Design of New Schiff Bases and Their Heavy Metal Ion Complexes for Environmental Applications: A Molecular Dynamics and Density Function Theory Study.

Schiff bases (SBs) are important ligands in coordination chemistry due to their unique structural properties. Their ability to form complexes with metal ions has been exploited for the environmental detection of emerging water contaminants. In this work, we evaluated the complexation ability of three newly proposed SBs, 1-3, by complete conformational analysis, using a combination of Molecular Dynamics and Density Functional Theory studies, to understand their ability to coordinate toxic heavy metal (HMs) ions. From this study, it emerges that all the ligands present geometries that make them suitable to complex HMs through the N-imino moieties or, in the case of 3, with the support of the oxygen atoms of the ethylene diether chain. In particular, this ligand shows the most promising coordination behavior, particularly with Pb2+.

On the Electroanalytical Detection of Zn Ions by a Novel Schiff Base Ligand-SPCE Sensor.

A novel bidentate Schiff base (L) is here proposed for the detection of Zn ions in water. The structure of the synthesized Schiff base L was characterized by FT-IR, 1H NMR and 13C NMR. Optical characteristics were addressed by UV-Visible spectroscopy and Photoluminescence (PL) measurements. PL demonstrated that L displays a "turn-off" type fluorescence quenching in the presence of Zn2+ ion in aqueous solution, indicating its ability to preferentially coordinate this ion. Based on these findings, an L-M (where M is a suitable membrane) modified screen-printed carbon electrode (SPCE) was developed to evaluate the electrochemical behavior of the Schiff base (L) with the final objective of undertaking the electroanalytical determination of Zn ions in water. Using various electrochemical techniques, the modified L-M/SPCE sensor demonstrates high sensitivity and selectivity to Zn ions over some common interferents ions, such as Ca2+, Mg2+, K+, Ni++ and Cd++. The potentiometric response of the L-M/SPCE sensor to Zn ions was found to be linear over a relatively wide concentration range from 1 µM to 100 mM.

Chemoselective Oxidation of Isoxazolidines with Ruthenium Tetroxide: A Successful Intertwining of Combined Theoretical and Experimental Data.

The direct oxidation reaction of isoxazolidines plays an important role in organic chemistry, leading to the synthesis of biologically active compounds. In this paper, we report a computational mechanistic study of RuO4-catalyzed oxidation of differently N-substituted isoxazolidines 1a-c. Attention was focused on the endo/exo oxidation selectivity. For all the investigated compounds, the exo attack is preferred to the endo one, showing exo percentages growing in parallel with the stability order of transient carbocations found along the reaction pathway. The study has been supported by experimental data that nicely confirm the modeling results.

Synthesis and Biological Evaluation of 2,3,4-Triaryl-1,2,4-oxadiazol-5-ones as p38 MAPK Inhibitors.

A series of azastilbene derivatives, characterized by the presence of the 1,2,4-oxadiazole-5-one system as a linker of the two aromatic rings of stilbenes, have been prepared as novel potential inhibitors of p38 MAPK. Biological assays indicated that some of the synthesized compounds are endowed with good inhibitory activity towards the kinase. Molecular modeling data support the biological results showing that the designed compounds possess a reasonable binding mode in the ATP binding pocket of p38α kinase with a good binding affinity.

1,2,4-Oxadiazole-5-ones as analogues of tamoxifen: synthesis and biological evaluation.

A series of 2,3,4-triaryl-substituted 1,2,4-oxadiazole-5-ones have been prepared as fixed-ring analogues of tamoxifen (TAM), a drug inhibitor of Estradiol Receptor (ER) used in breast cancer therapy, by an efficient synthetic protocol based on a 1,3-dipolar cycloaddition of nitrones to isocyanates. Some of the newly synthesized compounds (14d-f, 14h and 14k) show a significant cytotoxic effect in a human breast cancer cell line (MCF-7) possessing IC50 values between 15.63 and 31.82 µM. In addition, compounds 14d-f, 14h and 14k are able to increase the p53 expression levels, activating also the apoptotic pathway. Molecular modeling studies of novel compounds performed on the crystal structure of ER reveal the presence of strong hydrophobic interactions with the aromatic rings of the ligands similar to TAM. These data suggest that 1,2,4-oxadiazole-5-ones can be considered analogues of TAM, and that their anticancer activity might be partially due to ER inhibition.

Pyrimidine 2,4-Diones in the Design of New HIV RT Inhibitors.

