Isostructural Series of Ni(II), Pd(II), Pt(II), and Au(III) Azido Complexes with a N

An isoelectronic and isostructural series of cyclometalated azido complexes [M(N3)(dpb)] with M = Ni(II), Pd(II), Pt(II), and Au(III) based on the N^C^N pincer ligand 1,3-di(2-pyridyl)phenide (dpb) was characterized by X-ray diffraction analysis and investigated for reactivity in the iClick reaction with a wide range of internal and terminal alkynes by using 1H and 19F NMR spectroscopy. Reaction rate constants were found to increase with greater charge density in the order Ni(II) > Pd(II) > Pt(II) > Au(III). Terminal alkynes R-C≡C-R' with strongly electron-withdrawing groups R and R' exhibited faster kinetics than those with electron-donating substituents in the order CF3 > ketone > ester > H > phenyl ≫ amide, while R = CH3 resulted in complete loss of reactivity. Four symmetrical triazolato complexes [M(triazolatoCOOCH3,COOCH3)(dpb)] with M = Ni(II), Pd(II), Pt(II), and Au(III) as well as four nonsymmetrically substituted triazolato complexes [Pt(triazolatoR,R')(dpb)] originating from terminal and internal alkynes were shown by X-ray crystal structure analysis to exclusively feature N2-coordination of the five-membered ring ligand. However, the Pt(II) triazolato complexes exist as a mixture of N1- and N2-coordinated species in solution. Torsion angles between the mean planes of the N^C^N pincer and the triazolato ligand increase from a nearly coplanar to a perpendicular arrangement when going from Au(III)/Pt(II)/Pd(II) to Ni(II), while different substituents R and R' on the alkyne have no influence on the torsion angle and were rationalized by DFT calculations. Finally, a carbohydrate derivative obtained by glucuronic acid conjugation to methyl propiolate demonstrates the facile biofunctionalization of metal complexes via the iClick reaction.

Taming the Biological Activity of Pd(II) and Pt(II) Complexes with Triazolato "Protective" Groups: 1H, 77Se Nuclear Magnetic Resonance and X-ray Crystallographic Model Studies with Selenocysteine to Elucidate Differential Thioredoxin Reductase Inhibition.

The biological activity of Pd(II) and Pt(II) complexes toward three different cancer cell lines as well as inhibition of selenoenzyme thioredoxin reductase (TrxR) was modulated in an unexpected way by the introduction of triazolate as a "protective group" to the inner metal coordination sphere using the iClick reaction of [M(N3)(terpy)]PF6 [M = Pd(II) or Pt(II) and terpy = 2,2':6',2″-terpyridine] with an electron-poor alkyne. In a cell proliferation assay using A549, HT-29, and MDA-MB-231 human cancer cell lines, the palladium compound was significantly more potent than the isostructural platinum analogue and exhibited submicromolar activity on the most responsive cell line. This difference was also reflected in the inhibitory efficiency toward TrxR with IC50 values of 0.1 versus 5.4 µM for the Pd(II) and Pt(II) complexes, respectively. UV/Vis kinetic studies revealed that the Pt compound binds to selenocysteine faster than to cysteine [k = (22.9 ± 0.2)·10-3 vs (7.1 ± 0.2)·10-3 s-1]. Selective triazolato ligand exchange of the title compounds with cysteine (Hcys) and selenocysteine (Hsec)─but not histidine (His) and 9-ethylguanine (9EtG)─was confirmed by 1H, 77Se, and 195Pt NMR spectroscopy. Crystal structures of three of the four ligand exchange products were obtained, including [Pt(sec)(terpy)]PF6 as the first metal complex of selenocysteine to be structurally characterized.

The manganese carbonyl complex [Mn(CO)3(tqa-κ3N)]Br: A novel antimicrobial agent with the potential to treat avian pathogenic Escherichia coli (APEC) infections.

