Due to the global rise in the number of antibiotic resistant bacterial infections over the past 20 years, there is a dire need for the development of small molecule antibiotics capable of overcoming resistance mechanisms in pathogenic bacteria. Antibiotic development against Gram-negative pathogens, such as Pseudomonas aeruginosa, is especially challenging due their additional outer membrane which reduces antibiotic entry. Recently, it has been shown that a broad range of nitrogen functionality, including guanidines, amidines, primary amines, imidazolines and imidazoles, promote antibiotic and adjuvant activity in Gram-negative bacteria, but few of these have been targeted towards Pseudomonas aeruginosa specifically despite this pathogen being deemed a critical threat by the United States Centers for Disease Control and Prevention. Herein, we examined a small series of known and unknown nitrogenous dimers, with guanidine, amidine, dimethyl amine, and pyridine functionality, for antibacterial activity against multidrug resistant Pseudomonas aeruginosa. We found that two, with bisbenzguanidine and bisbenzamidine functionality, are potent against clinical isolates of multidrug resistant and biofilm forming Pseudomonas aeruginosa.
Effects of unpredictable chronic mild stress on the cellular redox state and mitochondrial energy homeostasis in rat adipose tissue: A comprehensive metabolic study
Abstract
Unpredictable chronic mild stress (UCMS) leads to variable metabolic effects. Oxidative stress (OS) of adipose tissue (AT) and mitochondrial energy homeostasis is little investigated. This work studied the effects of UCMS on OS and the antioxidant/redox status in AT and mitochondrial energy homeostasis in rats. Twenty-four male Wistar rats (180–220 g) were divided into two equal groups; the normal control (NC) group and the UCMS group which were exposed to various stresses for 28 days. An indirect calorimetry machine was used to measure volumes of respiratory gases (VO2& VCO2), total energy expenditure (TEE), and food intake (FI). The AT depots were collected, weighed, and used for measuring activities and gene expression of key antioxidant enzymes (GPx1, SOD, CAT, GR, GCL, and GS), OS marker levels including superoxide anion (SA), peroxynitrite radical (PON), nitric oxide (NO), hydrogen peroxide (H2O2), lipid peroxides (LPO), t-protein carbonyl content (PCC), and reduced/oxidized glutathione levels (GSH, GSSG). Additionally, AT mitochondrial fractions were used to determine the activities of the tricarboxylic acid cycle (TCA) cycle enzymes (CS, α-KGDH, ICDH, SDH, MDH), respiratory chain complexes I–III, II–III, IV, the nicotinamide coenzymes NAD+, NADH, and ATP/ADP levels. Compared with the NC group, the UCMS group showed very significantly increased OS marker levels, lowered antioxidant enzyme activities and gene expression, as well as lowered TCA cycle and respiratory chain activity and NAD+, NADH, and ATP levels (p < .001 for all comparisons). Besides, the UCMS group had lowered TEE and insignificant FI and weight gain. In conclusion, AT of the UCMS-subjected rats showed a state of disturbed redox balance linked to disrupted energy homeostasis producing augmentation of AT.
Discovery of Alkaloid Quinazolone‐Derived Imidazolenones with Novel Structural Scaffolds of Multitargeting Antibacterial Potential
Quinazolone and imidazole were introduced to both sides of ethenone to construct novel structural quinazolone-derived imidazolenones as unique multitargeting antibacterial agents. The medicinal identification revealed that quinazolone-derived imidazolenones were expected to be further developed into a novel class of multitargeting antimicrobial agents to cope with multi-drug resistant bacterial infections.
Comprehensive Summary
Alkaloids are one of the prominent members in the development of new antimicrobial agents. This work discovered a class of alkaloid quinazolone-derived imidazolenones as novel structural type of antibacterial agents with large potential to treat severe bacterial infections in the agricultural and food field. Preliminary bioactive assay displayed that some of the prepared compounds exhibited good inhibition against the tested strains, and cyclohexylimidazole-derived 7-fluoroquinazolone 22a (MIC = 0.002 mmol/L) exhibited a 12.5-fold stronger inhibition than norfloxacin against Escherichia coli ATCC 25922. Further studies revealed that compound 22a not only possessed the ability of rapid bactericidal property and low propensity to develop resistance but also showed low cytotoxic effects toward red blood cells. The preliminary mechanism exploration indicated that compound 22a could cause membrane damage by disrupting bacterial membrane as well as depolarizing the cell membrane. Moreover, compound 22a could insert into DNA, which might hinder the replication of DNA. Molecular docking suggested that compound 22a could bind to gyrase and topoisomerase, which might be due to the suppressed expression of related genes. Meanwhile, compound 22a could disorder the metabolism and stimulate the production of reactive oxygen species to affect bacterial growth. The series of investigations suggested the promise of alkaloid quinazolone-derived imidazolenones as novel multitargeting antibacterial candidates for treatment of bacterial infections.
