Environmentally Friendly Approach to the Synthesis of 3-[Benzylideneamino]-2-methylquinazolin-4(3H)-one Derivatives and Calculation of Their Toxicity.

Application of deep eutectic solvents in synthesis of different heterocyclic compounds was proven very efficient. These solvents are a new generation of green solvents showing excellent potential for different purposes, where they are used as environmentally acceptable substitute for toxic and volatile organic solvents. This research describes their application in the synthesis of series of quinazolinone Schiff bases in combination with microwave, ultrasound-assisted and mechanochemical methods. First, a model reaction was performed in 20 different deep eutectic solvents to find the best solvent and then reaction conditions (solvent, temperature and reaction time) were optimized for each method. Afterwards, 40 different quinazolinone derivatives were synthesized in choline chloride/malonic acid (1 : 1) DES by each method and compared by their yields. Here we show that deep eutectic solvents can be very efficient in the synthesis of quinazolinone derivatives as an excellent substitution for volatile organic solvents. With green chemistry approach in mind, we have also performed a calculation on compounds' toxicity and solubility, showing that most of them possess toxic and mutagenic properties with low water solubility.

Antifungal Activities of Fluorinated Pyrazole Aldehydes on Phytopathogenic Fungi, and Their Effect on Entomopathogenic Nematodes, and Soil-Beneficial Bacteria.

Fluoro-substituted pyrazoles have a wide range of biological activities, such as antibacterial, antiviral, and antifungal activities. The aim of this study was to evaluate the antifungal activities of fluorinated 4,5-dihydro-1H-pyrazole derivatives on four phytopathogenic fungi: Sclerotinia sclerotiorum, Macrophomina phaseolina, Fusarium oxysporum f. sp. lycopersici, and F. culmorum. Moreover, they were tested on two soil beneficial bacteria-Bacillus mycoides and Bradyrhizobium japonicum-as well as two entomopathogenic nematodes (EPNs)-Heterorhabditis bacteriophora and Steinernema feltiae. The molecular docking was performed on the three enzymes responsible for fungal growth, the three plant cell wall-degrading enzymes, and acetylcholinesterase (AChE). The most active compounds against fungi S. sclerotiorum were 2-chlorophenyl derivative (H9) (43.07% of inhibition) and 2,5-dimethoxyphenyl derivative (H7) (42.23% of inhibition), as well as H9 against F. culmorum (46.75% of inhibition). Compounds were shown to be safe for beneficial soil bacteria and nematodes, except for compound H9 on EPN H. bacteriophora (18.75% mortality), which also showed the strongest inhibition against AChE (79.50% of inhibition). The molecular docking study revealed that antifungal activity is possible through the inhibition of proteinase K, and nematicidal activity is possible through the inhibition of AChE. The fluorinated pyrazole aldehydes are promising components of future plant protection products that could be environmentally and toxicologically acceptable.

Experimental and computational evaluation of dipeptidyl peptidase III inhibitors based on quinazolinone-Schiff's bases.

Dipeptidyl peptidase III (DPP III) is a zinc-dependent enzyme that sequentially hydrolyzes biologically active peptides by cleaving dipeptides from their N-termini. Although its fundamental role is not been fully elucidated, human DPP III (hDPP III) has been recognized in several pathophysiological processes of interest for drug development. In this article 27 quinazolinone-Schiff's bases were studied for their inhibitory activity against hDPP III combining an in vitro experiment with a computational approach. The biochemical assay showed that most compounds exhibited inhibitory activity at the 100 µM concentration. The best QSAR model included descriptors from the following 2D descriptor groups: information content indices, 2D autocorrelations, and edge adjacency indices. Five compounds were found to be the most potent inhibitors with IC50 values below 10 µM, while molecular docking predicted that these compounds bind to the central enzyme cleft and interact with residues of the substrate binding subsites. Molecular dynamics simulations of the most potent inhibitor (IC50=0.96 µM) provided valuable information explaining the role of PHE109, ARG319, GLU327, GLU329, and ILE386 in the mechanism of the inhibitor binding and stabilization. This is the first study that gives insight into quinazolinone-Schiff's bases binding to this metalloenzyme.Communicated by Ramaswamy H. Sarma.

Effects of Coumarinyl Schiff Bases against Phytopathogenic Fungi, the Soil-Beneficial Bacteria and Entomopathogenic Nematodes: Deeper Insight into the Mechanism of Action.

