1,2,3-Triazole Hybrids Containing Isatins and Phenolic Moieties: Regioselective Synthesis and Molecular Docking Studies.

The synthesis of hybrid molecules is one of the current strategies of drug discovery for the development of new lead compounds. The 1,2,3-triazole moiety represents an important building block in Medicinal Chemistry, extensively present in recent years. In this paper, we presented the design and the synthesis of new 1,2,3-triazole hybrids, containing both an isatine and a phenolic core. Firstly, the non-commercial azide and the alkyne synthons were prepared by different isatines and phenolic acids, respectively. Then, the highly regioselective synthesis of 1,4-disubstituted triazoles was obtained in excellent yields by a click chemistry approach, catalyzed by Cu(I). Finally, a molecular docking study was performed on the hybrid library, finding four different therapeutic targets. Among them, the most promising results were obtained on 5-lipoxygenase, an enzyme involved in the inflammatory processes.

Thiol-functionalized cellulose for mercury polluted water remediation: Synthesis and study of the adsorption properties.

Mercury pollution poses a global health threat due to its high toxicity, especially in seafood where it accumulates through various pathways. Developing effective and affordable technologies for mercury removal from water is crucial. Adsorption stands out as a promising method, but creating low-cost materials with high selectivity and capacity for mercury adsorption is challenging. Here we show a sustainable method to synthesize low-cost sulfhydrylated cellulose with ethylene sulfide functionalities bonded glucose units. Thiol-functionalized cellulose exhibits exceptional adsorption capacity (1325 mg g-1) and selectivity for Hg(II) over other heavy metals (Co, Cu, Zn, Pb) and common cations (Ca++, Mg++) found in natural waters. It performs efficiently across a wide pH range and different aqueous matrices, including wastewater, and can be regenerated and reused multiple times without significant loss of performance. This approach offers a promising solution for addressing mercury contamination in water sources.

Reactive Deep Eutectic Solvent for an Eco-Friendly Synthesis of Cellulose Carbamate.

The limited solubility of natural cellulose in water and common organic solvents hinders its diverse applications, despite being one of the most abundant and easily accessible biopolymers on Earth. Chemical derivatization, such as cellulose carbamate (CC), offers a pathway to enhance both solubility and industrial processability. In this study, CC was synthesized by exploiting a novel type IV deep eutectic solvent (DES) composed of erbium trichloride and urea. This DES was shown to be not only an environmentally friendly reaction medium/catalyst but also actively participated in the synthetic process as a reagent. The resultant cellulose carbamate samples were characterized through FT-IR and elemental analysis. A nitrogen content value of 1.59% was afforded determining a degree of substitution corresponding to a value of 0.19. One of the key scientific advancements lies in the preparation of cellulose carbamate using a straightforward and cost-effective method. This approach utilizes non-toxic compounds, aligning with the principles of green chemistry and contributing to sustainable development in cellulose derivative production.

Molecular mechanisms of naringenin modulation of mitochondrial permeability transition acting on F1FO-ATPase and counteracting saline load-induced injury in SHRSP cerebral endothelial cells.

Naringenin (NRG) was characterized for its ability to counteract mitochondrial dysfunction which is linked to cardiovascular diseases. The F1FO-ATPase can act as a molecular target of NRG. The interaction of NRG with this enzyme can avoid the energy transmission mechanism of ATP hydrolysis, especially in the presence of Ca2+ cation used as cofactor. Indeed, NRG was a selective inhibitor of the hydrophilic F1 domain displaying a binding site overlapped with quercetin in the inside surface of an annulus made by the three α and the three ß subunits arranged alternatively in a hexamer. The kinetic constant of inhibition suggested that NRG preferred the enzyme activated by Ca2+ rather than the F1FO-ATPase activated by the natural cofactor Mg2+. From the inhibition type mechanism of NRG stemmed the possibility to speculate that NRG can prevent the activation of F1FO-ATPase by Ca2+. The event correlated to the protective role in the mitochondrial permeability transition pore opening by NRG as well as to the reduction of ROS production probably linked to the NRG chemical structure with antioxidant action. Moreover, in primary cerebral endothelial cells (ECs) obtained from stroke prone spontaneously hypertensive rats NRG had a protective effect on salt-induced injury by restoring cell viability and endothelial cell tube formation while also rescuing complex I activity.

