Green chemistry approach to the synthesis of 3-substituted-quinazolin-4(3H)-ones and 2-methyl-3-substituted-quinazolin-4(3H)-ones and biological evaluation

ABSTRACT

A synthesis of two series of 3-substituted quinazolinones was performed utilizing a green chemistry approach, deep eutectic solvents and microwaves, namely. 2-Methyl-3-substituted-quinazolin-4(3H)-one derivatives were synthesized in a two-step reaction, using choline chloride:urea deep eutectic solvent (DES). 3-Substituted-quinazolin-4(3H)-ones were synthesized in one-pot one-step reaction of anthranilic acid, amines and orthoester in a microwave reactor. For the synthesis of 2-methyl-3-substituted-quinazolin-4(3H)-ones, first conventional synthesis of benzoxazinone, as an intermediate, was performed. Further, benzoxazinone in reaction with corresponding amines, in choline choline:urea deep eutectic solvent, furnished desired compounds. These procedures are based on green principles with the aim of developing synthetic routes for the potential antitumor agents. All compounds were characterized by LC/MS, ¹H NMR and ¹³C NMR spectral techniques. Compound 1 bearing trifluoromethoxyphenyl group showed promising activity against HuT-78 cell line with IC₅₀ of 51.4?±?5.1?µM.     

Binary Simple Sugar Profiling in Corn and Small Grain Flour Authentication Using GC/EI-qMS Approach

There is an increasing demand for mixed flour bakery products in the world market, considering the health benefits of various cereal grains. The aim of this work was to develop a rapid approach for corn and small grain flour authentication. Simple sugars present in flour samples were extracted with 96 % ethanol solution, derivatized into corresponding trimethylsilyl oximes (TMSO), and analyzed on a GC/EI-qMS device. The presence of a specific simple sugar at a specific retention time was confirmed using mass spectrometer, thus providing a semi-qualitative approach. Binary matrices were developed based on the presence/absence of detected simple sugar compounds in the investigated cereal species, to minimize the influence of variability between investigated cultivars of the same species. By performing exploratory data analysis: hierarchical cluster analysis (HCA), principal coordinate analysis (PCO), and principal component analysis (PCA), flour samples of corn species were strongly separated from every investigated species of small grains, using all three multivariate tools, thus enabling its authentication in a small grain/corn flour mixture.

     

Neurotoxic Effect of Flavonol Myricetin in the Presence of Excess Copper

Oxidative stress (OS) induced by the disturbed homeostasis of metal ions is one of the pivotal factors contributing to neurodegeneration. The aim of the present study was to investigate the effects of flavonoid myricetin on copper-induced toxicity in neuroblastoma SH-SY5Y cells. As determined by the MTT method, trypan blue exclusion assay and measurement of ATP production, myricetin heightened the toxic effects of copper and exacerbated cell death. It also increased copper-induced generation of reactive oxygen species, indicating the prooxidative nature of its action. Furthermore, myricetin provoked chromatin condensation and loss of membrane integrity without caspase-3 activation, suggesting the activation of both caspase-independent programmed cell death and necrosis. At the protein level, myricetin-induced upregulation of PARP-1 and decreased expression of Bcl-2, whereas copper-induced changes in the expression of p53, p73, Bax and NME1 were not further affected by myricetin. Inhibitors of ERK1/2 and JNK kinases, protein kinase A and L-type calcium channels exacerbated the toxic effects of myricetin, indicating the involvement of intracellular signaling pathways in cell death. We also employed atomic force microscopy (AFM) to evaluate the morphological and mechanical properties of SH-SY5Y cells at the nanoscale. Consistent with the cellular and molecular methods, this biophysical approach also revealed a myricetin-induced increase in cell surface roughness and reduced elasticity. Taken together, we demonstrated the adverse effects of myricetin, pointing out that caution is required when considering powerful antioxidants for adjuvant therapy in copper-related neurodegeneration.     