The pyrimidine nucleus is a versatile core in the development of antiretroviral agents. On this basis, a series of pyrimidine-2,4-diones linked to an isoxazolidine nucleus have been synthesized and tested as nucleoside analogs, endowed with potential anti-HIV (human immunodeficiency virus) activity. Compounds 6a-c, characterized by the presence of an ethereal group at C-3, show HIV reverse transcriptase (RT) inhibitor activity in the nanomolar range as well as HIV-infection inhibitor activity in the low micromolar with no toxicity. In the same context, compound 7b shows only a negligible inhibition of RT HIV.

Graphene Quantum Dots Based Systems As HIV Inhibitors.

Graphene quantum dots (GQD) are the next generation of nanomaterials with great potential in drug delivery and target-specific HIV inhibition. In this study we investigated the antiviral activity of graphene based nanomaterials by using water-soluble GQD synthesized from multiwalled carbon nanotubes (MWCNT) through prolonged acidic oxidation and exfoliation and compared their anti-HIV activity with that exerted by reverse transcriptase inhibitors (RTI) conjugated with the same nanomaterial. The antiretroviral agents chosen in this study, CHI499 and CDF119, belong to the class of non-nucleoside reverse transcriptase inhibitors (NNRTI). From this study emerged the RTI-conjugated compound GQD-CHI499 as a good potential candidate for HIV treatment, showing an IC50 of 0.09 µg/mL and an EC50 value in cell of 0.066 µg/mL. The target of action in the replicative cycle of HIV of the drug conjugated samples GQD-CHI499 and GQD-CDF119 was also investigated by a time of addition (TOA) method, showing for both conjugated samples a mechanism of action similar to that exerted by NNRTI drugs.

Synthesis and Biological Evaluation of Pyrimidine-oxazolidin-2-arylimino Hybrid Molecules as Antibacterial Agents.

Pyrimidine-1,3-oxazolidin-2-arylimino hybrids have been synthesized as a new class of antibacterial agents. The synthetic approach exploits a Cu(II)-catalyzed intramolecular halkoxyhalogenation of alkynyl ureas, followed by a Suzuki coupling reaction with 2,4-dimethoxypyrimidin-5-boronic acid. Biological screenings revealed that most of the compounds showed moderate to good activity against two Gram-positive (B. subtilis, S. aureus) and three Gram-negative (P. aeruginosa, S. typhi, K. pneumonia) pathogenic strains. A molecular docking study, performed in the crystal structure of 50S ribosomal unit of Haloarcula marismortui, indicated that pyrimidine-oxazolidin-2-arylimino hybrids 8c and 8h exhibited a high binding affinity (-9.65 and -10.74 kcal/mol), which was in agreement with their good antibacterial activity. The obtained results suggest that the combination of pyrimidine and oxazolidone moieties can be considered as a valid basis to develop new further modifications towards more efficacious antibacterial compounds.

Hydroxyapatite-magnetite-MWCNT nanocomposite as a biocompatible multifunctional drug delivery system for bone tissue engineering.

New magnetic hydroxyapatite-based nanomaterials as bone-specific systems for controlled drug delivery have been synthesized. The synthesized hydroxyapatite, HA, decorated with magnetite nanoparticles by a deposition method (HA/Fe3O4) and the nanocomposite system obtained using magnetic multi-walled carbon nanotubes (HA/MWCNT/Fe3O4) as a filler for HA have been characterized by chemical and morphological analyses, and their biological behavior was investigated. The systems have also been doped with clodronate in order to combine the effect of bone biomineralization induced by hydroxyapatite-based composites with the decrease of osteoclast formation induced by the drug. An analysis of the preosteoclastic RAW264.7 cell proliferation by MTT assay confirmed the high biocompatibility of the three systems. TRAP staining of RAW 264.7 conditioned with sRAKL to induce osteoclastogenesis, cultured in the presence of the systems doped and undoped with clodronate, showed the inhibitory effect of clodronate after we counted the MNC TRAP(+)cells but only in the osteoclast formation; in particular, the system HA/Fe3O4-Clo exerted a high inhibitory effect compared to the drug alone. These results demonstrate that the synthesized nanocomposites are a biocompatible magnetic drug delivery system and can represent a useful multimodal platform for applications in bone tissue engineering.

Graphene-based materials as nanoplatforms for antiviral therapy and prophylaxis.

