The perferrate anion [FeVIIO4]-, the elusive iron analog of permanganate, has been extensively investigated, yet key questions remain unresolved concerning its stability with respect to isomerization. A previous computational work had been unable to reproduce the stability trend between the peroxide and perferrate: [FeVO2(η2-O2)]- > [FeVIIO4]-. Herein, the manifold of possible structures is revisited, for the first time, using an MRCISD+Q/x2c-TZVP//CASPT2(25,17)/ANO-RCC-VDZP level of theory. Computationally, we not only reproduce the correct stability trend but also find that the most stable species is a cyclometalated superoxide [FeIVO2(η2-O2)]- (6B1 ground state), perferrate being less stable by +29.2 kcal mol-1. In parallel, gas-phase ions of [FeO4]- stoichiometry were generated via an alternative electrospray ionization-based approach and probed by collision-induced dissociation mass spectrometry, providing complementary evidence for the presence of O-O motifs in the experimentally generated ions, in agreement with the computational results.

The replacement of conventional high-boiling polar organic solvents with sustainable and recyclable alternatives is a central challenge in green chemistry, especially for transformations that require harsh conditions and prolonged heating. In this work, we demonstrate that poly(ethylene glycol)-400 (PEG-400) can efficiently replace traditional and harmful solvents such as N,N-dimethylaminoethanol (DMAE) and N,N-dimethylformamide (DMF) in the synthesis of phthalocyanines. PEG-400 enables high-temperature cyclotetramerization reactions under operationally simple and comparatively safer conditions, providing isolated yields of 50-83% across a range of metalated and metal-free derivatives and substitution patterns, while maintaining solvent loss and waste generation at relatively low levels. Remarkably, PEG-400 is also compatible with in-pot palladium-catalyzed C-C coupling reactions. This enables sequential cyclotetramerization followed by Sonogashira or Suzuki coupling without isolation of the macrocyclic intermediate, affording functionalized products in up to 75% yield and providing access to more complex derivatives in a more practical way. Green metrics analyses, such as E-factor and PMI, further support the improved material-efficiency profile of the method when compared to representative literature procedures. Overall, these results demonstrate that PEG-400 combines thermal robustness with compatibility toward Pd-catalyzed cross-coupling reactions, establishing it as a versatile and sustainable medium for resource-efficient multi-step organic synthesis and the preparation of highly functionalized phthalocyanine derivatives. The strategy provides a basis for potential extension to preparative-scale processes.

Neurodegenerative disorders (NDs), such as Alzheimer's disease and Parkinson's disease (PD), represent a significant challenge for ageing populations, with their prevalence increasing worldwide. Elevated human Monoamine Oxidase B (hMAO-B) activity has been related to neurodegenerative progression, where it contributes, among others, to oxidative stress and neuroinflammation. The identification and optimization of selective hMAO-B inhibitors is therefore pivotal in addressing the progression of NDs. In this work we introduced 2-aroylbenzothiophene analogues as promising agents to mitigate neurodegeneration. The synthesized compounds were screened against hMAO-A and hMAO-B, identifying compounds 4, 11, and 12 as the most promising. In vitro studies in hGF and SH-SY5Y cells revealed distinct toxicity profiles, with compound 4 being the least tolerated at 100 µM. ROS generation was investigated as a possible mechanism underlying this toxicity. Compounds 4 (12.5 µM), 11, and 12 (100 µM) were further evaluated for neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced toxicity in SH-SY5Y cells, showing a modest neuroprotective effect after 72 h at a sub-toxic 6-OHDA concentration (250 µM), comparable to the clinically used hMAO-B inhibitor (R)-(-)-Deprenyl at 100 µM. Finally, molecular modelling studies revealed that compound 4 establishes key stabilizing interactions within hMAO-B, accounting for its high inhibitory potency and selectivity over hMAO-A.

