Nitro-imidazole-based ruthenium complexes with antioxidant and anti-inflammatory activities

Sasahara, Greyce Luri; Júnior, Florêncio Sousa Gouveia; Rodrigues, Rodrigo Rodrigues; Zampieri, Dávila; Fonseca, Said Gonçalves da Cruz; Gonçalves, Rita de Cássia Ribeiro; Athaydes, Brena Ramos; Kitagawa, Rodrigo Rezende; Santos, Flávia Almeida; Sousa, Eduardo Henrique Silva; Nagão-Dias, Aparecida Tiemi; Lopes, Luiz Gonzaga de França

doi:10.1016/j.jinorgbio.2020.111048

Cited by 26 publications

(12 citation statements)

References 87 publications

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“…Besides the successful introduction of Ru(II)−polypyridyl complexes bearing 2-nitroimidazole in the treatment and visualization of cancer, 26−28 the combination of this class of compounds with nitroimidazole derivatives to develop novel antibacterial agents still remains scarcely explored, being, to the best of our knowledge, the only exception recently reported by Sasahara and co-workers, 29 PF 6 , performed accordingly to the literature, 30,31 these intermediates were allowed to react with 5-nitroimidazole in a hot ethanol−water mixture, affording the replacement of the chloro ligand with the nitroimidazole ring. Addition of aqueous KPF 6 led to the precipitation of the hexafluorophosphate salts 1 and 2, which were obtained, after purification by flash chromatography, in 58% and 35% yields, respectively.…”

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“…Besides the successful introduction of Ru(II)–polypyridyl complexes bearing 2-nitroimidazole in the treatment and visualization of cancer, − the combination of this class of compounds with nitroimidazole derivatives to develop novel antibacterial agents still remains scarcely explored, being, to the best of our knowledge, the only exception recently reported by Sasahara and co-workers, who designed two kinetically inert compounds, [Ru(NO 2 )(bpy) 2 (5NIMH)]PF 6 and cis -[RuCl(bpy) 2 (MTZ)]PF 6 (bpy = 2,2′-bipyridine, MTZ = metronidazole), effective toward metronidazole-resistant strains of H. pylori .…”

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confidence: 99%

“…Therefore, in contrast to the “classical” Ru(II)-coordination by a neutral 5NIMH unit, , also proposed by Sasahara and co-workers for cis -[Ru(NO 2 )(bpy) 2 (5NIMH)] + , our findings indicate that metal coordination can effectively cause the deprotonation of 5-nitroimidazole. This occurs without using strong bases to preliminarily generate the imidazolate species, as generally required to produce Ru(II)-imidazolate species .…”

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Nitroimidazole-Based Ruthenium(II) Complexes: Playing with Structural Parameters to Design Photostable and Light-Responsive Antibacterial Agents

et al. 2021

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5-Nitroimidazole (5NIMH), chosen as a molecular model of nitroimidazole derivatives, which represent a broadspectrum class of antimicrobials, was incorporated into the ruthenium complexes [Ru(tpy)(phen)(5NIM)]PF 6 (1) and [Ru(tpy)(dmp)(5NIM)]PF 6 (2) (tpy = terpyridine, phen = phenanthroline, dmp = 2,9-dimethyl-1,10-phenanthroline). Besides the uncommon metal coordination of 5-nitroimidazole in its imidazolate form (5NIM), the different architectures of the spectator ligands (phen and dmp) were exploited to tune the "mode of action" of the resulting complexes, passing from a photostable compound where the redox properties of 5NIMH are preserved (1) to one suitable for the nitroimidazole phototriggered release (2) and whose antibacterial activity against B. subtilis, chosen as cellular model, is effectively improved upon light exposure. This study may provide a fundamental knowledge on the use of Ru(II)−polypyridyl complexes to incorporate and/or photorelease biologically relevant nitroimidazole derivatives in the design of a novel class of antimicrobials.