Essential Oil Volatile Fingerprint Differentiates Croatian cv. Oblica from Other Olea europaea L. Cultivars

Olive leaves are a highly available by-product from table olive and olive oil production. They are nowadays strongly valuable for their major bioactive compounds and their beneficial effects. To determine the differences between two Croatian domestic (Lastovka, Oblica) and two introduced (Leccino, Frantoio) cultivars, physical and chemical analysis of olive leaves were performed: surface area, color variability, total phenolic amounts, and essential oil volatile profiles were analyzed at three harvest periods. All cultivars greatly differed in surface area, with cv. Lastovka being the smallest. Color variability resulted in an overall decrease in darkness and amounts of green and yellow that could be attributed to a decrease in photosynthetic demand and chlorophyll content. The highest amount of total phenolic content occurred in the summer months, followed by a reduction until October. Essential oils volatiles were determined by GC-MS and showed great diversity not only amongst cultivars but also between harvest periods, with overall 45 compounds identified. Principal component analysis distinguished domestic cultivar Oblica from the other observed cultivars, mainly due to its essential oil volatile fingerprint. Compounds that differentiated cv. Oblica were aldehydes ((E,Z)-2,4-heptadienal, (E,E)-2,4-heptadienal, decanal), ketones ((E)-β-damascone, dihydrodehydro-β-ionone), sesquiterpenes (cyclosativene, α-copaene, α-muurolene) and saturated hydrocarbons (tetradecane, hexadecane). Essential oil volatile fingerprint attributed the highest to the biodiversity of domestic cv. Oblica through all three harvest periods.     

Supramolecular motifs and solvatomorphism within the compounds [M(bpy)3]2[NbO(C2O4)(3)]Cl.nH2O (M = Fe2+, Co2+, Ni2+, Cu2+ and Zn2+; n = 11, 12). Syntheses, structures and magnetic properties

Solvatomorphism has been found between two series of complexes of the composition [M(bpy)3]2[NbO(C2O4)3]Cl.nH2O [M = Fe2+ (1, 2), Co2+ (3, 4), Ni2+ (5, 6), Cu2+ (7) and Zn2+ (8, 9); bpy = 2,2'-bipyridine)], crystallizing in the monoclinic space group P2 1/c [3, 5, 8 (n = 11)] or in the orthorhombic space group P21 21 21 [2, 4, 6, 7 (n = 12)]. All the structures contain two symmetry independent [M(bpy)3]2+ cations, one [NbO(C2O4)3]3- anion, one Cl(-) anion, and crystal water molecules. The cations possess a trigonally distorted octahedral geometry, with an additional tetragonal distortion in 7. Analysis of crystal packing reveals a specific type of supramolecular contact comprising four bipyridine ligands from two neighbouring [M(bpy)3]2+ cations--quadruple aryl embrace (QAE) contact. The contact is realized by the alignment of two molecular two-fold rotation axes, preserving the parallel orientation of the molecular three-fold rotation axes. The resulting two-dimensional honeycomb lattices of [M(bpy)3]2+ cations are placed between the hydrogen bonding layers made of [NbO(C2O4)3]3- and Cl(-) anions and the majority of the crystal water molecules. The temperature-dependent magnetic susceptibility measurements (1.8-300 K) show a significant orbital angular momentum contribution for 3 and 4 (high-spin Co2+), the influence of zero-field splitting for 5 and 6(Ni2+) and a substantially paramagnetic Curie behaviour for the Cu2+ compound (7).     

Synthesis,spectroscopic and structural investigation of Zn(NCS)2(nicotinamide)2 and [Hg(SCN)2(nicotinamide)]n

Zinc(II) and mercury(II) thiocyanate complexes with nicotinamide, bis(nicotinamide-N)-bis(thiocyanato-N)zinc(II) (1) and catena-[nicotinamide-N-(μ-thiocyanato-S,N)(thiocyanato-S)mercury(II)] (2), have been prepared and characterized by spectroscopic, thermal and X-ray crystallographic methods. The vibrational bands of diagnostic value are compared to the values of the free ligand and the data are in good correlation with the X-ray results. Centrosymmetrical hydrogen bonded dimers are found, R₂²(10) in 1 and R₂²(8) in 2.     