Highly Diastereoselective Multicomponent Synthesis of Spirocyclopropyl Oxindoles Enabled by Rare-Earth Metal Salts.

The synthesis of polysubstituted spirocyclopropyl oxindoles using a series of rare-earth metal (REM) salts is reported. REMs, in particular Sc(OTf)3, allowed access to the target compounds by a multicomponent reaction with high diastereoselectivity (≤94:6:0:0). Density functional theory calculations on the model reaction are consistent with the observed selectivity and revealed that the special coordinating capabilities and the oxophilicity of the metal are key factors in inducing the formation of one main diastereoisomer.

Bio-Based Polyurethane Foams for the Removal of Petroleum-Derived Pollutants: Sorption in Batch and in Continuous-Flow.

In this paper, we evaluated the potential of two synthesized bio-based polyurethane foams, PU1 and PU2, for the removal of diesel and gasoline from water mixtures. We started the investigation with the experiment in batch. The total sorption capacity S (g/g) for the diesel/water system was slightly higher with respect to gasoline/water, with a value of 62 g/g for PU1 and 65 g/g for PU2. We found that the sorption follows a pseudo second-order kinetic model for both the materials. The experimental data showed that the best isotherm models were obtained with Langmuir and Redlich-Peterson models. In addition, to provide an idea of the process scalability for future industrial applications, we tested the sorption capacity of the foams using a continuous-flow of the same oil/water mixtures and we obtained performances even better with respect to the batch test. The regeneration can be performed up to 50 times by centrifuge, without losing efficacy.

Novel Regioselective Synthesis of 1,3,4,5-Tetrasubstituted Pyrazoles and Biochemical Valuation on F1FO-ATPase and Mitochondrial Permeability Transition Pore Formation.

An efficient, eco-compatible, and very cheap method for the construction of fully substituted pyrazoles (Pzs) via eliminative nitrilimine-alkene 1,3-dipolar cycloaddition (ENAC) reaction was developed in excellent yield and high regioselectivity. Enaminones and nitrilimines generated in situ were selected as dipolarophiles and dipoles, respectively. A deep screening of the employed base, solvent, and temperature was carried out to optimize reaction conditions. Recycling tests of ionic liquid were performed, furnishing efficient performance until six cycles. Finally, a plausible mechanism of cycloaddition was proposed. Then, the effect of three different structures of Pzs was evaluated on the F1FO-ATPase activity and mitochondrial permeability transition pore (mPTP) opening. The Pz derivatives' titration curves of 6a, 6h, and 6o on the F1FO-ATPase showed a reduced activity of 86%, 35%, and 31%, respectively. Enzyme inhibition analysis depicted an uncompetitive mechanism with the typical formation of the tertiary complex enzyme-substrate-inhibitor (ESI). The dissociation constant of the ESI complex (Ki') in the presence of the 6a had a lower order of magnitude than other Pzs. The pyrazole core might set the specific mechanism of inhibition with the F1FO-ATPase, whereas specific functional groups of Pzs might modulate the binding affinity. The mPTP opening decreased in Pz-treated mitochondria and the Pzs' inhibitory effect on the mPTP was concentration-dependent with 6a and 6o. Indeed, the mPTP was more efficiently blocked with 0.1 mM 6a than with 1 mM 6a. On the contrary, 1 mM 6o had stronger desensitization of mPTP formation than 0.1 mM 6o. The F1FO-ATPase is a target of Pzs blocking mPTP formation.

1,5-disubstituted-1,2,3-triazoles counteract mitochondrial dysfunction acting on F1FO-ATPase in models of cardiovascular diseases.

