The Electronic Effects of 3-Methoxycarbonylcoumarin Substituents on Spectral, Antioxidant, and Protein Binding Properties.

Coumarin derivatives are a class of compounds with pronounced biological activities that depend primarily on the present substituents. Four 3-methoxycarbonylcoumarin derivatives with substituents of different electron-donating/electron-withdrawing abilities (Br, NO2, OH, and OMe) were investigated structurally by NMR, IR, and UV-VIS spectroscopies and density functional theory methods. The appropriate level of theory (B3LYP-D3BJ/6-311++G(d,p) was selected after comparing similar compounds' experimental and theoretical structural parameters. The natural bond orbital and quantum theory of atoms in molecules were employed to investigate the intramolecular interactions governing stability. The electronic effects of substituents mostly affected the aromatic ring that the substituents are directly attached to. The antioxidant properties were investigated by electron paramagnetic resonance spectroscopy towards HO•, and the percentages of reduction were between 13% (6-Br) and 23% (6-OMe). The protein binding properties towards transport proteins were assessed by spectrofluorimetry, molecular docking, and molecular dynamics (MD). The experimentally determined binding energies were well reproduced by molecular docking, showing that the spontaneity of ibuprofen binding was comparable to the investigated compounds. The flexibility of HSA in MD simulations depended on the substituents. These results proved the importance of electronic effects for the protein binding affinities and antioxidant properties of coumarin derivatives.

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.

Antioxidant Activity, Metabolism, and Bioavailability of Polyphenols in the Diet of Animals.

As the world's population grows, so does the need for more and more animal feed. In 2006, the EU banned the use of antibiotics and other chemicals in order to reduce chemical residues in food consumed by humans. It is well known that oxidative stress and inflammatory processes must be combated to achieve higher productivity. The adverse effects of the use of pharmaceuticals and other synthetic compounds on animal health and product quality and safety have increased interest in phytocompounds. With the use of plant polyphenols in animal nutrition, they are gaining more attention as a supplement to animal feed. Livestock feeding based on a sustainable, environmentally friendly approach (clean, safe, and green agriculture) would also be a win-win for farmers and society. There is an increasing interest in producing healthier products of animal origin with a higher ratio of polyunsaturated fatty acids (PUFAs) to saturated fatty acids by modulating animal nutrition. Secondary plant metabolites (polyphenols) are essential chemical compounds for plant physiology as they are involved in various functions such as growth, pigmentation, and resistance to pathogenic organisms. Polyphenols are exogenous antioxidants that act as one of the first lines of cell defense. Therefore, the discoveries on the intracellular antioxidant activity of polyphenols as a plant supplement have contributed significantly to the improvement of antioxidant activity, as polyphenols prevent oxidative stress damage and eliminate excessively produced free radicals. To achieve animal welfare, reduce stress and the need for medicines, and increase the quality of food of animal origin, the addition of polyphenols to research and breeding can be practised in part with a free-choice approach to animal nutrition.

A Review: Per- and Polyfluoroalkyl Substances-Biological Degradation.

Per- and polyfluoroalkyl substances (PFASs), highly stable synthetic organic compounds with multiple carbon-fluorine bonds, are emerging as environmental contaminants, toxic, bioaccumulative, and environmentally persistent. PFASs are strongly resistant to biological and chemical degradation, and therefore PFASs present a challenge to researchers and scientists for a better understanding and application of remediation methods and biodegradation of PFASs and have become subject to strict government regulations. The review summarizes the recent knowledge of bacterial and fungal degradation of PFASs, as well as the enzymes involved in the processes of transformation/degradation of PFASs.

Degradation Mechanisms of 4,7-Dihydroxycoumarin Derivatives in Advanced Oxidation Processes: Experimental and Kinetic DFT Study.