Conformational Analyses of Physiological Binary and Ternary Copper(II) Complexes with l-Asparagine and l-Histidine; Study of Tridentate Binding of Copper(II) in Aqueous Solution

This study explores the structural properties and energy landscapes of the physiologically important bis(l -asparaginato)copper(II) [Cu(l -Asn)₂] and (l -histidinato)(l -asparaginato)copper(II) [Cu(l -His)(l -Asn)]. The conformational analyses in the gas phase and implicitly modeled water medium, and magnetic parameters of electron paramagnetic resonance spectra were attained using density functional theory calculations. The apical Cu^II coordination and hydrogen bonding were analyzed. Predicted lower-energy structures enabled the confirmation and, for apical bonding, also the refinement of structural proposals from literature. Available experimental results were indecisive regarding the amido-group binding in the Cu^II equatorial plane in solutions, but the examination of the relative stability of Cu(l -Asn)₂ conformers in 30 binding modes confirms the glycine-like mode as the most stable one. Previously reported experimental results for Cu(l -His)(l -Asn) were interpreted for l -His to have a tridentate histamine-like mode. However, the aqueous conformers with l -His in the glycinato mode are also predicted to have low energies, which does not contradict the tridentate l -His binding. The predicted magnetic parameters of conformers with an apical oxygen atom (intramolecular or from a water molecule) can reproduce the experimental data. An extent of conformational flexibility and abundance of l -His-containing ternary copper(II) amino acid complexes under physiological conditions may be related.     

Structure,stacking interactions and magnetism of compounds with oxalate-bridged dinuclear CuCu and CuNb units

Two novel compounds of the formulae [{Cu(phen)₂}₂(μ-C₂O₄)][Cu(phen)₂(μ-C₂O₄)NbO(C₂O₄)₂]₂ · 8H₂O (1) and [{Cu(bpy)₂}₂(μ-C₂O₄)][Cu(bpy)₂(μ-C₂O₄)NbO(C₂O₄)₂]₂ · 0.5bpy · 7H₂O (2) (phen = 1,10-phenanthroline, bpy = 2,2′-bipyridine) have been prepared and characterized by single crystal X-ray diffraction, IR spectroscopy and magnetic susceptibility measurements. The molecular structure of both 1 and 2 consists of a discrete Cu^IICu^II oxalate-bridged dinuclear [{Cu(L)₂}₂(μ-C₂O₄)]²⁺ cation (A unit) and two Cu^IINb^V oxalate-bridged dinuclear [Cu(L)₂(μ-C₂O₄)NbO(C₂O₄)₂]⁻ anions (B units) (L = phen, bpy). In 1 a crystallographic inversion centre is located in the middle of the oxalate bridge of the A unit, whereas in 2 an analogous inversion centre is missing. In the A units the copper(II) atoms adopt a tetragonally elongated octahedral coordination with the equatorial planes being perpendicular to the mean planes of the oxalate bridge and parallel to each other. In both structures, similar one-dimensional motifs are generated through the ligand stacking interactions, with a difference that one free bipyridine molecule, present in 2, intercalates into one of the motifs. It is shown that the phenanthroline ligand, due to its ability of stacking through the central aromatic ring, causes longer intermolecular Cu?Cu distances than the bipyridine ligand. The magnetic susceptibility measurements (1.8–290 K) show the ferromagnetic exchange interaction between the copper(II) atoms in the A units of both compounds, with J = +5.9 cm⁻¹ and +7.9 cm⁻¹ for 1 and 2, respectively (J – the exchange parameter in the isotropic spin Hamiltonian H_INT = −JS₁ · S₂).     

The Evaluation of Healing Properties of Galium verum-Based Oral Gel in Aphthous Stomatitis in Rats

Although oral ulcers represent one of the most frequent oral mucosal diseases, the available treatment is not sufficient to provide complete ulcer recovery without side-effects. Therefore, the aim of our study was to prepare a mucoadhesive oral gel based on Galium verum ethanol extract (GVL gel) and reveal its healing effects in the model of aphthous stomatitis in rats. Rats with oral ulcers were divided into the following groups: control (untreated), gel base (ulcer was treated with the gel base, three times per day for 10 days), and GVL gel group (the ulcer was treated with GVL gel in the same way as the gel base). Animals from each group were sacrificed on days 0, 3, 6, and 10 for collecting blood and ulcer tissue samples. Healing properties of oral gel were determined by clinical evaluation, as well as biochemical and histopathological examinations. Our findings suggest a significant decrease in the ulcer size in GVL gel group, with healing effects achieved through the alleviation of oxidative stress, reduction in COX-2 immunopositivity, and increase in collagen content in buccal tissue. Significant ulcer repairing potential of GVL gel highlights this oral mucoadhesive gel as a promising tool for prevention and treatment of RAS.     

CEJOR special issue of Croatian Operational Research Society

Central European Journal of Operations Research -