Indolin-2-one Nitroimidazole Antibiotics Exhibit an Unexpected Dual Mode of Action.

Nitroimidazoles such as metronidazole are used as anti-infective drugs against anaerobic bacteria. Upon in vivo reduction of the nitro group, reactive radicals damage DNA and proteins in the absence of oxygen. Unexpectedly, a recent study of nitroimidazoles linked to an indolin-2-one substituent revealed potent activities against aerobic bacteria. This suggests a different, yet undiscovered mode of action (MoA). To decipher this MoA, we first performed whole proteome analysis of compound-treated cells, revealing an upregulation of bacteriophage-associated proteins, indicative of DNA damage. Since DNA binding of the compound was not observed, we applied activity-based protein profiling (ABPP) for direct target discovery. Labeling studies revealed topoisomerase IV, an essential enzyme for DNA replication, as the most enriched hit in pathogenic Staphylococcus aureus cells. Subsequent topoisomerase assays confirmed the inhibition of DNA decatenation in the presence of indolin-2-one nitroimidazole with an activity comparable to ciprofloxacin, a known inhibitor of this enzyme. Furthermore, we determined significantly increased redox potentials of indolin-2-one nitroimidazoles compared to classic 5-nitroimidazoles such as metronidazole, which facilitates in vivo reduction. Overall, this study unravels that indolin-2-one-functionalized nitroimidazoles feature an unexpected dual MoA: first, the direct inhibition of the topoisomerase IV and second the classic nitroimidazole MoA of reductive bioactivation leading to damaging reactive species. Importantly, this dual MoA impairs resistance development. Given the clinical application of this compound class, the new mechanism could be a starting point to mitigate resistance.

Co-Mabiq Flies Solo: Light-Driven Markovnikov-Selective C- and N-Alkylation of Indoles and Indazoles without a Cocatalyst.

Indoles and indazoles are common moieties in pharmaceuticals and naturally occurring bioactive compounds. The development of light-driven methods using earth-abundant transition-metal catalysts offers an attractive route for functionalization of such compounds. Herein, we report a visible-light-induced method for the C3- and N-alkylation of indoles and indazoles with styrenes, catalyzed by Co complexes based on the macrocyclic Mabiq ligand (Mabiq = 2-4:6-8-bis(3,3,4,4-tetramethyldihydropyrrolo)-10-15-(2,2'-biquinazolino)-[15]-1,3,5,8,10,14-hexaene-1,3,7,9,11,14-N6). The photochemical behavior of two CoIII catalysts was examined: Co(Mabiq)Cl2 and the newly synthesized Co(MabiqBr)Cl2, which contains the Br-modified ligand. Both complexes undergo visible-light-induced homolysis that is significant to their activity but exhibit differences in reactivity. The alkylation reactions are regioselective, furnishing the alkylated indole and indazole products in a Markovnikov fashion with excellent yields of up to 96% across a broad range of substrates. Notably, in contrast to dual-transition-metal and photoredox-catalyzed cross-coupling reactions, our studies reveal that the Co complex plays a dual role─as a photosensitizer and catalytically active metal center with the Mabiq ligand offering regiocontrol.

Introducing Benzene-1,3,5-tri(dithiocarboxylate) as a Multidentate Linker in Coordination Chemistry.

Benzene-1,3,5-tri(dithiocarboxylate) (BTDTC3-), the sulfur-donor analogue of trimesate (BTC3-, benzene-1,3,5-tricarboxylate), is introduced, and its potential as a multidentate, electronically bridging ligand in coordination chemistry is evaluated. For this, the sodium salt Na3BTDTC has been synthesized, characterized, and compared with the sodium salt of the related ditopic benzene-1,4-di(dithiocarboxylate) (Na2BDDTC). Single-crystal X-ray diffraction of the respective tetrahydrofuran (THF) solvates reveals that such multitopic aromatic dithiocarboxylate linkers can form both discrete metal complexes (Na3BTDTC·9THF) and (two-dimensional) coordination polymers (Na2BDDTC·4THF). Additionally, the versatile coordination behavior of the novel BTDTC3- ligand is demonstrated by successful synthesis and characterization of trinuclear Cu(I) and hexanuclear Mo(II)2 paddlewheel complexes. The electronic structure and molecular orbitals of both dithiocarboxylate ligands as well as their carboxylate counterparts are investigated by density functional theory computational methods. Electrochemical investigations suggest that BTDTC3- enables electronic communication between the coordinated metal ions, rendering it a promising tritopic linker for functional coordination polymers.

Influence of a Lanthanide Ion on the Ni Site of a Heterobimetallic 3d-4f Mabiq Complex.

This work presents the synthesis and characterization of a 3d-4f bimetallic complex based on the redox-active macrocyclic biquinazoline ligand, Mabiq. The mixed Yb-Ni complex, [(Cp*)2Yb(Mabiq)Ni]BArF (3), was synthesized upon reaction of [NiII(Mabiq)]BArF (2) with (Cp*)2YbII(OEt2). The molecular structures of 3 and its sister complex, [(Cp*)2Yb(Mabiq)Ni][(Cp*)2Yb(OTf)2] (1), confirmed the presence of a Yb(III) center and a reduced Ni-Mabiq unit. Spectroscopy (absorption and NMR), cyclic voltammetry, and magnetic susceptibility studies were employed to analyze the electronic structure of 3, which is best described by the [(Cp*)2YbIII(Mabiq•)NiII]+ formulation. Notably, the ligand-centered radical is delocalized over both the diketiminate and bipyrimidine units of the Mabiq ligand. The magnetic susceptibility and variable temperature NMR studies for 3 denote coupling between the Ni-Mabiq site and the peripheral Yb center-previously unobserved in 3d-3d Mabiq complexes. The complex nature of the exchange interactions is highlighted by the multiconfigurational ground state for 3, comprising nearly degenerate singlet and triplet states.

Neighbouring effects on catalytic epoxidation by Fe-cyclam in M2-PDIxCy complexes.

The unsymmetric PDIeCy ligand, featuring pyridinediimine and cylam sites, can be selectively metalated. Complementing the diiron compound, we have synthesized two heterobimetallic isomers, [ZnPDIFeCy(PDIeCy)(OTf)4] (3) and [FePDIZnCy(PDIeCy)(OTf)4] (4), and a dizinc complex, [Zn2(PDIeCy)(OTf)4] (5). Olefin epoxidation by the series of complexes was investigated. The M-PDI site influences the reactivity of the M-cyclam, resulting in increased activity toward enones.

Dispersion forces drive water oxidation in molecular ruthenium catalysts.

Rational design of artificial water-splitting catalysts is central for developing new sustainable energy technology. However, the catalytic efficiency of the natural light-driven water-splitting enzyme, photosystem II, has been remarkably difficult to achieve artificially. Here we study the molecular mechanism of ruthenium-based molecular catalysts by integrating quantum chemical calculations with inorganic synthesis and functional studies. By employing correlated ab initio calculations, we show that the thermodynamic driving force for the catalysis is obtained by modulation of π-stacking dispersion interactions within the catalytically active dimer core, supporting recently suggested mechanistic principles of Ru-based water-splitting catalysts. The dioxygen bond forms in a semi-concerted radical coupling mechanism, similar to the suggested water-splitting mechanism in photosystem II. By rationally tuning the dispersion effects, we design a new catalyst with a low activation barrier for the water-splitting. The catalytic principles are probed by synthesis, structural, and electrochemical characterization of the new catalyst, supporting enhanced water-splitting activity under the examined conditions. Our combined findings show that modulation of dispersive interactions provides a rational catalyst design principle for controlling challenging chemistries.