Coumarin derivatives have been reported as strong antifungal agents against various phytopathogenic fungi. In this study, inhibitory effects of nine coumarinyl Schiff bases were evaluated against the plant pathogenic fungi (Fusarium oxysporum f. sp. lycopersici, Fusarium culmorum, Macrophomina phaseolina and Sclerotinia sclerotiourum). The compounds were demonstrated to be efficient antifungal agents against Macrophomina phaseolina. The results of molecular docking on the six enzymes related to the antifungal activity suggested that the tested compounds act against plant pathogenic fungi, inhibiting plant cell-wall-degrading enzymes such as endoglucanase I and pectinase. Neither compound exhibited inhibitory effects against two beneficial bacteria (Bacillus mycoides and Bradyrhizobium japonicum) and two entomopathogenic nematodes. However, compound 9 was lethal (46.25%) for nematode Heterorhabditis bacteriophora and showed an inhibitory effect against acetylcholinesterase (AChE) (31.45%), confirming the relationship between these two activities. Calculated toxicity and the pesticide-likeness study showed that compound 9 was the least lipophilic compound with the highest aquatic toxicity. A molecular docking study showed that compounds 9 and 8 bind directly to the active site of AChE. Coumarinyl Schiff bases are promising active components of plant protection products, safe for the environment, human health, and nontarget organisms.

Application of Deep Eutectic Solvents in the Synthesis of Substituted 2-Mercaptoquinazolin-4(3H)-Ones: A Comparison of Selected Green Chemistry Methods.

In this study, deep eutectic solvents (DESs) were used as green and eco-friendly media for the synthesis of substituted 2-mercaptoquinazolin-4(3H)-ones from different anthranilic acids and aliphatic or aromatic isothiocyanates. A model reaction on anthranilic acid and phenyl isothiocyanate was performed in 20 choline chloride-based DESs at 80 °C to find the best solvent. Based on the product yield, choline chloride:urea (1:2) DES was found to be the most effective, while DESs acted both as solvents and catalysts. Desired compounds were prepared with moderate to good yields using stirring, microwave-assisted, and ultrasound-assisted synthesis. Significantly, higher yields were obtained with mixing and ultrasonication (16-76%), while microwave-induced synthesis showed lower effectiveness (13-49%). The specific contribution of this research is the use of DESs in combination with the above-mentioned green techniques for the synthesis of a wide range of derivatives. The structures of the synthesized compounds were confirmed by 1H and 13C NMR spectroscopy.

Environmentally Friendly Approach to Knoevenagel Condensation of Rhodanine in Choline Chloride: Urea Deep Eutectic Solvent and QSAR Studies on Their Antioxidant Activity.

A series of rhodanine derivatives was synthesized in the Knoevenagel condensation of rhodanine and different aldehydes using choline chloride:urea (1:2) deep eutectic solvent. This environmentally friendly and catalyst free approach was very effective in the condensation of rhodanine with commercially available aldehydes, as well as the ones synthesized in our laboratory. All rhodanine derivatives were subjected to 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging activity investigation and quantitative structure-activity relationship (QSAR) studies were performed to elucidate their structure-activity relationship. The best multiple linear QSAR model demonstrate a stability in the internal validation and Y-randomization (R² = 0.81; F = 24.225; Q²loo = 0.72; R²Yscr = 0.148). Sphericity of the molecule, ratio of symmetric atoms enhanced atomic mass along the principle axes in regard to total number of atoms in molecule, and 3D distribution of the atoms higher electronegativity (O, N, and S) in molecules are important characteristic for antioxidant ability of rhodanine derivatives. Molecular docking studies were carried out in order to explain in silico antioxidant studies, a specific protein tyrosine kinase (2HCK). The binding interactions of the most active compound have shown strong hydrogen bonding and van der Waals interactions with the target protein.

Deep Eutectic Solvents as Convenient Media for Synthesis of Novel Coumarinyl Schiff Bases and Their QSAR Studies.

Deep eutectic solvents, as green and environmentally friendly media, were utilized in the synthesis of novel coumarinyl Schiff bases. Novel derivatives were synthesized from 2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetohydrazide and corresponding aldehyde in choline chloride:malonic acid (1:1) based deep eutectic solvent. In these reactions, deep eutectic solvent acted as a solvent and catalyst as well. Novel Schiff bases were synthesized in high yields (65-75%) with no need for further purification, and their structures were confirmed by mass spectra, ¹H and 13C NMR. Furthermore, their antioxidant activity was determined and compared to antioxidant activity of previously synthesized derivatives, thus investigating their structure-activity relationship utilizing quantitative structure-activity relationship QSAR studies. Calculation of molecular descriptors has been performed by DRAGON software. The best QSAR model (Rtr = 0.636; Rext = 0.709) obtained with three descriptors (MATS3m, Mor22u, Hy) implies that the pairs of atoms higher mass at the path length 3, three-dimensional arrangement of atoms at scattering parameter s = 21 Å-¹, and higher number of hydrophilic groups (-OH, -NH) enhanced antioxidant activity. Electrostatic potential surface of the most active compounds showed possible regions for donation of electrons to 1,1-diphenyl-2-picryhydrazyl (DPPH) radicals.