Ionic liquids (ILs) are a class of organic salts with melting points below 100°C. Owing to their unique chemical and physical properties, they are used as solvents and catalysts in various chemical transformations, progressively replacing common volatile organic solvents (VOCs) in green synthetic applications. However, their intrinsic ionic nature can restrict the use of mass spectrometric techniques to monitor the time progress of a reaction occurring in an IL medium, thus preventing one from following the formation of the reaction products or intercepting the reaction intermediates. The intense ionic signals related to the IL cation, anion, and their aggregates can indeed suppress the ionic intensities of substrates that are not intrinsically charged and often poorly ionizable. In this paper, we developed an atmospheric pressure chemical ionization mass spectrometry (APCI-MS) approach to overcome this limitation and minimize interference from the IL. The possibility of obtaining an estimation of the product yields by directly sampling the reaction mixture without quenching the process was tested by constructing calibration curves on three different model reactions, namely, (i) Knoevenagel condensation, (ii) oxidative esterification of aromatic aldehydes, and (iii) benzoin addition. A good correlation was obtained between the product yields measured by the APCI-MS procedure and those extrapolated from the isolated products. These results highlight the potential of this approach for real-time monitoring of reactions in ILs, eliminating the need for time-consuming extraction steps and minimizing the risk of losing critical mechanistic information.

The crucial role of human monoamine oxidases (hMAOs), particularly the B isoform, in the pathogenesis of neurodegenerative diseases has been extensively studied. Alongside numerous other factors, the clinical use of hMAO-B inhibitors to alleviate symptoms of Parkinson's disease is well-established. In order to develop novel hMAO-B inhibitors as potential candidates for the treatment of these conditions, we have designed and synthesized two libraries of compounds based on the 2-aroylbenzofuran-3-ol and the 2-aroylbenzofuran scaffolds. The hMAO inhibitory activity and selectivity of these compounds was thoroughly investigated. In general, the 2-aroylbenzofuran-3-ols were unable to inhibit hMAO isoforms. In contrast, 2-aroylbenzofuran derivatives acted as potent and selective hMAO-B inhibitors, showing IC50 values within the nanomolar range and as low as 8.2 nM. The best compounds exhibited broad safety ranges in human gingival fibroblasts (hGFs) and SH-SY5Y neuroblastoma cells. A preliminary evaluation of the compounds' neuroprotective effects was conducted through the co-exposure of the cells to the neurotoxic agent 6-hydroxydopamine (6-OHDA) and the synthesized compounds, whose activity was comparable to that of (R)-(-)-deprenyl, the reference hMAO-B inhibitors. The characterization of the compounds was enriched with the in silico prediction of the drug-likeness of the most active compounds among the 2-aroyl benzofurans using the free web tool SwissADME. All compounds were predicted to have high gastrointestinal absorption and to permeate the blood-brain barrier and molecular modelling studies provided insights into the molecular mechanisms responsible for the high hMAO-B inhibitory potency and selectivity of 2-aroylbenzofurans.

The perferrate anion [FeVIIO4]-, the elusive iron analogue of permanganate, has been extensively investigated, yet several questions remain unresolved concerning its structure and oxidation state. A previous computational work had been unable to reproduce the stability trend [FeVO2(η2-O2)]- > [FeVIIO4]-. Herein we revisit the manifold of possible structures with a MRCISD+Q/x2c-TZVP//CASPT2(25,17)/ANO-RCC-VDZP level of theory, and present a novel preparation procedure for the generation of ions of composition [FeO4]- in the gas phase. Conclusively we not only reproduce the correct stability trend, but also find that the most stable species is the superoxide [FeIVO2(η2-O2)]- (6B1 ground state), with perferrate being less stable by +29.2 kcal mol-1. Results from ESI-MS/CID experiments are consistent with [FeO4]- ions exhibiting a peroxidic rather than a tetrahedral bonding pattern.

The oxidation of cysteine to cystine was investigated in aqueous thin films generated by the deposition of electrospray ionization (ESI) microdroplets. The confined volume of the thin film promotes the reaction, resulting in up to 80% conversion of cysteine to cystine at a thin film temperature of 40 °C. The pH of the solution is a critical parameter, influencing both the yield and the kinetics of the reaction. Strong reaction acceleration factors in thin film with respect to the bulk were measured.