Heteroditopic NHC Ligand Supported Manganese(I)‐Complexes: Synthesis, Characterization, and Activity as Non‐bifunctional Phosphine‐Free Catalyst for the α‑Alkylation of Nitriles
In the present work, several manganese(I) complexes of chelating heteroditopic ligands Mn1-3, featuring ImNHC (imidazol-2-ylidene) connected to a 1,2,3-triazole-N or tzNHC (1,2,3-triazol-5-ylidene) donors via a methylene spacer, with possible modifications at the triazole backbone have been synthesized and completely characterized. Notably, the CO stretching frequencies, electrochemical analysis, and frontier orbital analysis certainly suggests that the chelating ImNHC-tzNHC ligands have stronger donation capabilities than the related ImNHC-Ntz ligand in the synthesized complexes. Moreover, these well-defined phosphine free Mn(I)-NHC complexes have been found to be effective non-bifunctional catalysts for the α-alkylation of nitriles using alcohols and importantly, the catalyst Mn1 containing ImNHC connected to a weaker triazole-N donor displayed higher activity compared to Mn2/Mn3 containing an unsymmetrical bis-carbene donors (ImNHC and tzNHC). A wide range of aryl nitriles were coupled with diverse (hetero)aromatic as well as aliphatic alcohols to get the corresponding products in good to excellent yields (32 examples, up to 95% yield). The detailed mechanistic studies including deuterium labelling experiments reveal that the reaction follows a Borrowing Hydrogen pathway.
Discovery of NSD2‐degraders from Novel and Selective DEL hits
NSD2 is a histone methyltransferase predominantly catalyzing di-methylation of histone H3 on lysine K36. Increased NSD2 activity due to mutations or fusion-events affecting the gene encoding NSD2 is considered an oncogenic event and a driver in various cancers, including multiple myelomas carrying t(4;14) chromosomal translocations and acute lymphoblastic leukemia's expressing the hyperactive NSD2 mutant E1099K. Using DNA-encoded libraries, we have identified small molecule ligands that selectively and potently bind to the PWWP1 domain of NSD2, inhibit NSD2 binding to H3K36me2-bearing nucleosomes, but do not inhibit the methyltransferase activity. The ligands were subsequently converted to selective VHL1-recruiting NSD2 degraders and by using one of the most efficacious degraders in cell lines, we show that its leads to NSD2 degradation, decrease in K3K36me2 levels and inhibition of cell proliferation.
Low‐temperature upcycling of polypropylene waste into H2 fuel via a novel hydrothermal tandem process
Plastic waste is a promising and abundant resource for H2 production. However, upcycling plastic waste into H2 fuel via conventional thermochemical routes requires relatively considerable energy input and severe reaction conditions, particularly for polyolefin waste. Here, we report a tandem strategy for the selective upcycling of polypropylene (PP) waste into H2 fuel in a mild and clean manner. PP waste was first oxidized into small-molecule organic acids using pure O2 as oxidant at 190 °C, followed by the catalytic reforming of oxidation aqueous products over ZnO–modified Ru/NiAl2O4 catalysts to produce H2 at 300 °C. A high H2 yield of 44.5 mol/kgPP and a H2 mole fraction of 60.5% were obtained from this tandem process. The entire process operated with almost no solid residue remaining and equipment contamination, ensuring relative stability and clean of the reaction system. This strategy provides a new route for low-temperature transforming PP and improving the sustainability of plastic waste disposal processes.
Benzothiazol‐Propanamide Linker Pyrrolidine (Morpholine) as Monoamine Oxidase‐B and Butyrylcholinesterase Inhibitors
According to the fusion technique create effective multi-target-directed ligands, in this study, we designed and synthesized a series of benzo[d]thiazol-2-yl)-3-(pyrrolidin-1-yl) or 3-(morpholino-1-yl)propanamide derivatives, and evaluated their inhibitory potency against MAOs, AChE, BuChE by in vitro enzyme effect assays. Based on activity results, we found that derivatives N-(5-methylbenzo[d]thiazol-2-yl)-3-(pyrrolidin-1-yl)propanamide (2c) and N-(6-bromo- benzo[d]thiazol-2-yl)-3-(pyrrolidin-1-yl)propanamide (2h) showed good inhibitory potency against BuChE with IC50 values of 15.12 μM and 12.33 μM, respectively. Besides, 2c and 2h also exhibited selective MAO-B inhibitory effects with inhibition rates of 60.10 % and 66.30 % at 100 µM, respectively. In contrast, all designed derivatives were poor active against AChE and MAO-A at a concentration of 100 μM. The toxicity analysis in vitro by MTT and AO/EB fluorescence staining confirmed that 2c and 2h were nontoxic up to 100 μM. Molecular modeling studies showed that 2c and 2h could bind to the active site of BuChE. This research paves the way for further study aimed at designing MAO-B and BuChE inhibitors for the treatment of neurodegenerative disorders.