The compromised viability and function of cardiovascular cells are rescued by small molecules of triazole derivatives (Tzs), identified as 3a and 3b, by preventing mitochondrial dysfunction. The oxidative phosphorylation improves the respiratory control rate in the presence of Tzs independently of the substrates that energize the mitochondria. The F1FO-ATPase, the main candidate in mitochondrial permeability transition pore (mPTP) formation, is the biological target of Tzs and hydrophilic F1 domain of the enzyme is depicted as the binding region of Tzs. The protective effect of Tz molecules on isolated mitochondria was corroborated by immortalized cardiomyocytes results. Indeed, mPTP opening was attenuated in response to ionomycin. Consequently, increased mitochondrial roundness and reduction of both length and interconnections between mitochondria. In in-vitro and ex-vivo models of cardiovascular pathologies (i.e., hypoxia-reoxygenation and hypertension) were used to evaluate the Tzs cardioprotective action. Key parameters of porcine aortic endothelial cells (pAECs) oxidative metabolism and cell viability were not affected by Tzs. However, in the presence of either 1 µM 3a or 0.5 µM 3b the impaired cell metabolism of pAECs injured by hypoxia-reoxygenation was restored to control respiratory profile. Moreover, endothelial cells isolated from SHRSP exposed to high-salt treatment rescued the Complex I activity and the endothelial capability to form vessel-like tubes and vascular function in presence of Tzs. As a result, the specific biochemical mechanism of Tzs to block Ca2+-activated F1FO-ATPase protected cell viability and preserved the pAECs bioenergetic metabolism upon hypoxia-reoxygenation injury. Moreover, SHRSP improved vascular dysfunction in response to a high-salt treatment.

Regioselective Synthesis and Molecular Docking Studies of 1,5-Disubstituted 1,2,3-Triazole Derivatives of Pyrimidine Nucleobases.

1,2,3-triazoles are versatile building blocks with growing interest in medicinal chemistry. For this reason, organic chemistry focuses on the development of new synthetic pathways to obtain 1,2,3-triazole derivatives, especially with pyridine moieties. In this work, a novel series of 1,5-disubstituted-1,2,3-triazoles functionalized with pyrimidine nucleobases were prepared via 1,3-dipolar cycloaddition reaction in a regioselective manner for the first time. The N1-propargyl nucleobases, used as an alkyne intermediate, were obtained in high yields (87-92%) with a new two-step procedure that selectively led to the monoalkylated compounds. Then, FeCl3 was employed as an efficient Lewis acid catalyst for 1,3-dipolar cycloaddition between different aryl and benzyl azides and the N1-propargyl nucleobases previously synthesized. This new protocol allows the synthesis of a series of new 1,2,3-triazole derivatives with good to excellent yields (82-92%). The ADME (Absorption, Distribution, Metabolism, and Excretion) analysis showed good pharmacokinetic properties and no violations of Lipinsky's rules, suggesting an appropriate drug likeness for these new compounds. Molecular docking simulations, conducted on different targets, revealed that two of these new hybrids could be potential ligands for viral and bacterial protein receptors such as human norovirus capsid protein, SARS-CoV-2 NSP13 helicase, and metallo-ß-lactamase.

Efficient and Fast Removal of Oils from Water Surfaces via Highly Oleophilic Polyurethane Composites.

In this study we evaluated the oil adsorption capacity of an aliphatic polyurethane foam (PU 1) and two of its composites, produced through surface coating using microparticles of silica (PU-Si 2) and activated carbon (PU-ac 3). The oil adsorption capacity in diesel was improved up to 36% using the composite with silica and up to 50% using the composite with activated carbon with respect to the initial PU 1. Excellent performances were retained in gasoline and motor oil. The adsorption was complete after a few seconds. The process follows a monolayer adsorption fitted by the Langmuir isotherm, with a maximum adsorption capacity of 29.50 g/g of diesel for the composite with activated carbon (PU-ac 3). These materials were proved to be highly oleophilic for oil removal from fresh water and sea water samples. Regeneration and reuse can be repeated up to 50 times by centrifugation, without a significant loss in adsorption capacity.

Synthesis, Characterization and Mechanical Properties of Novel Bio-Based Polyurethane Foams Using Cellulose-Derived Polyol for Chain Extension and Cellulose Citrate as a Thickener Additive.

A novel series of bio-based polyurethane composite foams was prepared, employing a cellulose-derived polyol for chain extension and cellulose-citrate as a thickener additive. The utilized polyol was obtained from the reduction reaction of cellulose-derived bio-oil through the use of sodium borohydride and iodine. Primarily, we produced both rigid and flexible polyurethane foams through chain extension of the prepolymers. Secondly, we investigated the role of cellulose citrate as a polyurethane additive to improve the mechanical properties of the realized composite materials. The products were characterized by FT-IR spectroscopy and their morphologies were analysed by SEM. Mechanical tests were evaluated to open new perspectives towards different applications.

Cellulose citrate: a convenient and reusable bio-adsorbent for effective removal of methylene blue dye from artificially contaminated water.