The development of alternatives to antibiotics is essential for the treatment of animal infections and as a measure to reduce the selective pressure on antibiotics that are critical for human medicine. Metal complexes have been highlighted for their antimicrobial activity against several bacterial pathogens. In particular, manganese carbonyl complexes have shown efficacy against multidrug-resistant Gram-negative pathogens, and relatively low cytotoxicity against avian macrophages and in wax moth larval models. They are thus potential candidates for deployment against Avian Pathogenic Escherichia coli (APEC), the aetiological agent of avian colibacillosis, which results in severe animal welfare issues and financial losses worldwide. This study aimed to determine the efficacy of [Mn(CO)3(tqa-κ3N)]Br in Galleria mellonella and chick models of infection against APEC. The results demonstrated in vitro and in vivo antibacterial activity against all antibiotic-resistant APEC test isolates screened in the study.

Ferrocenoyl-substituted quinolinone and coumarin as organometallic inhibitors of SARS-CoV-2 3CLpro main protease.

The 3-chymotrypsin-like protease 3CLpro from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a potential target for antiviral drug development. In this work, three organometallic ferrocene-modified quinolinones and coumarins were compared to their benzoic acid ester analogues with regard to inhibition of 3CLpro using an HPLC-based assay with a 15mer model peptide as the substrate. In contrast to FRET-based assays, this allows direct identification of interference of buffer constituents with the inhibitors, as demonstrated by the complete abolishment of ebselen inhibitory activity in the presence of dithiothreitol as a redox protectant. The presence of the organometallic ferrocene moiety significantly increased the stability of the title compounds towards hydrolysis. Among the studied compounds, 4-ferrocenyloxy-1-methyl-quinol-2-one was identified as the most stable and potent inhibitor candidate. IC50 values determined for ebselen and this sandwich complex compound are (0.40 ± 0.07) and (2.32 ± 0.21) µM, respectively.

Electrospray Mass Spectrometry to Study Combinatorial iClick Reactions and Multiplexed Kinetics of [Ru(N3)(N∧N)(terpy)]PF6 with Alkynes of Different Steric and Electronic Demand.

In a combinatorial approach, a family of ruthenium(II) azido complexes [Ru(N3)(N∧N)(terpy)]PF6 with terpy = 2,2':6',2″-terpyridine and N∧N as a bidentate chelator derived from 2,2'-biypridine and its 4,4'-disubstituted derivatives, 2,2'-bipyrimidine, and 1,10-phenanthroline were reacted with different internal and terminal alkynes to give access to a total of 7 × 7 = 49 triazolato complexes in a room-temperature catalyst-free iClick reaction. The reactants were mixed in a repurposed high-performance liquid chromatography (HPLC) autosampler, and the reaction progress was monitored by direct injection into an electrospray mass spectrometer. The ratio of the peak intensities of [Ru(N3)(N∧N)(terpy)]+ and [Ru(triazolato)(N∧N)(terpy)]+ was converted to a colored heat map for facile visual inspection of the conversion ratio. By automated multiple injections of the reaction mixture in fixed time intervals and plotting peak intensities over reaction time, pseudo-first-order rate constants were easily determined. Finally, nonoverlapping isotope patterns of the azido starting materials and triazolato products enabled multiplexed parallel determination of rate constants for four different ruthenium(II) azido complexes from a single sample vial, thereby reducing experiment time by 75%.

SELFIES and the future of molecular string representations.

Artificial intelligence (AI) and machine learning (ML) are expanding in popularity for broad applications to challenging tasks in chemistry and materials science. Examples include the prediction of properties, the discovery of new reaction pathways, or the design of new molecules. The machine needs to read and write fluently in a chemical language for each of these tasks. Strings are a common tool to represent molecular graphs, and the most popular molecular string representation, Smiles, has powered cheminformatics since the late 1980s. However, in the context of AI and ML in chemistry, Smiles has several shortcomings-most pertinently, most combinations of symbols lead to invalid results with no valid chemical interpretation. To overcome this issue, a new language for molecules was introduced in 2020 that guarantees 100% robustness: SELF-referencing embedded string (Selfies). Selfies has since simplified and enabled numerous new applications in chemistry. In this perspective, we look to the future and discuss molecular string representations, along with their respective opportunities and challenges. We propose 16 concrete future projects for robust molecular representations. These involve the extension toward new chemical domains, exciting questions at the interface of AI and robust languages, and interpretability for both humans and machines. We hope that these proposals will inspire several follow-up works exploiting the full potential of molecular string representations for the future of AI in chemistry and materials science.