INTRODUCTION: The dramatic effects caused by viral diseases have prompted the search for effective therapeutic and preventive agents. In this context, 2D graphene-based nanomaterials (GBNs) have shown great potential for antiviral therapy, enabling the functionalization and/or decoration with biomolecules, metals and polymers, able to improve their interaction with viral nanoparticles. AREAS COVERED: This review summarizes the most recent advances of the antiviral research related to 2D GBNs, based on their antiviral mechanism of action. Their ability to inactivate viruses by inhibiting the entry inside cells, or through drug/gene delivery, or by stimulating the host immune response are here discussed. As reported, biological studies performed in vitro and/or in vivo allowed to demonstrate the antiviral activity of the developed GBNs, at different stages of the virus life cycle and the evaluation of their long-term toxicity. Other mechanisms closely related to the physicochemical properties of GBNs are also reported, demonstrating the potential of these materials for antiviral prophylaxis. EXPERT OPINION: GBNs represent valuable tools to fight emerging or reemerging viral infections. However, their translation into the clinic requires standardized scale-up procedures leading to the reliable and reproducible synthesis of these nanomaterials with suitable physicochemical properties, as well as more in-depth pharmacological and toxicological investigations. We believe that multidisciplinary approaches will give valuable solutions to overcome the encountered limitations in the application of GBNs in biomedical and clinical field.

Functionalization of Carbon Nanofibers with an Aromatic Diamine: Toward a Simple Electrochemical-Based Sensing Platform for the Selective Sensing of Glucose.

Despite a variety of glucose sensors being available today, the development of nonenzymatic devices for the determination of this biologically relevant analyte is still of particular interest in several applicative sectors. Here, we report the development of an impedimetric, enzyme-free electrochemical glucose sensor based on carbon nanofibers (CNFs) functionalized with an aromatic diamine via a simple wet chemistry functionalization. The electrochemical performance of the chemically modified carbon-based screen-printed electrodes (SPCEs) was evaluated by electrical impedance spectroscopy (EIS), demonstrating a high selectivity of the sensor for glucose with respect to other sugars, such as fructose and sucrose. The sensing parameters to obtain a reliable calibration curve and the selective glucose sensing mechanism are discussed here, highlighting the performance of this novel electrochemical sensor for the selective sensing of this important analyte. Two linear trends were noted, one at low concentrations (0-1200 µM) and the other from 1200 to 5000 µM. The limit of detection (LOD), calculated as the (standard error/slope)*3.3, was 18.64 µM. The results of this study highlight the performance of the developed novel electrochemical sensor for the selective sensing of glucose.

Theranostic Applications of 2D Graphene-Based Materials for Solid Tumors Treatment.

Solid tumors are a leading cause of cancer-related deaths globally, being characterized by rapid tumor growth and local and distant metastases. The failures encountered in cancer treatment are mainly related to the complicated biology of the tumor microenvironment. Nanoparticles-based (NPs) approaches have shown the potential to overcome the limitations caused by the pathophysiological features of solid cancers, enabling the development of multifunctional systems for cancer diagnosis and therapy and allowing effective inhibition of tumor growth. Among the different classes of NPs, 2D graphene-based nanomaterials (GBNs), due to their outstanding chemical and physical properties, easy surface multi-functionalization, near-infrared (NIR) light absorption and tunable biocompatibility, represent ideal nanoplatforms for the development of theranostic tools for the treatment of solid tumors. Here, we reviewed the most recent advances related to the synthesis of nano-systems based on graphene, graphene oxide (GO), reduced graphene oxide (rGO), and graphene quantum dots (GQDs), for the development of theranostic NPs to be used for photoacoustic imaging-guided photothermal-chemotherapy, photothermal (PTT) and photodynamic therapy (PDT), applied to solid tumors destruction. The advantages in using these nano-systems are here discussed for each class of GBNs, taking into consideration the different chemical properties and possibility of multi-functionalization, as well as biodistribution and toxicity aspects that represent a key challenge for their translation into clinical use.

Antiviral Compounds to Address Influenza Pandemics: An Update from 2016-2022.

In recent decades, the world has gained experience of the dangerous effects of pandemic events caused by emerging respiratory viruses. In particular, annual epidemics of influenza are responsible for severe illness and deaths. Even if conventional influenza vaccines represent the most effective tool for preventing virus infections, they are not completely effective in patients with severe chronic disease and immunocompromised and new small molecules have emerged to prevent and control the influenza viruses. Thus, the attention of chemists is continuously focused on the synthesis of new antiviral drugs able to interact with the different molecular targets involved in the virus replication cycle. To date, different classes of influenza viruses inhibitors able to target neuraminidase enzyme, hemagglutinin protein, Matrix-2 (M2) protein ion channel, nucleoprotein or RNA-dependent RNA polymerase have been synthesized using several synthetic strategies comprising the chemical modification of currently used drugs. The best results, in terms of inhibitory activity, are in the nanomolar range and have been obtained from the chemical modification of clinically used drugs such as Peramivir, Zanamivir, Oseltamir, Rimantadine, as well as sialylated molecules, and hydroxypyridinone derivatives. The aim of this review is to report, covering the period 2016-2022, the most recent routes related to the synthesis of effective influenza virus inhibitors.

