Design, synthesis and in vivo evaluation of 3-arylcoumarin derivatives of rhenium(I) tricarbonyl complexes as potent antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA)

• Published in: European journal of medicinal chemistry Vol. 205; pp. 112533 - 112548
• Main Authors: Sovari, Sara Nasiri, Vojnovic, Sandra, Bogojevic, Sanja Skaro, Crochet, Aurelien, Pavic, Aleksandar, Nikodinovic-Runic, Jasmina, Zobi, Fabio
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.11.2020; Elsevier
• Subjects: Animals; Antibiotic; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Coumarins - chemical synthesis; Coumarins - chemistry; Coumarins - pharmacology; Drug Design; Life Sciences & Biomedicine; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; MRSA; Pharmacology & Pharmacy; Rhenium - chemistry; Rhenium(I) tricarbonyl complex; Science & Technology; Staphylococcus aureus; Zebrafish; Antibiotic; Rhenium(I) tricarbonyl complex; Staphylococcus aureus; MRSA; VITRO; ORGANOMETALLIC COMPOUNDS; ZEBRAFISH; DRUG DISCOVERY; ANTIMICROBIAL AGENTS; PHOTOPHYSICAL PROPERTIES; IRIDIUM(III) COMPLEXES; BIOLOGICAL EVALUATION; BLOOD-STREAM INFECTIONS; COUMARIN DERIVATIVES
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112533

We have prepared a series of ten 3-arylcoumarin molecules, their respective fac-[Re(CO)3(bpy)L]+ and fac-[Re(CO)3(L⁀L)Br] complexes and tested all compounds for their antimicrobial efficacy. Whereas the 3-arylcoumarin ligands are virtually inactive against the human-associated pathogens with minimum inhibitory concentrations (MICs) > 150 μM, when coordinated to the fac-[Re(CO)3]+ core, most of the resulting complexes showed remarkable antibacterial potency. Several rhenium complexes exhibit activity in nanomolar concentrations against Gram-positive pathogens such as Staphylococcus aureus strains, including methicillin-resistant S. aureus (MRSA) and Enterococcus faecium. The molecules do not affect bacterial cell membrane potential, but some of the most potent complexes strongly interact with DNA, indicating it as a possible target for their mode of action. In vivo studies in the zebrafish model showed that the complexes with anti-staphylococcal/MRSA activity were non-toxic to the organism even at much higher doses of the corresponding MICs. In the zebrafish-MRSA infection model, the complexes increased the survival rate of infected fish up to 100% and markedly reduced bacterial burden. Moreover, all rescued fish developed normally following the treatments with the metallic compounds. [Display omitted] •3-arylcoumarin derivatives of rhenium with antimicrobial properties.•Active complexes against S. aureus and E. faecium in nanomolar concentrations.•DNA interaction possible mode of activity.•Complexes efficient in the zebrafish-MRSA infection model.