The overarching goal of this study was the development and validation of a non-targeted method for the determination of the authenticity of dried oregano leaves by atmospheric pressure matrix-assisted laser desorption ionization mass spectrometry (AP-MALDI-MS). To this aim, 44 samples (23 authentic oregano, 5 pure adulterants, 16 adulterated oregano) were analyzed in positive and negative ion mode. The most abundant signals were characterized by collision induced dissociation and library search, the spectral data were submitted to statistical analysis. A basal inquiry of the data by partial least squared discriminant analysis (PLS-DA) was carried out for the simple assessment of the discrimination capabilities of the +/- AP-MALDI-MS signatures. Then, we constructed two distinct random forest (RF) classifiers using the positive and negative most informative ions teased out by recursive feature elimination from the training sets. The aforementioned most significant variables (m/z values) were also merged by mid-level data fusion and used to build a third RF classifier. The crossvalidations of the three RF classifiers achieved good outcomes as demonstrated by the satisfactory values of overall accuracy (84.9 %, 92.1 %, and 92.8%, respectively). The three RF classifiers were tested on the hold-out data, which revealed reliable classifier performances (accuracy 80.1 %, 87.0%, and 85.4 %).

The present study provides the design, synthesis, molecular modelling investigation and biological evaluation of a series of coumalic acid-based selective inhibitors of hCA IX and XII. Based on the previously obtained results with carboxamide analogues of coumalic acid, here we explored some modifications of the original scaffold with the aim to expand our knowledge about these compounds and to promote structure-activity relationship (SAR) studies. Structural modifications as lactone-to-lactam conversion, repositioning of the carboxylic acid moiety, and the introduction of ester or amidic linkers, as well as triazole-based elongation via click chemistry have been performed. The synthesised compounds were tested for their inhibitory activities against hCA I, II, IX, and XII showing the lactone moiety to be crucial for inhibitory potency. Particularly, ester derivatives demonstrated selectivity for hCA IX and XII, with certain compounds exhibiting micromolar affinities. Notably, compound 8, featuring a bromine substitution, displayed the highest selectivity and potency against hCA IX and XII. Molecular docking studies further elucidated the binding mechanisms, revealing that the lactone ring hydrolysis plays a significant role in the inhibition process. These results offer valuable insights into the structure-activity relationships (SAR) of coumalic acid analogues and support their further biological investigation for cancer therapy by targeting hCA IX and XII.

Asymmetric synthesis of warfarin in ESI-microdroplets by using chiral 1,2-diamino organocatalysts.

Chronic intestinal inflammation and neo-angiogenesis are interconnected in colorectal carcinoma (CRC) pathogenesis. Molecules reducing inflammation and angiogenesis hold promise for CRC prevention and treatment. N-Palmitoyl-d-glucosamine (PGA), a natural glycolipid analog with anti-inflammatory properties, has shown efficacy against acute colitis. Micronized PGA (mPGA) formulations exhibit superior anti-inflammatory activity. This study investigates the in vivo anti-angiogenic and protective effects of mPGA in a mouse model of colitis-associated CRC induced by azoxymethane/dextran sodium sulfate (AOM/DSS). CRC was induced in C57BL/6J mice using intraperitoneal azoxymethane followed by three cycles of 2.5% dextran sodium sulfate (DSS) in drinking water. Mice were treated with mPGA (30-150 mg/kg) with or without the PPARα inhibitor MK886 (10 mg/kg). At Day 70 post-azoxymethane injection, mice underwent anesthetized endoscopic colon evaluation. Post-mortem analysis of tumorigenesis and angiogenesis was performed using histological, immunohistochemical, and immunoblotting techniques. mPGA improved disease progression and survival rates in a dose- and PPARα-dependent manner in AOM/DSS-exposed mice. It reduced polyp formation, decreased pro-angiogenic CD31, pro-proliferative Ki67, and pro-inflammatory TLR4 expression levels, and inhibited VEGF and MMP-9 secretion by disrupting the pAkt/mTOR/HIF1α pathway. mPGA increased colon PEA levels, restoring anti-tumoral PPARα and wtp53 protein expression. Given its lack of toxicity, mPGA shows potential as a nutritional intervention to counteract inflammation-related angiogenesis in CRC.

