Design, synthesis and biological evaluation of a series of iron and copper chelating deferiprone derivatives as new agents active against Candida albicans

Martina Bortolami; Fabiana Pandolfi; Antonella Messore; Daniele Rocco; Marta Feroci; Roberto Di Santo; Daniela De Vita; Roberta Costi; Paola Cascarino; Giovanna Simonetti; Luigi Scipione

doi:10.1016/j.bmcl.2021.128087

Design, synthesis and biological evaluation of a series of iron and copper chelating deferiprone derivatives as new agents active against Candida albicans

Bioorg Med Chem Lett. 2021 Jun 15:42:128087. doi: 10.1016/j.bmcl.2021.128087. Epub 2021 May 6.

Authors

Affiliations

¹ Department of Scienze di Base e Applicate per l'Ingegneria, Sapienza University of Rome, via Castro Laurenziano 7, 00161 Rome, Italy.
² Department of Scienze di Base e Applicate per l'Ingegneria, Sapienza University of Rome, via Castro Laurenziano 7, 00161 Rome, Italy. Electronic address: fabiana.pandolfi@uniroma1.it.
³ Department of Chimica e Tecnologia del Farmaco, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
⁴ Department of Chimica e Tecnologia del Farmaco, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; Istituto Pasteur, Fondazione Cenci Bolognetti, Department of Chemistry and Technology of Drug, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
⁵ Department of Environmental Biology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
⁶ Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
⁷ Department of Environmental Biology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy. Electronic address: giovanna.simonetti@uniroma1.it.

PMID: 33964446
DOI: 10.1016/j.bmcl.2021.128087

Abstract

Candida albicans, in specific conditions, is responsible of severe invasive systemic candidiasis that are related to its ability to produce biofilm on biological and artificial surfaces. Many studies reported the role of iron in fungal growth and virulence and the ability of metal chelating agents to interfere with C. albicans metabolism, virulence and biofilm formation. Here we report the activity of 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone (deferiprone) derivatives against C. albicans planktonic cells and biofilm. Some of the studied compounds (2b and 3b) were able to chelate Fe(III) and Cu(II), and showed an interesting activity on planktonic cells (MIC₅₀ of 32 μg/mL and 16 μg/mL respectively) and on biofilm formation (BMIC₅₀ of 32 μg/mL and 16 μg/mL respectively) in cultured ATCC 10,231C. albicans; this activity was reduced, in a concentration dependent way, by the addition of Fe(III) and Cu(II) to the culture media. Furthermore, the most active compound 3b showed a low toxicity on Galleria mellonella larvae.

Keywords: Biofilm; Candida albicans; Deferiprone; Galleria mellonella; Metal chelation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antifungal Agents / chemical synthesis
Antifungal Agents / chemistry
Antifungal Agents / pharmacology*
Candida albicans / drug effects*
Chelating Agents / chemical synthesis
Chelating Agents / chemistry
Chelating Agents / pharmacology*
Copper / chemistry
Copper / pharmacology*
Deferiprone / chemistry
Deferiprone / pharmacology*
Dose-Response Relationship, Drug
Drug Design
Iron / chemistry
Iron / pharmacology*
Microbial Sensitivity Tests
Molecular Structure
Structure-Activity Relationship

Substances

Antifungal Agents
Chelating Agents
Deferiprone
Copper
Iron