Uptake of Breathable Nano- and Micro-Sized Polystyrene Particles: Comparison of Virgin and Oxidised nPS/mPS in Human Alveolar Cells.

Airborne micro- and nanoplastics are widely spread and pose a risk to human health. The third polymer plastic most commonly produced and present in atmospheric fallout is polystyrene (PS). For these reasons and for a more realistic assessment of biological effects, we examined in-home oxidised (ox-, simulating photoaging) nPS/mPS (0.1 and 1 µm), comparing the effects with virgin ones (v-). On human alveolar cells (A549), we quantified the cellular uptake, using FITC-functionalised nPS/mPS, while cytotoxicity, changes in the acidic compartment, ROS production, mitochondrial function, and DNA damage were assessed to study the effects of internalised v- and ox-nPS/mPS. The results showed that the uptake was dose-dependent and very fast (1 h), since, at the lowest dose (1.25 µg/well), it was 20.8% and 21.8% of nPS and mPS, respectively. Compared to v-, significant ROS increases, DNA damage, and mitochondrial impairment were observed after exposure to ox-nPS/mPS. The enhancement of effects due to environmental aging processes highlighted the true potential impact on human health of these airborne pollutants.

Enhancement of biological effects of oxidised nano- and microplastics in human professional phagocytes.

Micro and nanoplastics are ubiquitous pollutants that can cause adverse health effects even in humans. Effects of virgin and oxidised (simulating the aging processes) polystyrene nano (nPS) and micro particles (mPS) with diameters of 0.1 and 1 µm were studied on human professional phagocytes (i.e., monocyte cells THP-1 and macrophage-like mTHP-1 cells). After characterization by ATR-FTIR, UV-Vis spectroscopy, SEM and dynamic light-scattering analyses, the particles were FITC functionalised to quantify cellular uptake. Changes in the cell compartments were studied by acrydine orange and the pro-oxidant, cytotoxic and genotoxic effects were assessed. Phagocytosis was dose- and time- dependent and at 24 h 52% of nPS and 58% of mPS were engulfed. Despite the high homeostasis of professional phagocytes, significant ROS increases and DNA damage were observed after exposure to oxidised particles. The results highlight that the environmental aging processes enhances the adverse health effects of micro and nanoplastics.

Promising Materials in the Fight against Healthcare-Associated Infections: Antibacterial Properties of Chitosan-Polyhedral Oligomeric Silsesquioxanes Hybrid Hydrogels.

New technologies and materials could help in this fight against healthcare-associated infections. As the majority of these infections are caused by antibiotic-resistant bacteria, the development of materials with intrinsic antibacterial properties is a promising field of research. We combined chitosan (CS), with antibacterial properties, with polyhedral oligomeric silsesquioxanes (POSS), a biocompatible polymer with physico-chemical, mechanical, and rheological properties, creating a hydrogel using cross-linking agent genipin. The antibacterial properties of CS and CS-POSS hydrogels were investigated against nosocomial Gram-positive and Gram-negative bacteria both in terms of membrane damage and surface charge variations, and finally, the anti-biofilm property was studied through confocal microscopy. Both materials showed a good antibacterial capacity against all analyzed strains, both in suspension, with % decreases between 36.36 and 73.58 for CS and 29.86 and 66.04 for CS-POSS, and in plates with % decreases between 55.29 and 78.32 and 17.00 and 53.99 for CS and CS-POSS, respectively. The treated strains compared to the baseline condition showed an important membrane damage, which also determined a variation of surface charges, and finally, for both hydrogels, a remarkable anti-biofilm property was highlighted. Our findings showed a possible future use of these biocompatible materials in the manufacture of medical and surgical devices with intrinsic antibacterial and anti-biofilm properties.

Using the Aqueous Phase Produced from Hydrothermal Carbonization Process of Brown Seaweed to Improve the Growth of Phaseolus vulgaris.

