most suitable compounds to undergo further pre-clinical development studies.

Insights on the relationship between structure vs. toxicological activity of antibacterial rhodamine-labelled 3-hydroxy-4-pyridinone iron(III) chelators in HepG2 cells

REQUIMTE-LAQV, Department of Chemistry and Biochemistry

Faculty of Sciences of University of Porto

Laboratory of Toxicology of Department of Biological Sciences

Faculty of Pharmacy of University of Porto

REQUIMTE-LAQV, Institute of Biomedical Sciences Abel Salazar

Interdisciplinary Toxicology

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

In the present study we investigated the in vitro hepatotoxicity of a set of rhodamine-labelled 3-hydroxy-4-pyridinones (3,4-HPO) that had previously...

Insights on the relationship between structure vs. toxicological activity of antibacterial rhodamine-labelled 3-hydroxy-4-pyridinone iron(III) chelators in HepG2 cells

Published Online: Oct 18, 2019

Page range: 189 - 199

Received: Feb 26, 2018

Accepted: Jul 24, 2018

DOI: https://doi.org/10.2478/intox-2018-0016

Keywords
iron chelator, 3-hydroxy-4-pyridinone (3,4-HPO), rhodamine, toxicity, HepG2 cells

© 2018 Interdisciplinary Toxicology, published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Insights on the relationship between structure vs. toxicological activity of antibacterial rhodamine-labelled 3-hydroxy-4-pyridinone iron(III) chelators in HepG2 cells

Published Online: Oct 18, 2019

Page range: 189 - 199

Received: Feb 26, 2018

Accepted: Jul 24, 2018

DOI: https://doi.org/10.2478/intox-2018-0016

Keywordsiron chelator, 3-hydroxy-4-pyridinone (3,4-HPO), rhodamine, toxicity, HepG2 cells

© 2018 Interdisciplinary Toxicology, published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Keywords
iron chelator, 3-hydroxy-4-pyridinone (3,4-HPO), rhodamine, toxicity, HepG2 cells