Coumarins represent a broad class of compounds with pronounced pharmacological properties and therapeutic potential. The pursuit of the commercialization of these compounds requires the establishment of controlled and highly efficient degradation processes, such as advanced oxidation processes (AOPs). Application of this methodology necessitates a comprehensive understanding of the degradation mechanisms of these compounds. For this reason, possible reaction routes between HO• and recently synthesized aminophenol 4,7-dihydroxycoumarin derivatives, as model systems, were examined using electron paramagnetic resonance (EPR) spectroscopy and a quantum mechanical approach (a QM-ORSA methodology) based on density functional theory (DFT). The EPR results indicated that all compounds had significantly reduced amounts of HO• radicals present in the reaction system under physiological conditions. The kinetic DFT study showed that all investigated compounds reacted with HO• via HAT/PCET and SPLET mechanisms. The estimated overall rate constants (koverall) correlated with the EPR results satisfactorily. Unlike HO• radicals, the newly formed radicals did not show (or showed negligible) activity towards biomolecule models representing biological targets. Inactivation of the formed radical species through the synergistic action of O2/NOx or the subsequent reaction with HO• was thermodynamically favored. The ecotoxicity assessment of the starting compounds and oxidation products, formed in multistage reactions with O2/NOx and HO•, indicated that the formed products showed lower acute and chronic toxicity effects on aquatic organisms than the starting compounds, which is a prerequisite for the application of AOPs procedures in the degradation of compounds.

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.

Polyphenols in Ruminant Nutrition and Their Effects on Reproduction.

The feeding of domestic animals with diets in which polyphenols are present is increasingly attracting the attention of nutritionists and scientists. This review summarizes the knowledge regarding polyphenols' possible positive and negative effects and their bioavailability. The bioavailability of substances is a prerequisite for any postabsorption effect in vivo. Positive and negative properties have been confirmed in previous studies on the diets of domestic animals rich in polyphenols, such as secondary metabolites of plants. Free radicals are formed in every organism, leading to oxidative stress. Free radicals are highly reactive molecules and can react in cells with macromolecules and can cause damage, including in reproductive cells. Some polyphenols at specific concentrations have antioxidant properties that positively affect animal reproduction by improving the quality of male and female gametes. The intake of phytoestrogens that mimic estrogen function can induce various pathological conditions in the female reproductive tract, including ovarian, fallopian, and uterine dysfunction. The metabolism of genistein and daidzein yields the metabolites equol and p-phenyl-phenol, leading to a decline in cow fertilization. The findings so far confirm that numerous questions still need to be answered. This review points out the importance of using polyphenols that have both benificial and some unfavorable properties in specific diets.

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.

Coumarin Derivatives Act as Novel Inhibitors of Human Dipeptidyl Peptidase III: Combined In Vitro and In Silico Study.

Dipeptidyl peptidase III (DPP III), a zinc-dependent exopeptidase, is a member of the metalloproteinase family M49 with distribution detected in almost all forms of life. Although the physiological role of human DPP III (hDPP III) is not yet fully elucidated, its involvement in pathophysiological processes such as mammalian pain modulation, blood pressure regulation, and cancer processes, underscores the need to find new hDPP III inhibitors. In this research, five series of structurally different coumarin derivatives were studied to provide a relationship between their inhibitory profile toward hDPP III combining an in vitro assay with an in silico molecular modeling study. The experimental results showed that 26 of the 40 tested compounds exhibited hDPP III inhibitory activity at a concentration of 10 µM. Compound 12 (3-benzoyl-7-hydroxy-2H-chromen-2-one) proved to be the most potent inhibitor with IC50 value of 1.10 µM. QSAR modeling indicates that the presence of larger substituents with double and triple bonds and aromatic hydroxyl groups on coumarin derivatives increases their inhibitory activity. Docking predicts that 12 binds to the region of inter-domain cleft of hDPP III while binding mode analysis obtained by MD simulations revealed the importance of 7-OH group on the coumarin core as well as enzyme residues Ile315, Ser317, Glu329, Phe381, Pro387, and Ile390 for the mechanism of the binding pattern and compound 12 stabilization. The present investigation, for the first time, provides an insight into the inhibitory effect of coumarin derivatives on this human metalloproteinase.

Validation of flavonoids as potential dipeptidyl peptidase III inhibitors: Experimental and computational approach.