Tuning the coordination properties of chiral pseudopeptide bis(2-picolyl)amine and iminodiacetamide ligands in Zn(II) and Cu(II) complexes.

Seven bis(2-picolyl)amine (bpa) and five iminodiacetamide (imda) ligands were prepared with different modifications in their side chain structure. The coordination properties of the ligands (L) were influenced by changes in the aliphatic linker length (C1, C2, or C3), amide group isomers and type of chiral terminal group. Complexation with Cu(II) afforded two polymorphs of a ML complex which features tetradentate coordination of a ligand with C2 linkers, while crystal structures of three trans-fac ML2 complexes with Cu(II) and Ni(II) show tridentate coordination of ligands with a C3 linker. The stoichiometry and stereochemistry of Zn(II) and Cu(II) complexes was further studied in solution by NMR and UV-Vis spectroscopy. DFT calculations gave an insight into the relative stability of isomers, as well as potential hydrogen bonding between two ligands in a ML2 complex. Furthermore, ML complexes of Cu(II) exhibited DNA cleavage activity.

TUCAN: A molecular identifier and descriptor applicable to the whole periodic table from hydrogen to oganesson.

TUCAN is a canonical serialization format that is independent of domain-specific concepts of structure and bonding. The atomic number is the only chemical feature that is used to derive the TUCAN format. Other than that, the format is solely based on the molecular topology. Validation is reported on a manually curated test set of molecules as well as a library of non-chemical graphs. The serialization procedure generates a canonical "tuple-style" output which is bidirectional, allowing the TUCAN string to serve as both identifier and descriptor. Use of the Python NetworkX graph library facilitated a compact and easily extensible implementation.

Metallodrug Profiling against SARS-CoV-2 Target Proteins Identifies Highly Potent Inhibitors of the S/ACE2 interaction and the Papain-like Protease PLpro.

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has called for an urgent need for dedicated antiviral therapeutics. Metal complexes are commonly underrepresented in compound libraries that are used for screening in drug discovery campaigns, however, there is growing evidence for their role in medicinal chemistry. Based on previous results, we have selected more than 100 structurally diverse metal complexes for profiling as inhibitors of two relevant SARS-CoV-2 replication mechanisms, namely the interaction of the spike (S) protein with the ACE2 receptor and the papain-like protease PLpro . In addition to many well-established types of mononuclear experimental metallodrugs, the pool of compounds tested was extended to approved metal-based therapeutics such as silver sulfadiazine and thiomersal, as well as polyoxometalates (POMs). Among the mononuclear metal complexes, only a small number of active inhibitors of the S/ACE2 interaction was identified, with titanocene dichloride as the only strong inhibitor. However, among the gold and silver containing complexes many turned out to be very potent inhibitors of PLpro activity. Highly promising activity against both targets was noted for many POMs. Selected complexes were evaluated in antiviral SARS-CoV-2 assays confirming activity for gold complexes with N-heterocyclic carbene (NHC) or dithiocarbamato ligands, a silver NHC complex, titanocene dichloride as well as a POM compound. These studies might provide starting points for the design of metal-based SARS-CoV-2 antiviral agents.

Ultrafast photochemistry of a molybdenum carbonyl-nitrosyl complex with a triazacyclononane coligand.

Transition metal complexes capable of releasing small molecules such as carbon monoxide and nitric oxide upon photoactivation are versatile tools in various fields of chemistry and biology. In this work, we report on the ultrafast photochemistry of [Mo(CO)2(NO)(iPr3tacn)]PF6 (iPr3tacn = 1,4,7-triisopropyl-1,4,7-triazacyclononane), which was characterized under continuous illumination and with femtosecond UV-pump/UV-probe and UV-pump/MIR-probe spectroscopy, as well as with stationary calculations. The experimental and theoretical results demonstrate that while the photodissociation of one of the two CO ligands upon UV excitation can be inferred both on an ultrafast timescale as well as under exposure times of several minutes, no evidence of NO release is observed under the same conditions. The binding mode of the diatomic ligands is impacted by the electronic excitation, and transient intermediates are observed on a timescale of tens of picoseconds before CO is released from the coordination sphere. Furthermore, based on calculated potential energy scans, we suggest that photolysis of NO could be possible after a subsequent excitation of an electronically excited state with a second laser pulse, or by accessing low-lying excited states that otherwise cannot be directly excited by light.

