Covalent Conjugates of Allylbenzenes and Terpenoids as Antibiotics Enhancers with the Function of Prolonged Action.

The drug resistance of pathogenic bacteria is often due efflux pumps-specific proteins that remove foreign compounds from bacterial cells. To overcome drug resistance, adjuvants are often used that can inhibit efflux pumps or other systems that ensure the resistance of bacteria to the action of antibiotics. We assumed that a new level of effectiveness with the use of an antibiotic + an adjuvant pair could be achieved by their joint delivery into the pathogen. To test this hypothesis, we constructed a series of molecular carriers based on poly-(olygo-, dendry)mers based on cyclodextrin-grafted PEI or mannan, as well as glycol chitosan, covalently bound to antibiotic, adjuvant, and the oligosaccharide ligand to the macrophage mannose receptor (CD206), which we studied earlier and showed high efficiency and selectivity of delivery of a therapeutic "cargo" to macrophages. Moxifloxacin was used as an antibiotic, and terpenoid and allylbenzene compounds were used as adjuvants, for which we previously discovered the ability to inhibit bacterial efflux pumps. We show that: (a) the resulting structures were stable in vitro for a long time (up to 10 days); (b) they were adsorbed on bacterial cells, providing a local increase in the concentration of the antibiotic and adjuvant in pathogen cells; (c) they were internalized by bacterial cells, ensuring the accumulation of both antibiotic and adjuvant inside bacterial cells; (d) the adjuvant, after entering the bacterial cell, provided inhibition of the efflux pumps; (e) due to this action of the adjuvant, combined with the targeted delivery by the carrier, the antibiotic's half-life in rats increased by more than 2 times, the effective concentration of the drug in the blood plasma (AUC) increased up to 8-10 times; (f) a significant increase in the effectiveness of the antibacterial action against Gram+ and Gram- cells was achieved (up to 3 times). Potentially, such an approach would significantly increase the effectiveness of therapies for a number of infectious and other diseases, reduce the dosage of antibiotics, shorten the duration of treatment, and reduce the risk of developing bacterial resistance. Moreover, the use of a polymer carrier with covalently bound organic molecules of different structures will avoid problems linked to different (suboptimal) solubility and bio-distribution of the administered molecules, which would be almost inevitable when using the same compounds separately. It would be very difficult to find antibiotic/adjuvant pairs that simultaneously achieve optimal concentrations in the same target cells. In our case, terpenoids and alkylbenzenes used as adjuvants are practically insoluble as individual compounds, and their unacceptable pharmacological properties would not allow them to be used as efflux pump inhibitors.

Strong Magnetically-Responsive Circularly Polarized Phosphorescence and X-Ray Scintillation in Ultrarobust Mn(II)-Organic Helical Chains.

Over recent years, Mn(II)-organic materials showing circularly polarized luminescence (CPL) have attracted great interest because of their eco-friendliness, cheapness, and room temperature phosphorescence. Using the helicity design strategy, herein, chiral Mn(II)-organic helical polymers are constructed featuring long-lived circularly polarized phosphorescence with exceptionally high glum and ΦPL magnitudes of 0.021% and 89%, respectively, while remaining ultrarobust toward humidity, temperature, and X-rays. Equally important, it is disclosed for the first time that the magnetic field has a remarkably high negative effect on CPL for Mn(II) materials, suppressing the CPL signal by 4.2-times at B ⃗ $\vec{B}$  = 1.6 T. Using the designed materials, UV-pumped CPL light-emitting diodes are fabricated, demonstrating enhanced optical selectivity under right- and left-handed polarization conditions. On top of all this, the reported materials display bright triboluminescence and excellent X-ray scintillation activity with a perfectly linear X-ray dose rate response up to 174 µGyair  s-1 . Overall, these observations significantly contribute to the CPL phenomenon for multi-spin compounds and promote the design of highly efficient and stable Mn(II)-based CPL emitters.

Mannosylated Systems for Targeted Delivery of Antibacterial Drugs to Activated Macrophages.