Recent Advances in Non‐Precious Metal Single‐Atom Electrocatalysts for Oxygen Reduction Reaction in Low‐Temperature Polymer‐Electrolyte Fuel Cells
Fuel cells have emerged as a promising clean energy technology with a great potential in various sectors, including transportation and power generation. However, the high cost and scarcity of the noble metals currently used to synthesise electrocatalysts for low-temperature fuel cells has hindered their widespread commercialisation. In recent decades, the development of non-precious metal electrocatalysts for the cathodic oxygen reduction reaction (ORR) have gained significant attention. Among those, electrocatalysts with atomically dispersed active sites, referred to as single-atom catalysts (SACs), are gaining more interest. Nanocarbon materials containing single transition metal atoms coordinated to nitrogen atoms are active electrocatalysts for the ORR in both acidic and alkaline conditions and thus have a great promise to be utilised as non-precious metal cathode electrocatalysts in low-temperature fuel cells. This review article provides an overview of the recent advancements in the utilisation of transition metal-based SACs in proton exchange membrane fuel cells (PEMFCs) and anion exchange membrane fuel cells (AEMFCs). We highlight the main strategies and synthetic approaches for tailoring the properties of SACs to enhance their ORR activity and durability. Based on the already achieved results, it is evident that SACs indeed could be suitable for the cathode of the low-temperature fuel cells.
Isomeric effect of π bridge in IDT‐based nonfused electron photovoltaic acceptor
One pair of isomers, IDT-BOF containing S···O/F···H noncovalently configurational locks and IDT-BFO containing F···H/O···H noncovalently configurational locks, were designed and synthesized with an acceptor-π-donor-π-acceptor (A-π-D-π-A) structure by choosing 4,9-dihydro-s-indaceno[1,2-b:5,6-b']dithiophene (IDT) as the D unit, F/n-hexyloxy substituted phenyl ring as π bridge, and 3-(dicyanomethylidene)indan-1-one as the A unit. Owing to the S···O/F···H or F···H/O···H noncovalently configurational locks, both IDT-BOF and IDT-BFO show completely planar structure. In comparison to IDT-BFO, IDT-BOF exhibits similar LUMO but higher HOMO energy levels, leading to a smaller optical bandgap and red-shifted absorption. However, IDT-BOF-based bulk-heterojunction organic solar cells (BHJ-OSCs) coupled with PBDB-T, and PCE-10 as donor materials both exhibited a lower PCE than that of IDT-BFO (PBDB-T: 5.2% vs. 6.1%; PCE-10: 1.7% vs. 3.2%). Comprehensively comparing and investigating IDT-BOF:PBDB-T and IDT-BFO:PBDB-T OSCs suggested that the large phase separation and serious charge recombination of IDT-BOF based OSCs contributed to its lower PCE. Importantly, ternary solar cells based on PBDB-T:Y5 as control devices by adding 10% IDT-BFO exhibited a 5% enhancement in the PCE compared to the control device (14.3% vs. 13.6%).
Enabling N2 to ammonia conversion in Bi2WO6‐based materials: A new avenue in photocatalytic applications
The field of photocatalysis has been evolving since 1972 since Honda and Fujishima’s initial push for using light as an energy source to accomplish redox reactions. Since then, many photocatalysts have been studied, semiconductors or otherwise. A new photocatalytic application to convert N2 gas to ammonia (N2 fixation or nitrogen reduction reaction; NRR) has emerged. Many researchers have steered their research in this direction due to developments in the ease of ammonia detection through UV-Vis spectroscopy. This concept will specifically discuss Bi2WO6-based materials, techniques to enhance their photocatalytic activity (CO2 reduction, H2 production, pollutant removal, etc.), and their current application in photocatalytic NRR. Initially, a brief introduction of Bi2WO6 along with its VB and CB potentials will be compared to various redox potentials. A final topic of interest would be a brief description of photocatalytic nitrogen fixation with additional consideration to Bi2WO6-based materials in N2 fixation. A major problem with photocatalytic NRR is the false ammonia quantification in Bi-based materials, which will be discussed in detail and also ways to minimize them.