Antibacterial activity of Mn(I) and Re(I) tricarbonyl complexes conjugated to a bile acid carrier molecule.

A bifunctional cholic acid-bis(2-pyridylmethyl)amine (bpa) ligand featuring an amide linker was coordinated to a manganese(i) or rhenium(i) tricarbonyl moiety to give [M(bpacholamide)(CO)3] with M = Mn, Re in good yield and very high purity. Strong antibacterial activity was observed against four strains of methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus, with minimum inhibitory concentrations (MICs) in the range of 2-3.5 µM. No difference in response was observed for the MSSA vs. MRSA strains. Activity was also independent of the nature of the metal center, as the Mn and Re complexes showed essentially identical MIC values. In contrast to some other metal carbonyl complexes, the activity seems to be unrelated to the release of carbon monoxide, as photoactivation of the Mn complex reduced the potency by a factor of 2-8. Both metal complexes were non-toxic in Galleria mellonella larvae at concentrations of up to 100× the MIC value. In vivo testing in Galleria larvae infected with MRSA/MSSA demonstrated a significant increase in overall survival rates from 46% in the control to 88% in the group treated with the metal complexes. ICP-MS analysis showed that the Mn and Re cholamide complexes are efficiently internalized by E. coli cells and do not interfere with membrane integrity, as evident from a lack of release of intracellular ATP. An increased sensitivity was observed in acrB, acrD, and mdt mutants that are defective in multidrug exporters, indicating that the compounds have an intracellular mechanism of action. Furthermore, E. coli mntP mutants defective in the gene encoding an Mn exporter were more sensitive than the wildtype, while inactivation of the regulator that controls expression of the Mn uptake proteins MntP and MntH slightly increased sensitivity to the compound. Single knockout mutants defective in genes linked to bile salt and oxidative stress response (dinF, yiaH, sodA, katE, and soxS) did not show increased sensitivity relative to the wild type. Overall, neither the cholic acid moiety nor the metal-carbonyl fragment alone appear to be responsible for the biological activity observed and thus the search for the primary intracellular target continues.

Manganese complex [Mn(CO)3(tpa-κ3N)]Br increases antibiotic sensitivity in multidrug resistant Streptococcus pneumoniae.

OBJECTIVES: The emergence of multidrug-resistance (MDR) in Streptococcus pneumoniae clones and non-vaccine serotypes necessitate the development of novel treatment strategies. This work aimed to determine the efficacy of the Mn complex [Mn(CO)3(tpa-κ3N)]Br against clinically important MDR strains of S. pneumoniae. METHODS: Twenty MDR clinicalS. pneumoniae strains were included in this study. Minimum inhibitory concentrations (MICs) of [Mn(CO)3(tpa-κ3N)]Br were determined via broth microdilution alone and in combination with other antimicrobial agents using checkerboard assays and/or disc diffusion tests. In vitro efficacy was assessed by time-kill assays while in vivo efficacy was tested using the insect model Galleria mellonella. RESULTS: [Mn(CO)3(tpa-κ3N)]Br showed moderate in vitro efficacy against S. pneumoniae coupled with bactericidal activity. Checkerboard and disc diffusion assays showed synergy between [Mn(CO)3(tpa-κ3N)]Br and tetracycline, and the combination of both agents caused rapid kill-kinetics and reduced the MIC below the susceptibility breakpoint of 1 mg/L even for tetracycline-resistant strains of S. pneumoniae. Similar results were observed for the erythromycin- and the co-trimoxazole-Mn complex combination. In the G. mellonella infection model, mortality and morbidity rates at 96 h were significantly lower in larvae treated with [Mn(CO)3(tpa-κ3N)]Br than phosphate buffered saline, while treatment with the tetracycline-Mn complex combination was superior to monotherapy, resulting in significantly lower mortality and morbidity rates (p < 0.049). CONCLUSIONS: We show that [Mn(CO)3(tpa-κ3N)]Br has in vitro and in vivo antibacterial activity against clinically relevant strains of S. pneumoniae and has the potential to be used in combination with currently available antibiotics to increase their effectiveness against MDR S. pneumoniae.

