Precious metal complexes of bis(pyridyl)allenes: synthesis and catalytic and medicinal applications

Maliszewska, Hanna K.; Valle, Carla Arnau del; Xia, Ying; Marín, María J.; Waller, Zoë A. E.; Muñoz, María Paz

doi:10.1039/d1dt02929k

Cited by 8 publications

(7 citation statements)

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“…The first class of compounds with the allene in the structure have recently been reported in several catalytic applications, in their interaction with i-motif DNA and as potential anticancer agents. 105 From this series, the free ligands (Au-Ligand1 and Au-Ligand2) as well as the platinum(IV) complexes did not show any activity against any tested strains in CO-ADD (Table S6 in SI). The palladium(II) analogues showed good activity against MRSA and the two yeasts tested but also exhibited high levels of cytotoxicity against the mammalian cell line.…”

Section: Resultsmentioning

confidence: 91%

Metal Complexes as Antifungals? – From a Crowd-Sourced Compound Library to First In Vivo Experiments

Frei

Elliott

Kan

et al. 2022

Preprint

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There are currently fewer than ten antifungal drugs in clinical development, but new fungal strains, which are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains, compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties at similar concentrations. The structures of 21 metal complexes which display high antifungal activity (MIC ≤ 1.25 µM) are discussed and evaluated further against a broad panel of yeasts. Most of these have not been evaluated for antifungal activity. Eleven of these metal complexes were tested for toxicity in the Galleria mellonella moth larvae model, revealing that only one compound showed signs of toxicity at the highest injected concentration. Lastly, we demonstrated that the organo-Pt(II) cyclooctadiene complex Pt1 significantly reduces fungal load in an in vivo G. mellonella infection model. These findings showcase that the structural and chemical diversity of metal-based compounds can be an invaluable tool in the development of new drugs against infectious diseases.

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Section: Resultsmentioning

confidence: 91%

Metal Complexes as Antifungals? – From a Crowd-Sourced Compound Library to First In Vivo Experiments

Frei

Elliott

Kan

et al. 2022

Preprint

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“…Compound 6, bearing N-methylpiperazine periphery, showed much higher activity against methicillinresistant S. aureus (MRSA) with a low MIC of only 1 μg/mL (D max = 98.5%). MRSA is one of the most prominent and widespread pathogenic organisms responsible for serious hospital and community-acquired infections and is therefore considered a high priority for new antibiotic discovery [33][34][35]. Te obtained MIC value for compound 6 against MRSA (ATCC 43300) is superior relative to the reference oxacillin (MIC = 2 μg/mL) when examined against the same strain [36].…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Antimicrobial, and Anticancer Activities of Novel Nitrofuran Derivatives

Mohamed

Elamin

Alenazy

et al. 2023

Journal of Chemistry

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Keeping in view the varying therapeutic attributes of 5-nitrofuran and isatin derivatives, novel 5-nitrofuran‒isatin molecular hybrids (2, 5–7) were synthesized by standard protocols, characterized by various spectroscopic techniques, and eventually evaluated against a group of pathogenic bacteria and fungi. Greater potency against Methicillin-resistant Staphylococcus aureus (MRSA) was exhibited by hybrids 5 and 6 with minimum inhibitory concentration values of 8 and 1 μg/mL, respectively. Cytotoxicity against both human embryonic kidney cells (HEK-293) and human red blood cells (RBCs) was investigated for the hybrids in hand. All hybrids appeared to have good safety; all of them were devoid of cytotoxicity, and none displayed hemolytic activity at the highest test concentration (CC50 and HI10 > 32 μg/mL). To support the postulation that these hybrids would be analogous to drugs containing the 5-nitrofurn ring system, molecular docking was carried out to streamline the binding affinity of the investigated hybrids towards the E. coli nitroreductase (NTR). Compared to the standard drug nitrofurazone, hybrid 6 demonstrated a higher affinity and better binding interactions with the NTR binding pocket. Therefore, it could be concluded that 6 displays its antibacterial action through a mechanism similar to that of nitrofurazone. Nonetheless, further wet investigations are to be conducted to confirm this finding. Encouraged by the well-established anticancer activity of isatin derivatives, 2, 5–7 were assessed for their potential antitumor activity, and they well demonstrated potent inhibitory activity against the human colon cancer cell line HCT 116 (IC50 = 1.62–8.8 μM) with isatin hybrid 3 being the best (IC50 = 1.62 μM). Thus, it is herein reported that these 5-nitrofuran‒isatin molecular hybrids could represent an ideal starting point for future studies to develop potent antimicrobial agents.

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“…Lastly, Au4 (Figure ) was part of a series of complexes containing an intact bis(pyridyl)allene framework (formed with palladium(II), platinum(IV), and gold(III)), a vinyl-platinum(II) metallacycle, and a series of gold(I) and gold(III) carbenes formed by the nucleophilic attack of an allenic pyridine into the allene moiety (Figure S10 in SI). Allene-containing complexes have recently been reported as potential anticancer agents, among other activities . The free ligands ( Au-Ligand1 and Au-Ligand2 ), as well as the corresponding platinum(IV) complexes, did not show any antimicrobial activity (Table S6 in SI).…”

Section: Resultsmentioning

confidence: 99%

“…Allenecontaining complexes have recently been reported as potential anticancer agents, among other activities. 106 The free ligands (Au-Ligand1 and Au-Ligand2), as well as the corresponding platinum(IV) complexes, did not show any antimicrobial activity (Table S6 in SI). The palladium(II) analogues showed good activity against MRSA and the two yeasts tested but were cytotoxic.…”

Section: Add Were Originally Made With Very Different Applications In...mentioning

confidence: 99%

Metal Complexes as Antifungals? From a Crowd-Sourced Compound Library to the First In Vivo Experiments

Frei

Elliott

Kan

et al. 2022

JACS Au

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There are currently fewer than 10 antifungal drugs in clinical development, but new fungal strains that are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work, we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or hemolytic properties at similar concentrations. The structures of 21 metal complexes that display high antifungal activity (MIC ≤1.25 μM) are discussed and evaluated further against a broad panel of yeasts. Most of these have not been previously tested for antifungal activity. Eleven of these metal complexes were tested for toxicity in the Galleria mellonella moth larva model, revealing that only one compound showed signs of toxicity at the highest injected concentration. Lastly, we demonstrated that the organo-Pt(II) cyclooctadiene complex Pt1 significantly reduces fungal load in an in vivo G. mellonella infection model. These findings showcase that the structural and chemical diversity of metal-based compounds can be an invaluable tool in the development of new drugs against infectious diseases.

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Precious metal complexes of bis(pyridyl)allenes: synthesis and catalytic and medicinal applications

Abstract: Bis(pyridyl)allenes: unique 3D scafolds for novel metal coordination complexes with unreported applications in catalysis and as metallodrugs.

Cited by 8 publications

References 105 publications

Metal Complexes as Antifungals? – From a Crowd-Sourced Compound Library to First In Vivo Experiments

Metal Complexes as Antifungals? – From a Crowd-Sourced Compound Library to First In Vivo Experiments

Synthesis, Antimicrobial, and Anticancer Activities of Novel Nitrofuran Derivatives

Metal Complexes as Antifungals? From a Crowd-Sourced Compound Library to the First In Vivo Experiments

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