Macrophages are a promising target for drug delivery to influence macrophage-associated processes in the body, namely due to the presence of resistant microorganisms in macrophages. In this work, a series of mannosylated carriers based on mannan, polyethylenimine (PEI) and cyclodextrin (CD) was synthesized. The molecular architecture was studied using FTIR and 1H NMR spectroscopy. The particle size, from small 10-50 nm to large 500 nm, depending on the type of carrier, is potentially applicable for the creation of various medicinal forms: intravenous, oral and inhalation. Non-specific capture by cells with a simultaneous increase in selectivity to CD206+ macrophages was achieved. ConA was used as a model mannose receptor, binding galactosylated (CD206 non-specific) carriers with constants of the order of 104 M-1 and mannosylated conjugates of 106-107 M-1. The results of such primary "ConA-screening" of ligands are in a good agreement in terms of the comparative effectiveness of the interaction of ligands with the CD206+ macrophages: non-specific (up to 10%) absorption of highly charged and small particles; weakly specific uptake of galactosylated polymers (up to 50%); and high affine capture (more than 70-80%) of the ligands with grafted trimannoside was demonstrated using the cytometry method. Double and multi-complexes of antibacterials (moxifloxacin with its adjuvants from the class of terpenoids) were proposed as enhanced forms against resistant pathogens. In vivo pharmacokinetic experiments have shown that polymeric carriers significantly improve the efficiency of the antibiotic: the half-life of moxifloxacin is increased by 2-3 times in conjugate-loaded forms, bio-distribution to the lungs in the first hours after administration of the drug is noticeably greater, and, after 4 h of observation, free moxifloxacin was practically removed from the lungs of rats. Although, in polymer systems, its content is significant-1.2 µg/g. Moreover, the importance of the covalent crosslinking carrier with mannose label was demonstrated. Thus, this paper describes experimental, scientifically based methods of targeted drug delivery to macrophages to create enhanced medicinal forms.

New Approach toward Dual-Emissive Organic-Inorganic Hybrids by Integrating Mn(II) and Cu(I) Emission Centers in Ionic Crystals.

Inorganic-organic hybrid luminescent materials have received great attention for their potential applications in a wide range of clean/renewable energy-related areas, including photovoltaics and solid-state lighting. Herein, we present a unique and general "Mn + Cu" approach by blending two earth-abundant luminogenic metals, manganese and copper, within a single ionic structure to construct a remarkable family of low-cost and multifunctional hybrid materials featuring dual emission, as well as triboluminescence and second-harmonic generation response. The novel hybrid materials are made of diphosphine dioxide-chelated [Mn(O∧O)3]2+ cations and various anionic [CuxIy](y-x)- clusters, ensuring manifestation of dual phosphorescence streamed from octahedral Mn2+ ions (605-648 nm) and iodocuprate anions (480-728 nm). Noteworthily, the relative ratio of the emission bands, and hence a resulting emission chromaticity, can be tuned in a wide range through modification of cluster [CuxIy](y-x)- modules. The structural diversity, enhanced robustness, and up to 100% luminescence quantum yield make the designed materials promising phosphors for lighting and sensing applications.

Dicopper(I) Paddle-Wheel Complexes with Thermally Activated Delayed Fluorescence Adjusted by Ancillary Ligands.

A suite of paddle-wheel shaped [Cu2(PymPPh2)3(Lan)n](PF6)2 complexes showing efficient thermally activated delayed fluorescence (TADF) has been synthesized. In these complexes, Cu(I) ions are P,N-bridged by three diphenyl(2-pyrimidyl)phosphine (PymPPh2, L) ligands in a "head-to-tail" fashion, and one or both metals are also capped by the ancillary ligand (Lan = MeOH, Me2CO, MeCN, PhCN). At ambient temperature, the solid complexes emit TADF with the quantum yield of up to 85% and the lifetimes of from 9.6 to 27 µs. The ancillary ligands, whose orbitals negligibly contribute to the radiative 1(M + L + Lan)LCT state, remarkably adjust emission energies and ΔE(S1-T1) energy splitting magnitudes of the emitters obtained. Thus, depending on structure and/or number of the Lan molecules, the emission maxima vary from 500 to 563 nm, and the ΔE(S1-T1) gaps range 550-1100 cm-1. Such tunable TADF characteristics coupled with the excellent solubility and air-stability make the complexes presented to be promising TADF materials.

Luminescence of the Mn2+ ion in non-Oh and Td coordination environments: the missing case of square pyramid.