Biological activity of manganese(i) tricarbonyl complexes on multidrug-resistant Gram-negative bacteria: From functional studies to in vivo activity in Galleria mellonella.

Three new manganese(i) tricarbonyl complexes [Mn(bpqa-κ3N)(CO)3]Br, [Mn(bqpa-κ3N)(CO)3]Br, and [Mn(CO)3(tqa-κ3N)]Br as well as the previously described compound [Mn(CO)3(tpa-κ3N)]Br with bpqa = bis(2-pyridinylmethyl)(2-quinolinylmethyl)amine, bqpa = bis(2-quinolinylmethyl)(2-pyridinylmethyl)amine, tqa = tris(2-quinolinylmethyl)amine, and tpa = tris(2-pyridinylmethyl)amine were examined for their antibacterial activities on 14 different multidrug-resistant clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa, in recognition of the current antimicrobial resistance (AMR) concerns with these pathogens. Minimal inhibitory concentrations (MIC) of the most potent tqa compound were in the mid-micromolar range and generally lower than that of the free ligand. Activity against both bacterial species increased with the number of quinolinylmethyl groups and lipophilicity in the order of tpa < bpqa < bqpa ≈ tqa, consistent with measured increases in release of ATP, a uniquely cytoplasmic biomolecule and induced permeability to exogenous fluorescent intercalating compounds. [Mn(CO)3(tqa-κ3N)]Br was also evaluated in the Galleria mellonella model of infection, and displayed a lack of host toxicity combined with effective bacterial clearance.

iClick Reactions of Square-Planar Palladium(II) and Platinum(II) Azido Complexes with Electron-Poor Alkynes: Metal-Dependent Preference for N1 vs N2 Triazolate Coordination and Kinetic Studies with 1H and 19F NMR Spectroscopy.

Two square-planar palladium(II) and platinum(II) azido complexes [M(N3)(L)] with L = N-phenyl-2-[1-(2-pyridinyl)ethylidene]hydrazine carbothioamide reacted with four different electron-poor alkynes R-C≡C-R' with R = R' = COOCH3, COOEt, COOCH2CH2OCH3 or R = CF3, R' = COOEt in a [3 + 2] cycloaddition "iClick" reaction. The resulting triazolate complexes [M(triazolateR,R')(L)] were isolated by simple precipitation and/or washing in high purity and good yield. Six out of the eight new compounds feature the triazolate ligand coordinated to the metal center via the N2 nitrogen atom, but fortuitous solubility properties allowed isolation of the N1 isomer in two cases from acetone. When the solvent was changed to DMSO, the N1 → N2 isomerization could be studied by NMR spectroscopy and took several days to complete. 19F NMR studies of the iClick reaction with F3C-C≡C-COOEt led to identification of a putative early linear intermediate in addition to the N1 and N2 isomers, however with the latter as the final product. Rate constants determined by 1H or 19F NMR spectroscopy increased in the order Pd > Pt and CF3/COOEt > COOR/COOR with R = CH3, Et, CH2CH2OCH3. The second-order rate constant k2 > 3.7 M-1 s-1 determined for the reaction of [Pd(N3)(L)] with F3C-C≡C-COOEt is the fastest observed for an iClick reaction so far and compares favorably with that of the most evolved strained alkynes reported for the SPAAC (strain-promoted azide-alkyne cycloaddition) to date. Selected title compounds were evaluated for their anticancer activity on the GaMG human glioblastoma brain cancer cell line and gave EC50 values in the low micromolar range (2-16 µM). The potency of the Pd(II) complexes increased with the chain length of the substituents in the 4- and 5-positions of the triazolate ligand.

2,2':6',2''-Terpyridine switches from tridentate to monodentate coordination in a gold(iii) terpy complex upon reaction with sodium azide.

Reaction of [AuCl(terpy-κ3-N1,1',1'')]Cl2 with an excess of sodium azide did not result in the expected exchange of the chlorido by an azido ligand to give [Au(N3)(terpy-κ3-N1,1',1'')]2+. Instead, X-ray structure analysis showed that the isolated product is [Au(N3)3(terpy-κ1-N1)], in which the terpyridine ligand is in a very rare monodentate coordination mode. This is also the dominant species in solution, together with a minor amount of [Au(N3)2(terpy-κ2-N1,1')]+. The stability of the tris(azido)gold(iii) moiety relative to other possible species was also confirmed by DFT calculations.