Fifteen flavonoids were studied for their inhibitory activity against human dipeptidyl peptidase III (hDPP III) combining an in vitro assay with an in silico molecular modeling study. All analyzed flavonoids showed inhibitory effects against hDPP III with the IC50 values ranging from 22.0 to 437.2 µm. Our 3D QSAR studies indicate that the presence of hydrophilic regions at a flavonoid molecule increases its inhibitory activity, while the higher percentage of hydrophobic surfaces has negative impact on enzyme inhibition. Furthermore, molecular dynamics (MD) simulations of the complex of hDPP III with one of the most potent inhibitors, luteolin, were performed, and binding mode analysis revealed that the 3' and 4' hydroxyl group on B-ring as well as 5 and 7 hydroxyl group on A-ring helps luteolin to interact with the Asn391, Asn406, Tyr417, His450, Glu451, Val447, Glu512, Asn545, Gln566, and Arg572 residues. The MD results clearly provide valuable information explaining the importance of flavonoid hydroxyl groups in the mechanism for the binding pattern at the active site of hDPP III.

The sum-connectivity index--an additive variant of the Randic connectivity index.

This review discusses structure-property modeling applications of a novel variant of the Randic connectivity index that is called the sum-connectivity index. We compare published one-descriptor quantitative structure-property relationship (QSPR) models obtained with the new sum-connectivity index and with the Randic connectivity index, called here the product-connectivity index. Additionally, the efficiency of both variants of connectivity indices in QSPR modeling is tested on five datasets of alkanes and two datasets of polycyclic hydrocarbons. Several physicochemical properties of alkanes (i.e. boiling and melting points, retention index, molar volume, molar refraction, heat of vaporization, standard Gibbs energy of formation, critical temperature, critical pressure, surface tension, density) and π- electronic energies of two sets of polycyclic hydrocarbons were correlated with the product- and sum-connectivity indices. A comparison of these QSPR models shows that both variants of connectivity indices are equivalent, and only slightly (but not significantly) better results are obtained with the sum-connectivity index. Inter-correlations between the product- and sum-connectivity indices are mostly linear with a slope very close to 1.0 for alkanes, and with a slope more different from 1.0 (0.88) for polycyclic compounds. The comparative analysis presented here supports the use of the sumconnectivity index in QSPR/QSAR studies together with the product-connectivity index. Further studies on larger and more heterogeneous datasets should test the sum-connectivity index in QSPR/QSAR models.

SAR and QSAR of the antioxidant activity of flavonoids.

Flavonoids are a group of naturally occurring phytochemicals abundantly present in fruits, vegetables, and beverages such as wine and tea. In the past two decades, flavonoids have gained enormous interest because of their beneficial health effects such as anti-inflammatory, cardio-protective and anticancer activities. These findings have contributed to the dramatic increase in the consumption and use of dietary supplements containing high concentrations of plant flavonoids. The pharmacological effect of flavonoids is mainly due to their antioxidant activity and their inhibition of certain enzymes. In spite of abundant data, structural requirements and mechanisms underlying these effects have not been fully understood. This review presents the current knowledge about structure-activity relationships (SARs) and quantitative structure-activity relationships (QSARs) of the antioxidant activity of flavonoids. SAR and QSAR can provide useful tools for revealing the nature of flavonoid antioxidant action. They may also help in the design of new and efficient flavonoids, which could be used as potential therapeutic agents.

Influence of the beehive type on the quality of honey.

Agricultural producers apply numerous technological procedures, and enlarging efforts to produce the high-quality products. This initiative is present in the beekeeping, too. The quality of the honey produced by the honey bee colonies depends of various factors, but prevailing are the ecological conditions and the floristic composition of the honeyfull plants. The aim of our research was to discover the influence of the beehive type on the quality of honey, which is produced at apiaries under the similar environmental conditions. The whole studied honey bee colonies belong to the European race, Apis mellifera carnica, and they used the same honeyfull plants pastures. The results indicate that different beehive type used at apiaries influenced on the quality of honey.