In the present work, we proved the efficacy of cellulose citrate to remove methylene blue (MB) from artificially contaminated water. MB is a widely used dye, but because of its chemical aromatic structure, it is significantly stable with quite slow biodegradation, causing consequent serious health problems for people and significant environmental pollution. Cellulose citrate, the bio-adsorbent proposed and studied by us to remediate water polluted by MB, is produced by a green, cheap and fast procedure that makes use of two abundant natural products, cellulose and citric acid. The average of two citrate groups for each glucose unit of cellulose chains allows this material to have many carboxylic groups available for interaction with the cationic dye. The characterization was carried out through FT-IR, SEM, specific surface area, pore structure parameters and zeta potential. The negative value of the zeta potential at neutral pH is consistent with the affinity of this material for the adsorption of cationic compounds like MB. The activity of the adsorbent at different times, temperatures, pH and concentrations was investigated. The process followed monolayer adsorption typical of the Langmuir model, with a maximum adsorption capacity of 96.2 mg g-1, while for the kinetic studies the process followed a pseudo-second order model. The highest levels of adsorption were reported using solutions of dye with concentrations under 100 mg L-1. The adsorbent can be regenerated several times without a significant loss in the adsorption capacity, and it is not strongly affected by temperature and pH, giving rise to a simple and eco-sustainable procedure for water remediation. Therefore, we conclude that cellulose citrate can be considered as a promising bio-adsorbent for the removal of MB and other cationic pollutants from the environment.

1,5-Disubstituted-1,2,3-triazoles as inhibitors of the mitochondrial Ca2+ -activated F1 FO -ATP(hydrol)ase and the permeability transition pore.

The mitochondrial permeability transition pore (mPTP), a high-conductance channel triggered by a sudden Ca2+ concentration increase, is composed of the F1 FO -ATPase. Since mPTP opening leads to mitochondrial dysfunction, which is a feature of many diseases, a great pharmacological challenge is to find mPTP modulators. In our study, the effects of two 1,5-disubstituted 1,2,3-triazole derivatives, five-membered heterocycles with three nitrogen atoms in the ring and capable of forming secondary interactions with proteins, were investigated. Compounds 3a and 3b were selected among a wide range of structurally related compounds because of their chemical properties and effectiveness in preliminary studies. In swine heart mitochondria, both compounds inhibit Ca2+ -activated F1 FO -ATPase without affecting F-ATPase activity sustained by the natural cofactor Mg2+ . The inhibition is mutually exclusive, probably because of their shared enzyme site, and uncompetitive with respect to the ATP substrate, since they only bind to the enzyme-ATP complex. Both compounds show the same inhibition constant (K'i ), but compound 3a has a doubled inactivation rate constant compared with compound 3b. Moreover, both compounds desensitize mPTP opening without altering mitochondrial respiration. The results strengthen the link between Ca2+ -activated F1 FO -ATPase and mPTP and suggest that these inhibitors can be pharmacologically exploited to counteract mPTP-related diseases.

Sequestering Ability of a Synthetic Chelating Agent towards Copper(II) and Iron(III): A Detailed Theoretical and Experimental Analysis.

In the continuous effort to identify selective chelators towards bioavailable and toxic metal ions, the potential selectivity of a novel N,O chelating ligand, recently synthesized and claimed to be able to bind to Cu(II) ions forming stable complexes while leaving unaltered the level of essential metal ions, was scrutinized using a combined theoretical and experimental approach. A multistep synthetic procedure was used to synthesize the ligand, whose chelating properties along with the stability of the complexes formed binding Cu(II) and, for comparison, Fe(III) ions were evaluated using potentiometric measurements and UV-Vis spectroscopy. DFT analysis allowed to disclose the structural characteristics of the formed complexes. In the plethora of all the possible structures, a selection of the most reliable ones was achieved by means of a stringent comparison between experimental and simulated UV-Vis spectra. The outcomes of the present investigation demonstrate that the Cu(II) sequestering ability of the ligand is smaller than that towards Fe(III). The strategy used here should allow to check the propensity of ligands in selectively binding metal ions.

Natural Deep Eutectic Solvent as Extraction Media for the Main Phenolic Compounds from Olive Oil Processing Wastes.