Metallointercalators and Metalloinsertors: Structural Requirements for DNA Recognition and Anticancer Activity.

As the carrier of the inheritable information in cells, DNA has been the target of metal complexes for over 40 years. In this chapter, the focus will be on non-covalent recognition of the highly structured DNA surface by substitutionally inert metal complexes capable of either sliding in between the normal base pairs as metallointercalators or flipping out thermodynamically destabilized mispaired nucleobases as metalloinsertors. While most of the compounds discussed are based on ruthenium(II) and rhodium(III) due to their stable octahedral coordination environment and low-spin 4d6 electronic configuration, most recent developments of alternative metal complexes, based on both transition metals and main group elements, will also be highlighted. A particular focus of the coverage is on structural data from X-ray structure analysis, which now provides details of the interaction at unprecedented details and will enable development of novel DNA binding probes for fundamental studies as well as new anticancer drug candidates.

Antimicrobial activity of carbon monoxide-releasing molecule [Mn(CO)3(tpa-κ3N)]Br versus multidrug-resistant isolates of Avian Pathogenic Escherichia coli and its synergy with colistin.

Antimicrobial resistance is a growing global concern in human and veterinary medicine, with an ever-increasing void in the arsenal of clinicians. Novel classes of compounds including carbon monoxoide-releasing molecules (CORMs), for example the light-activated metal complex [Mn(CO)3(tpa-κ3N)]Br, could be used as alternatives/to supplement traditional antibacterials. Avian pathogenic Escherichia coli (APEC) represent a large reservoir of antibiotic resistance and can cause serious clinical disease in poultry, with potential as zoonotic pathogens, due to shared serotypes and virulence factors with human pathogenic E. coli. The in vitro activity of [Mn(CO)3(tpa-κ3N)]Br against multidrug-resistant APECs was assessed via broth microtitre dilution assays and synergy testing with colistin performed using checkerboard and time-kill assays. In vivo antibacterial activity of [Mn(CO)3(tpa-κ3N)]Br alone and in combination with colistin was determined using the Galleria mellonella wax moth larvae model. Animals were monitored for life/death, melanisation and bacterial numbers enumerated from larval haemolymph. In vitro testing produced relatively high [Mn(CO)3(tpa-κ3N)]Br minimum inhibitory concentrations (MICs) of 1024 mg/L. However, its activity was significantly increased with the addition of colistin, bringing MICs down to ≤32 mg/L. This synergy was confirmed in time-kill assays. In vivo assays showed that the combination of [Mn(CO)3(tpa-κ3N)]Br with colistin produced superior bacterial killing and significantly increased larval survival. In both in vitro and in vivo assays light activation was not required for antibacterial activity. This data supports further evaluation of [Mn(CO)3(tpa-κ3N)]Br as a potential agent for treatment of systemic infections in humans and animals, when used with permeabilising agents such as colistin.

A manganese photosensitive tricarbonyl molecule [Mn(CO)3(tpa-κ3N)]Br enhances antibiotic efficacy in a multi-drug-resistant Escherichia coli.

Carbon monoxide-releasing molecules (CORMs) are a promising class of new antimicrobials, with multiple modes of action that are distinct from those of standard antibiotics. The relentless increase in antimicrobial resistance, exacerbated by a lack of new antibiotics, necessitates a better understanding of how such novel agents act and might be used synergistically with established antibiotics. This work aimed to understand the mechanism(s) underlying synergy between a manganese-based photoactivated carbon monoxide-releasing molecule (PhotoCORM), [Mn(CO)3(tpa-κ3N)]Br [tpa=tris(2-pyridylmethyl)amine], and various classes of antibiotics in their activities towards Escherichia coli EC958, a multi-drug-resistant uropathogen. The title compound acts synergistically with polymyxins [polymyxin B and colistin (polymyxin E)] by damaging the bacterial cytoplasmic membrane. [Mn(CO)3(tpa-κ3N)]Br also potentiates the action of doxycycline, resulting in reduced expression of tetA, which encodes a tetracycline efflux pump. We show that, like tetracyclines, the breakdown products of [Mn(CO)3(tpa-κ3N)]Br activation chelate iron and trigger an iron starvation response, which we propose to be a further basis for the synergies observed. Conversely, media supplemented with excess iron abrogated the inhibition of growth by doxycycline and the title compound. In conclusion, multiple factors contribute to the ability of this PhotoCORM to increase the efficacy of antibiotics in the polymyxin and tetracycline families. We propose that light-activated carbon monoxide release is not the sole basis of the antimicrobial activities of [Mn(CO)3(tpa-κ3N)]Br.