The first observation of luminescence for Mn(ii) complexes with a square-pyramidal geometry (C4v) of the metal is reported. The complexes of such type, namely [Mn(L)2Hal]X, where L is an O,O'-chelating ligand Me2N-CH(Ph2P[double bond, length as m-dash]O)2, Hal = Cl or Br, and X = Br, I or [MnCl4], show at ambient temperature red photoluminescence (λ≈ 620 nm) with millisecond lifetimes (3.8-7.6 ms). This emission, stemming from spin-forbidden 4E(G) →6A1(S) transitions in square-pyramidally coordinated Mn2+, is found to be responsive to temperature. Upon cooling the complexes from 300 to 77 K, the red-shift of the emission band by ≈20 nm takes place, which is accompanied by the increase of its integral intensity and lifetime. The peculiarities of the discovered Mn2+(C4v) luminescence are discussed against the classical luminescence that occurs in octahedral (Oh) and tetrahedral (Td) surroundings.

Determination of Hyperfine Coupling Constants of Fluorinated Diphenylacetylene Radical Anions by Magnetic Field-Affected Reaction Yield Spectroscopy.

Magnetic field-affected reaction yield (MARY) spectroscopy is a spin chemistry technique for detecting short-lived radical ions. Having sensitivity to transient species with lifetimes as short as nanoseconds, MARY spectroscopy usually does not provide detailed information on their magnetic resonance parameters, except for simple systems with equivalent magnetic nuclei. In this work, the radical anions of two fluorinated diphenylacetylene derivatives with nonequivalent magnetic nuclei and unknown hyperfine coupling constants ( AHF) were investigated by MARY spectroscopy. The MARY spectra were found to be resolved and have resonance lines in nonzero magnetic fields, which are determined by the AHF values. Simple relationships between the positions of resonance MARY lines and the AHF values were established from the analysis of the different Hamiltonian block contributions to the MARY spectrum. The obtained experimental AHF values are in agreement with the results of quantum chemical calculations at the density functional theory level.

X-ray Generated Recombination Exciplexes of Substituted Diphenylacetylenes with Tertiary Amines: A Versatile Experimental Vehicle for Targeted Creation of Deep-Blue Electroluminescent Systems.

Customizable and technology-friendly functional materials are one of the mainstays of emerging organic electronics and optoelectronics. We show that recombination exciplexes of simple substituted diphenylacetylenes with tertiary amines can be a convenient source of tunable deep-blue emission with possible applications in organic electroluminescent systems. The optically inaccessible exciplexes were produced via recombination of radiation-generated radical ion pairs in alkane solution, which mimics charge transport and recombination in the active layer of practical organic light-emitting diodes in a simple solution-based experiment. Despite varying and rather poor intrinsic emission properties, diphenylacetylene and its prototypical methoxy (donor) or trifluoromethyl (acceptor) monosubstituted derivatives readily form recombination exciplexes with N,N-dimethylaniline and other tertiary amines that produce emission with maxima ranging from 385 to 435 nm. The position of emission band maximum linearly correlates with readily calculated gas-phase electron affinity of the corresponding diphenylacetylene, which can be used for fast computational prescreening of the candidate molecules, and various substituted diphenylacetylenes can be synthesized via relatively simple and universal cross-coupling reactions of Sonogashira and Castro. Together, the simple solution-based experiment, computationally cheap prescreening method, and universal synthetic strategy may open a very broad and chemically convenient class of compounds to obtain OLEDs and OLED-based multifunctional devices with tunable emission spectrum and high conversion efficiency that has yet not been seriously considered for these purposes.

Dissecting alkynes: full cleavage of polarized C≡C moiety via sequential bis-Michael addition/retro-Mannich cascade.

The reaction of diaryl ketoalkynes with 1,2-diamino ethane leads to the full scission of the triple bond with the formation of acetophenone and imidazoline fragments. In this transformation, one of the alkyne carbons undergoes formal reduction with the formation of three C-H bonds, whereas the other carbon undergoes formal oxidation via the formation of three C-N bonds (one π and two σ). Computational analysis confirmed that the key fragmentation step proceeds via a six-membered TS in a concerted manner. Both amines are involved in the fragmentation: the N-H moiety of one amine transfers a proton to the developing negative charge at the enolate oxygen, while the other amine provides direct stereoelectronic assistance to the C-C bond cleavage via a hyperconjugative n(N) → σ*(C-C) interaction.