In this new century, sustainable development challenges chemical sciences to develop new and clean technological processes. The agri-food industry produces significant quantities of waste, raising significant economic and environmental concerns. Food waste valorization using environmentally friendly procedures is of increasing importance. This study describes the use of several Natural Deep Eutectic Solvents (NADESs) for the microwave-assisted extraction (MAE) of valuable bioactive phenolic compounds from olive oil processing wastes. The extracted samples were characterized by liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (LC-ESI-QTOF/MS) analysis and the quantification of the phenolic compounds was performed by HPLC analysis. The obtained data were compared with those obtained using water as the solvent in the same extraction conditions. The extraction process is nontoxic, simple and selective and meets most of the criteria to be considered as a sustainable process, with the solvents arising directly from nature.

Totally green cellulose conversion into bio-oil and cellulose citrate using molten citric acid in an open system: synthesis, characterization and computational investigation of reaction mechanisms.

The simultaneous transformation of crystalline or amorphous cellulose into a furan-based bio-oil and cellulose citrate was realized avoiding the use of strong inorganic acids, drastic conditions, enzymatic treatments or microorganism fermentation. This innovative method is very eco-friendly and involves the use of molten citric acid under solvent free conditions at atmospheric pressure. An accurate discussion on chemical composition of the bio-oil enriched in bioprivileged molecules as well as structural and morphological characterization of cellulose citrate was reported. Moreover, mechanistic hypotheses were formulated on the basis of experimental findings and detailed DFT quantum-mechanical simulations were carried out to confirm, step by step, the proposed reaction paths.

Green Synthesis of Privileged Benzimidazole Scaffolds Using Active Deep Eutectic Solvent.

The exploitation and use of alternative synthetic methods, in the face of classical procedures that do not conform to the ethics of green chemistry, represent an ever-present problem in the pharmaceutical industry. The procedures for the synthesis of benzimidazoles have become a focus in synthetic organic chemistry, as they are building blocks of strong interest for the development of compounds with pharmacological activity. Various benzimidazole derivatives exhibit important activities such as antimicrobial, antiviral, anti-inflammatory, and analgesic activities, and some of the already synthesized compounds have found very strong applications in medicine praxis. Here we report a selective and sustainable method for the synthesis of 1,2-disubstituted or 2-substituted benzimidazoles, starting from o-phenylenediamine in the presence of different aldehydes. The use of deep eutectic solvent (DES), both as reaction medium and reagent without any external solvent, provides advantages in terms of yields as well as in the work up procedure of the reaction.

Synthesis, Biological and In Silico Evaluation of Pure Nucleobase-Containing Spiro (Indane-Isoxazolidine) Derivatives as Potential Inhibitors of MDM2-p53 Interaction.

Nucleobase-containing isoxazolidines spiro-bonded to an indane core have been synthesized in very good yields by regio- and diastereoselective 1,3-dipolar cycloaddition starting from indanyl nitrones and N-vinylnucleobases by using environmentally benign microwave technology. The contemporary presence of various structural groups that are individually active scaffolds of different typology of drugs, has directed us to speculate that these compounds may act as inhibitors of MDM2-p53 interaction. Therefore, both computational calculations and antiproliferative screening against A549 human lung adenocarcinoma cells and human SH-SY5Y neuroblastoma cells were carried out to support this hypothesis.

Antiproliferative activity of novel isatinyl/indanyl nitrones (INs) as potential spin trapping agents of free radical intermediates.

A series of ketonitrones derived from isatin and indanone (INs) were synthesized and evaluated for their antiproliferative activities against several human cancer cell lines. Then, the antioxidant properties of these substrates were measured by the DPPH test to report their biological activity in terms of their spin trapping action. In particular, one substrate has showed very high biological and scavenging activity, probably due to the strong correlation between its spin trapping activity and structure.

Biorenewable Deep Eutectic Solvent for Selective and Scalable Conversion of Furfural into Cyclopentenone Derivatives.

The development of novel synthetic routes to produce bioactive compounds starting from renewable sources has become an important research area in organic and medicinal chemistry. Here, we present a low-cost procedure for the tunable and selective conversion of biomass-produced furfural to cyclopentenone derivatives using a mixture of choline chloride and urea as a biorenewable deep eutectic solvent (DES). The proposed medium is a nontoxic, biodegradable, and could be reused up to four times without any unfavorable effect on the reaction yield. The process is tunable, clean, cheap, simple and scalable and meets most of the criteria; therefore, it can be considered as an environmental sustainable process in a natural reaction medium.