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Nitroimidazole-Based Ruthenium(II) Complexes: Playing with Structural Parameters to Design Photostable and Light-Responsive Antibacterial Agents

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“…Considering an increased interest in identification of antibacterial nitro-heterocyclic compounds [ 31 , 35 , 38 , 39 , 40 ], we initiated investigations of fexinidazole and its two principal metabolites, fexinidazole sulfoxide and fexinidazole sulfone, against H. pylori . Moreover, the recent FDA approval of fexinidazole makes it a good candidate to repurpose for the treatment of H. pylori infection cost-effectively.…”

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A Bioluminescence-Based Drug Screen Identifies Activities of Fexinidazole and Its Metabolites against Helicobacter pylori

et al. 2022

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Helicobacter pylori is responsible for a wide range of gastric diseases, including gastric cancer and gastritis. With half of the world’s population infected by H. pylori and the current standard of care associated with suboptimal outcomes, a search for more effective drugs is critical. To facilitate drug screening for H. pylori, we developed a microtiter plate-based compound screening method that is faster and can screen multiple compounds. We identified activities of fexinidazole and its sulfoxide and sulfone metabolites against H. pylori. Both fexinidazole and its metabolites exhibited equipotency against SS1, 60190, and G27 strains, which were about 3–6-fold more potent than the currently used metronidazole. We also determined the minimal inhibitory concentration (MIC) of metronidazole, fexinidazole, and its metabolites against these strains by a traditional agar plate-based method. While MIC values of fexinidazole and metronidazole were similar against all the strains, both sulfoxide and sulfone showed lower MIC values than metronidazole against SS1 and 60190. Given the recent FDA approval of fexinidazole, our data on the in vitro antibacterial activities of fexinidazole and its metabolites support further evaluation of this drug with the goal of producing an alternative nitro-based antimicrobial with good safety profiles for the treatment of H. pylori infection.

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“…In addition, molecular docking using FOR811A showed a strong interaction with the heme group of cGC [262]. Another compound, cis-[Ru(NO 2 )(bpy) 2 (5NIM)]PF 6 complex showed a potential pharmacological application as an antioxidant and anti-inflammatory (inhibition of pro-inflammatory cytokines) in in vitro studies [263].…”

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confidence: 99%

Nitric Oxide as a Central Molecule in Hypertension: Focus on the Vasorelaxant Activity of New Nitric Oxide Donors

Silva

Nascimento

et al. 2021

Biology

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Cardiovascular diseases include all types of disorders related to the heart or blood vessels. High blood pressure is an important risk factor for cardiac complications and pathological disorders. An increase in circulating angiotensin-II is a potent stimulus for the expression of reactive oxygen species and pro-inflammatory cytokines that activate oxidative stress, perpetuating a deleterious effect in hypertension. Studies demonstrate the capacity of NO to prevent platelet or leukocyte activation and adhesion and inhibition of proliferation, as well as to modulate inflammatory or anti-inflammatory reactions and migration of vascular smooth muscle cells. However, in conditions of low availability of NO, such as during hypertension, these processes are impaired. Currently, there is great interest in the development of compounds capable of releasing NO in a modulated and stable way. Accordingly, compounds containing metal ions coupled to NO are being investigated and are widely recognized as having great relevance in the treatment of different diseases. Therefore, the exogenous administration of NO is an attractive and pharmacological alternative in the study and treatment of hypertension. The present review summarizes the role of nitric oxide in hypertension, focusing on the role of new NO donors, particularly the metal-based drugs and their protagonist activity in vascular function.

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Nitro-imidazole-based ruthenium complexes with antioxidant and anti-inflammatory activities

Cited by 26 publications

References 87 publications

Nitroimidazole-Based Ruthenium(II) Complexes: Playing with Structural Parameters to Design Photostable and Light-Responsive Antibacterial Agents

Nitroimidazole-Based Ruthenium(II) Complexes: Playing with Structural Parameters to Design Photostable and Light-Responsive Antibacterial Agents

A Bioluminescence-Based Drug Screen Identifies Activities of Fexinidazole and Its Metabolites against Helicobacter pylori

Nitric Oxide as a Central Molecule in Hypertension: Focus on the Vasorelaxant Activity of New Nitric Oxide Donors

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