Catalyst-free room-temperature iClick reaction of molybdenum(ii) and tungsten(ii) azide complexes with electron-poor alkynes: structural preferences and kinetic studies.

Two isostructural and isoelectronic group VI azide complexes of the general formula [M(η3-allyl)(N3)(bpy)(CO)2] with M = Mo, W and bpy = 2,2'-bipyridine were prepared and fully characterized, including X-ray structure analysis. Both reacted smoothly with electron-poor alkynes such as dimethyl acetylenedicarboxylate (DMAD) and 4,4,4-trifluoro-2-butynoic acid ethyl ester in a catalyst-free room-temperature iClick [3 + 2] cycloaddition reaction. Reaction with phenyl(trifluoromethyl)acetylene, on the other hand, did not lead to any product formation. X-ray structures of the four triazolate complexes isolated showed the monodentate ligand to be N2-coordinated in all cases, which requires a 1,2-shift of the nitrogen from the terminal azide to the triazolate cycloaddition product. On the other hand, a 19F NMR spectroscopic study of the reaction of the fluorinated alkyne with the tungsten azide complex at 27 °C allowed detection of the N1-coordinated intermediate. With this method, the second-order rate constant was determined as (7.3 ± 0.1) × 10-2 M-1 s-1, which compares favorably with that of first-generation compounds such as difluorocyclooctyne (DIFO) used in the strain-promoted azide-alkyne cycloaddition (SPAAC). In contrast, the reaction of the molybdenum analogue was too fast to be studied with NMR methods. Alternatively, solution IR studies revealed pseudo-first order rate constants of 0.4 to 6.5 × 10-3 s-1, which increased in the order of Mo > W and F3C-C[triple bond, length as m-dash]C-COOEt > DMAD.

Antimicrobial Activity of the Manganese Photoactivated Carbon Monoxide-Releasing Molecule [Mn(CO)3(tpa-κ(3)N)](+) Against a Pathogenic Escherichia coli that Causes Urinary Infections.

AIMS: We set out to investigate the antibacterial activity of a new Mn-based photoactivated carbon monoxide-releasing molecule (PhotoCORM, [Mn(CO)3(tpa-κ(3)N)](+)) against an antibiotic-resistant uropathogenic strain (EC958) of Escherichia coli. RESULTS: Activated PhotoCORM inhibits growth and decreases viability of E. coli EC958, but non-illuminated carbon monoxide-releasing molecule (CORM) is without effect. NADH-supported respiration rates are significantly decreased by activated PhotoCORM, mimicking the effect of dissolved CO gas. CO from the PhotoCORM binds to intracellular targets, namely respiratory oxidases in strain EC958 and a bacterial globin heterologously expressed in strain K-12. However, unlike previously characterized CORMs, the PhotoCORM is not significantly accumulated in cells, as deduced from the cellular manganese content. Activated PhotoCORM reacts avidly with hydrogen peroxide producing hydroxyl radicals; the observed peroxide-enhanced toxicity of the PhotoCORM is ameliorated by thiourea. The PhotoCORM also potentiates the effect of the antibiotic, doxycycline. INNOVATION: The present work investigates for the first time the antimicrobial activity of a light-activated PhotoCORM against an antibiotic-resistant pathogen. A comprehensive study of the effects of the PhotoCORM and its derivative molecules upon illumination is performed and mechanisms of toxicity of the activated PhotoCORM are investigated. CONCLUSION: The PhotoCORM allows a site-specific and time-controlled release of CO in bacterial cultures and has the potential to provide much needed information on the generality of CORM activities in biology. Understanding the mechanism(s) of activated PhotoCORM toxicity will be key in exploring the potential of this and similar compounds as antimicrobial agents, perhaps in combinatorial therapies with other agents. Antioxid. Redox Signal. 24, 765-780.