Seaweeds are considered a biomass for third-generation biofuel, and hydrothermal carbonization (HTC) is a valuable process for efficiently disposing of the excess of macroalgae biomass for conversion into multiple value-added products. However, the HTC process produces a liquid phase to be disposed of. The present study aims to investigate the effects of seed-priming treatment with three HTC-discarded liquid phases (namely AHL180, AHL240, and AHL300), obtained from different experimental procedures, on seed germination and plant growth and productivity of Phaseolus vulgaris L. To disentangle the osmotic effects from the use of AHL, isotonic solutions of polyethylene glycol (PEG) 6000 have also been tested. Seed germination was not affected by AHL seed-priming treatment. In contrast, PEG-treated samples showed significantly lower seed germination success. AHL-treated samples showed changes in plant biomass: higher shoot biomass was recorded especially in AHL180 samples. Conversely, AHL240 and AHL300 samples showed higher root biomass. The higher plant biomass values recorded in AHL-treated samples were the consequence of higher values of photosynthesis rate and water use efficiency, which, in turn, were related to higher stomatal density. Recorded data strongly support the hypothesis of the AHL solution reuse in agriculture in the framework of resource management and circular green economy.

Solid Lipid Nanoparticles Containing Morin: Preparation, Characterization, and Ex Vivo Permeation Studies.

In recent years, bioactive compounds have been the focus of much interest in scientific research, due to their low toxicity and extraordinary properties. However, they possess poor solubility, low chemical stability, and unsustainable bioavailability. New drug delivery systems, and among them solid lipid nanoparticles (SLNs), could minimize these drawbacks. In this work, morin (MRN)-loaded SLNs (MRN-SLNs) were prepared using a solvent emulsification/diffusion method, using two different lipids, Compritol® 888 ATO (COM) or Phospholipon® 80H (PHO). SLNs were investigated for their physical-chemical, morphological, and technological (encapsulation parameters and in vitro release) properties. We obtained spherical and non-aggregated nanoparticles with hydrodynamic radii ranging from 60 to 70 nm and negative zeta potentials (about -30 mV and -22 mV for MRN-SLNs-COM and MRN-SLNs-PHO, respectively). The interaction of MRN with the lipids was demonstrated via µ-Raman spectroscopy, X-ray diffraction, and DSC analysis. High encapsulation efficiency was obtained for all formulations (about 99%, w/w), particularly for the SLNs prepared starting from a 10% (w/w) theoretical MRN amount. In vitro release studies showed that about 60% of MRN was released within 24 h and there was a subsequent sustained release within 10 days. Finally, ex vivo permeation studies with excised bovine nasal mucosa demonstrated the ability of SLNs to act as a penetration enhancer for MRN due to the intimate contact and interaction of the carrier with the mucosa.

Functionalization of multi-walled carbon nanotubes with coumarin derivatives and their biological evaluation.

We report the synthesis and the characterization of different multi-walled carbon nanotubes (MWCNTs) linked to natural molecules, 5,7-coumarins and/or oleic acid, obtained from purified pristine MWCNTs by a cascade of chemical functionalization. The activities of these modified MWCNTs were investigated in vitro on human umbilical vein endothelial cells (HUVECs) by evaluating their ability to influence cell viability and to induce cell apoptosis. Our data showed that pristine MWCNTs are markedly cytotoxic; conversely, the carboxylated carbon nanotubes, much more readily dispersed in aqueous solutions and CNT-Link, the key intermediate designed by us for the drug anchorage, are biocompatible at the tested concentrations (1 and 10 µg ml(-1)).

Titanium Surface Modification for Implantable Medical Devices with Anti-Bacterial Adhesion Properties.

Pure titanium and titanium alloys are widely used in dentistry and orthopedics. However, despite their outstanding mechanical and biological properties, implant failure mainly due to post-operative infection still remains a significant concern. The possibility to develop inherent antibacterial medical devices was here investigated by covalently inserting bioactive ammonium salts onto the surface of titanium metal substrates. Titanium discs have been functionalized with quaternary ammonium salts (QASs) and with oleic acid (OA), affording the Ti-AEMAC Ti-GTMAC, Ti-AUTEAB, and Ti-OA samples, which were characterized by ATR-FTIR and SEM-EDX analyses and investigated for the roughness and hydrophilic behavior. The chemical modifications were shown to deeply affect the surface properties of the metal substrates and, as a consequence, their bio-interaction. The bacterial adhesion tests against the Gram-negative Escherichia Coli and Gram-positive Staphylococcus aureus, at 1.5 and 24 h of bacterial contact, showed good anti-adhesion activity for Ti-AUTEAB and Ti-OA samples, containing a long alkyl chain between the silicon atom and the ammonium functionality. In particular, the Ti-AUTEAB sample showed inhibition of bacteria adhesion against Escherichia Coli of about one log with respect to the other samples, after 1.5 h. The results of this study highlight the importance of chemical functionalization in addressing the antimicrobial activity of metal surfaces and could open new perspectives in the development of inherent antibacterial medical devices.