Ruthenium(II) Polypyridyl Complexes and Metronidazole Derivatives: A Powerful Combination in the Design of Photoresponsive Antibacterial Agents Effective under Hypoxic Conditions

Abstract

Ruthenium(II) polypyridyl complexes (RPCs) are gaining momentum in photoactivated chemotherapy (PACT), thanks to the possibility of overcoming the classical reliance on molecular oxygen of photodynamic therapy while preserving the selective drug activation by using light. However, notwithstanding the intriguing perspectives, the translation of such an approach in the development of new antimicrobials has been only barely considered. Herein, MTZH-1 and MTZH-2, two novel analogues of metronidazole (MTZ), a mainstay drug in the treatment of anaerobic bacterial infections, were designed and inserted in the strained ruthenium complexes [Ru(tpy)(dmp)(MTZ-1)]PF6 (Ru2) and [Ru(tpy)(dmp)(MTZ-2)]PF6 (Ru3) (tpy = terpyridine, dmp = 2,9-dimethyl-1,10-phenanthroline) (Chart 1). Analogously to the parental compound [Ru(tpy)(dmp)(5NIM)]PF6 (Ru1) (5-nitroimidazolate), the Ru(II)-imidazolate coordination of MTZ derivatives resulted in promising Ru(II) photocages, capable to easily unleash the bioactive ligands upon light irradiation and increase the antibacterial activity against Bacillus subtilis, which was chosen as a model of Gram-positive bacteria. The photoreleased 5-nitroimidazole-based ligands led to remarkable phototoxicities under hypoxic conditions (<1% O2), with the lead compound Ru3 that exhibited the highest potency across the series, being comparable to the one of the clinical drug MTZ. Besides, the chemical architectures of MTZ derivatives made their interaction with NimAunfavorable, being NimA a model of reductases responsible for bacterial resistance against 5-nitroimidazole-based antibiotics, thus hinting at their possible use to combat antimicrobial resistance. This work may therefore provide fundamental knowledge in the design of novel photoresponsive tools to be used in the fight against infectious diseases. For the first time, the effectiveness of the “photorelease antimicrobial therapy” under therapeutically relevant hypoxic conditions was demonstrated.

Half‐sandwich ruthenium(II) and iridium(III) complexes of imidazole based phosphinite ligands: antioxidant and antibacterial activities as well as electrochemical properties

“…Complexes were shown expressive in vitro antioxidant activity, reducing lipid peroxidation and decreasing intracellular ROS levels with comparable effectiveness to the standard steroidal drug dexamethasone or α‐tocopherol [31] . Futhermore, nitroimidazole derivatives reported usage in the design of a novel class of antimicrobials and tools to be used in the fight against infectious diseases [32,33] . Since many biological structures, like RNA and DNA, a variety of phospholipids, and some parts of proteins, are negatively charged, the positive charges of the metal complexes may facilitate the binding to targets in cell via electrostatic interaction [34,35] .…”

“…Futhermore, nitroimidazole derivatives reported usage in the design of a novel class of antimicrobials and tools to be used in the fight against infectious diseases. [32,33] Since many biological structures, like RNA and DNA, a variety of phospholipids, and some parts of proteins, are negatively charged, the positive charges of the metal complexes may facilitate the binding to targets in cell via electrostatic interaction. [34,35] Therefore, the preparation of metal complexes based on imidazolium and the analysis of their biological activity were the main goals of this work.…”

Photosensitizers Based on Bichromophoric Dyads Combining Ru(II)-Polypyridyl Complexes and Dissymmetric Perylene Monoimide Derivatives: The Nontrivial Role of Ligand Substitution

“…Ruthenium polypyridyl complexes (RPCs) continue to attract increasing interest for their use in photodynamic therapy (PDT), a therapeutic cancer treatment relying on the photoactivation of a photosensitizer molecule, ultimately producing harmful cytotoxic oxygen species. The main advantage of this method as compared with traditional therapies is the complete spatiotemporal control over the drug activation, allowing to considerably limit the side effects normally associated with chemotherapy. − The interest in employing RPCs as PDT photosensitizers arises from the possibility of accessing a variety of excited-state configurations − by tuning the nature of ligands in their octahedral geometries, thus modulating their capacity to efficiently sensitize the formation of singlet oxygen ( 1 O 2 ), which is highly cytotoxic . Since singlet oxygen ( 1 Δ g ) is produced from the energy transfer between the triplet excited state of the photosensitizer (PS*) and ground-state molecular oxygen ( 3 Σ g – ) through type II pathways, prolonging the triplet excited-state lifetimes represents a suitable strategy to boost the singlet oxygen sensitizing properties.…”

Development of Ruthenium Nanophotocages with Red or Near‐Infrared Light‐Responsiveness

“…Furthermore, Giorgi et al employed nitroimidazole-based Ru complexes, which released imidazole ligands when exposed to light (434 nm, 384 J cm À 2 ), achieving an enhanced antibacterial effect (Figure 1c). [12] Although small-molecule Ru photocages exhibit remarkable PACT or PDT effects, their practical use is often reduced due to their limited tumor targeting capabilities. In addition, the rapid metabolism of small Ru complexes also hinders their clinical application.…”