Background SARS-CoV-2 belongs to the coronaviridae family and infects human cells by directly interacting with the angiotensin-converting enzyme-2 (ACE-2) through the viral Spike Protein (SP). While vaccines are crucial, much attention has been directed towards managing the symptoms of acute respiratory distress syndrome. Our present study highlights the potential in counteracting lung inflammation triggered by SARS-CoV-2 SP of the intranasal administration of the engineered probiotic Lactobacillus paracasei F19 expressing the enzyme NAPE-PLD (pNAPE-LP) able to in situ release palmitoylethanolamide (PEA) under a super-low boost of palmitate. Methods C57BL/6J mice undergo prophylactic treatment with intranasal pNAPE-LP/palmitate for 7 days before a 7 days challenge with intranasal SARS-CoV-2 SP. Then the capability of pNAPE-LP of colonizing the lungs and actively release PEA in situ have been determined by immunofluorescence, western blot and HPLC-MS. Moreover, the innate immune system downregulation and the histological damage rescue exerted by pNAPE-LP have been tested by immunofluorescence, hematoxylin and eosin staining, western blot analysis and ELISA test for the release of the pro-inflammatory mediators. Results pNAPE-LP effectively colonizes mice lungs and releases the anti-inflammatory compound PEA. Moreover, pNAPE-LP exhibits a protective effect on alveolar morphology, innate immune cells infiltration and in the reduction of neutrophil count, effectively reducing lung injury induced by SARS-CoV-2 SP. This is achieved by mitigating TLR4-mediated NLRP3 activation and the downstream pro-inflammatory products such as ILs, TNFα, C-reactive protein and the myeloperoxidase activity. Interestingly we observed a global reduction ACE2 expression in the lungs. Conclusion pNAPE-LP actively protect from severe inflammatory-related symptoms in SP-challenged mice. Also, it can downregulate the expression of ACE-2 receptors at the lung site potentially preventing the spreading of the infection.

Accelerated synthesis of gold nanoparticles (AuNPs) in charged microdroplets produced by electrospray ionization (ESI) was exploited to modify the surface of graphite screen-printed electrodes (GSPEs). The deposited AuNPs were then functionalized by the charged microdroplets deposition of 6-ferrocenyl-hexanethiol (6Fc-ht) solutions that act as reducing and stabilizing agents and provide electrochemical properties for the modified electrodes. The morphology and composition of the AuNPs were characterized by scanning electron microscopy (SEM). Cyclic voltammetry (CV), differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) were used to investigate the electrochemical behavior of the modified electrodes. The results showed that the ESI microdroplets deposition technique produces uniform and well-dispersed AuNPs on GSPE, and optimal conditions for deposition were identified, enhancing GSPE electrocatalytic performance. Further functionalization by ESI microdroplets of AuNPs with 6Fc-ht demonstrated improved redox properties compared with the conventional self-assembled monolayer (SAM) method, highlighting the technique’s potential for the easy and fast functionalization of electrochemical sensors.

Carbon dots (CDs) obtained from 5-(hydroxymethyl)furfural (5-HMF) were activated by a 365 nm-UV irradiation source and employed in the Knoevenagel condensation to investigate their photocatalytic mechanism. To this end, electrospray ionization mass spectrometry (ESI-MS) was used to monitor the time progress of the condensation and follow the formation of the final product in positive and negative ion modes at once. The intervention of the superoxide radical anion in the photocatalytic mechanism of CDs was highlighted.

Photoinduced chemical reactions and the development of new materials represent a current and significant topic. We present a sustainable and eco-friendly approach to the Knoevenagel condensation reaction involving carbonyl and active methylene compounds. Our method utilizes photo-activated carbon dots (CDs) derived from 5-hydroxymethylfurfural (5HMF) within an aqueous medium and does not require acidic, basic, or thermal conditions. This protocol operates effectively with aromatic, aliphatic, and heteroaromatic aldehydes and ketones. The 5HMF-derived-CDs can be reused four times without significant loss of activity. Moreover, this methodology is suitable for scaling up reactions, thereby highlighting its potential for industrial applications.

Fruit seeds belonging to the pomegranate cultivar "Granata" were subjected to extraction and oily component analysis, with the aim of obtaining information about their composition. The presence of conjugated isomers of linolenic acid (CLNA isomers) in the oily phase extracted from the seeds gives a high added value to this part of the fruit, which is too often considered and treated as waste. The separated seeds were subjected to a classic Soxhlet extraction with n-hexane or extraction with supercritical CO2, assisted by ethanol. The resulting oils were evaluated by 1H and 13C-NMR and AP-MALDI-MS techniques. Differences in the triacylglycerols composition, with particular regard to punicic acid and other CLNA content, were studied in depth. Results showed the prevalence of punicic acid in the triacylglycerol mixture up to the 75%, with clear preponderance in the extract by supercritical fluids. Consequently, other CLNA isomers are, altogether, two-fold less represented in the supercritical extract than in the Soxhlet one. The two oily residues were subjected to solid phase extraction (SPE) and to HPLC-DAD analysis for the polyphenolic isolation and characterization. In addition to HPLC analysis, which showed different content and composition, DPPH analysis to evaluate the antiradical potential showed that the extract obtained with supercritical CO2 was much more active.

Different oxidative pathways of sulfur dioxide promoted by ZnO(NO3)(2), Zn(NO3)(2) and Zn(NO2)(NO3) are revealed by a joint investigation by mass spectrometry and theoretical calculations. The reactions are triggered by [Zn2+ -O-center dot](+) or by the low-valence Zn+ through oxygen ion transfer or electron transfer to SO2, respectively. The NOx- ligands intervene in the oxidation only when sulfur dioxide is converted to SO3- or SO2-, leading to the formation of zinc sulfate and zinc sulfite coordinated to nitrate or nitrite anions. Kinetic analyses show that the reactions are fast and efficient, and theory discloses the elementary steps, namely oxygen ion transfer, oxygen atom transfer and electron transfer, occurring through similar energy landscapes for the three reactive anions.

The peroxymonocarbonate anion, HCO4−, the covalent adduct between the carbon dioxide and hydrogen peroxide anion, effectively reacts with SO2 in the gas phase following three oxidative routes. Mass spectrometric and electronic structure calculations show that sulphur dioxide is oxidised through a common intermediate to the hydrogen sulphate anion, sulphur trioxide, and sulphur trioxide anion as primary products through formal HO2−, oxygen atom, and oxygen ion transfers. The hydrogen sulphite anion is also formed as a secondary product from the oxygen atom transfer path. The uncommon nucleophilic behaviour of HCO4− is disclosed by the Lewis acidic properties of SO2, an amphiphilic molecule that forms intermediates with characteristic and diagnostic geometries with peroxymonocarbonate.

Improving clinical outcomes and delaying disease recrudescence in Ulcerative Colitis (UC) patients is crucial for clinicians. In addition to traditional and new pharmacological therapies that utilize biological drugs, the development of medical devices that can ameliorate UC and facilitate the remission phase should not be overlooked. Drug-based therapy requires time to be personalized and to evaluate the benefit/risk ratio. However, the increasing number of diagnosed UC cases worldwide necessitates the exploration of new strategies to enhance clinical outcomes. By incorporating medical devices alongside pharmacological treatments, clinicians can provide additional support to UC patients, potentially improving their condition and slowing down the recurrence of symptoms. Chemically identified as an azelaic acid derivative and palmitoylethanolamide (PEA) analog, adelmidrol is a potent anti-inflammatory and antioxidant compound. In this study, we aimed to evaluate the effect of an intrarectal administration of 2% adelmidrol (Ade) and 0.1% hyaluronic acid (HA) gel formulation in both the acute and resolution phase of a mouse model of colitis induced via DNBS enema. We also investigated its activity in cultured human colon biopsies isolated from UC patients in the remission phase at follow-up when exposed in vitro to a cytomix challenge. Simultaneously, with its capacity to effectively alleviate chronic painful inflammatory cystitis when administered intravesically to urological patients such as Vessilen, the intrarectal administration of Ade/HA gel has shown remarkable potential in improving the course of colitis. This treatment approach has demonstrated a reduction in the histological damage score and an increase in the expression of ZO-1 and occludin tight junctions in both in vivo studies and human specimens. By acting independently on endogenous PEA levels and without any noticeable systemic absorption, the effectiveness of Ade/HA gel is reliant on a local antioxidant mechanism that functions as a “barrier effect” in the inflamed gut. Building on the findings of this preliminary study, we are confident that the Ade/HA gel medical device holds promise as a valuable adjunct in supporting traditional anti-UC therapies.