Flavones’ and Flavonols’ Antiradical Structure–Activity Relationship—A Quantum Chemical Study

Flavonoids are known for their antiradical capacity, and this ability is strongly structure-dependent. In this research, the activity of flavones and flavonols in a water solvent was studied with the density functional theory methods. These included examination of flavonoids’ molecular and radical structures with natural bonding orbitals analysis, spin density analysis and frontier molecular orbitals theory. Calculations of determinants were performed: specific, for the three possible mechanisms of action—hydrogen atom transfer (HAT), electron transfer–proton transfer (ETPT) and sequential proton loss electron transfer (SPLET); and the unspecific—reorganization enthalpy (RE) and hydrogen abstraction enthalpy (HAE). Intramolecular hydrogen bonding, catechol moiety activity and the probability of electron density swap between rings were all established. Hydrogen bonding seems to be much more important than the conjugation effect, because some structures tends to form more intramolecular hydrogen bonds instead of being completely planar. The very first hydrogen abstraction mechanism in a water solvent is SPLET, and the most privileged abstraction site, indicated by HAE, can be associated with the C3 hydroxyl group of flavonols and C4’ hydroxyl group of flavones. For the catechol moiety, an intramolecular reorganization to an o-benzoquinone-like structure occurs, and the ETPT is favored as the second abstraction mechanism.

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Mechanism of Antiradical Activity of Newly Synthesized 4,7-Dihydroxycoumarin Derivatives-Experimental and Kinetic DFT Study

International Journal of Molecular Sciences ◽

10.3390/ijms222413273 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13273

Author(s):

Žiko Milanović ◽

Dušan Dimić ◽

Milan Žižić ◽

Dejan Milenković ◽

Zoran Marković ◽

...

Keyword(s):

Electron Transfer ◽

Hydrogen Atom ◽

Density Functional ◽

Biological Activities ◽

Radical Scavenging ◽

Hydrogen Atom Transfer ◽

Dft Study ◽

Paramagnetic Resonance ◽

Radical Adduct ◽

Intramolecular Hydrogen

Coumarin derivatives have proven beneficial biological activities, but the mechanism of their radical scavenging potency is not fully understood. In this study, the antiradical capacity of two newly synthesized 4,7-dihydroxycoumarin derivatives: (E)-3-(1-((3-hydroxy-4-methoxyphenyl)amino)-ethylidene)-2,4-dioxochroman-7-yl acetate (A-3OH) and (E)-3-(1-((4-hydroxy-3-methoxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (A-4OH) towards HO• were examined by Electron Paramagnetic Resonance (EPR) Spectroscopy and Density Functional Theory (DFT). The compounds were fully characterized by the elemental microanalysis, IR, and NMR spectroscopies. The effect of pH on the acid–base equilibria is separately discussed and the predominant species at the physiological pH were determined. Several common mechanisms (Hydrogen Atom Transfer (HAT), Single-Electron Transfer followed by Proton Transfer (SET-PT), Sequential Proton Loss followed by Electron Transfer (SPLET), Radical Adduct Formation (RAF), and Intramolecular Hydrogen Atom Abstraction (iHAA)) of radical scavenging were investigated based on thermodynamic and kinetic parameters. EPR results indicated that both compounds significantly reduce the amount of present HO•. The results of the kinetic DFT study demonstrated that both compounds predominantly exhibit antiradical capacity through HAT and SPLET mechanisms. The estimated overall rate constants (koverall) proved that A-4OH shows better antioxidant capacity than A-3OH which is well-correlated with the results obtained by EPR measurement.

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Synthesis, DFT Calculations, and In Vitro Antioxidant Study on Novel Carba-Analogs of Vitamin E

Antioxidants ◽

10.3390/antiox8120589 ◽

2019 ◽

Vol 8 (12) ◽

pp. 589 ◽

Cited By ~ 1

Author(s):

Aneta Baj ◽

Jakub Cedrowski ◽

Ewa Olchowik-Grabarek ◽

Artur Ratkiewicz ◽

Stanislaw Witkowski

Keyword(s):

Antioxidant Activity ◽

Electron Transfer ◽

Vitamin E ◽

Density Functional ◽

Lone Pair ◽

Hydrogen Atom Transfer ◽

Hydroxyl Group ◽

Styrene Oxidation ◽

Chain Breaking

Vitamin E is the most active natural lipophilic antioxidant with a broad spectrum of biological activity. α-Tocopherol (α-T), the main representative of the vitamin E family, is a strong inhibitor of lipid peroxidation as a chain-breaking antioxidant. Antioxidant and antiradical properties of vitamin E result from the presence of a phenolic hydroxyl group at the C-6 position. Due to stereoelectronic effects in the dihydropyranyl ring, the dissociation enthalpy for phenolic O–H bond (BDEOH) is reduced. The high chain-breaking reactivity of α-T is mainly attributed to orbital overlapping of the 2p-type lone pair on the oxygen atom (O1) in para position to the phenolic group, and the aromatic π-electron system. The influence of the O1 atom on the antioxidant activity of vitamin E was estimated quantitatively. The all-rac-1-carba-α-tocopherol was synthesized for the first time. Along with model compounds, 1-carba-analog of Trolox and its methyl ester were screened for their in vitro antioxidant activity by inhibition of styrene oxidation, and for the radical-reducing properties by means of 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH) scavenging assay. To study the antioxidant activity, density functional theory (DFT) was also applied. Reaction enthalpies related to HAT (hydrogen atom transfer), SET–PT (sequential electron transfer—proton transfer), and SPLET (sequential proton loss—electron transfer) mechanisms were calculated.

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NMR of Natural Products as Potential Drugs

Molecules ◽

10.3390/molecules26123763 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3763

Author(s):

Poul Erik Hansen

Keyword(s):

Natural Products ◽

Hydrogen Bonding ◽

Density Functional ◽

Chemical Shifts ◽

Isotope Effects ◽

Density Functional Theory Calculations ◽

Intramolecular Hydrogen Bonding ◽

Chemical Equilibria ◽

Nmr Techniques ◽

Intramolecular Hydrogen

This review outlines methods to investigate the structure of natural products with emphasis on intramolecular hydrogen bonding, tautomerism and ionic structures using NMR techniques. The focus is on 1H chemical shifts, isotope effects on chemical shifts and diffusion ordered spectroscopy. In addition, density functional theory calculations are performed to support NMR results. The review demonstrates how hydrogen bonding may lead to specific structures and how chemical equilibria, as well as tautomeric equilibria and ionic structures, can be detected. All these features are important for biological activity and a prerequisite for correct docking experiments and future use as drugs.

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Green One-Pot Synthesis of Coumarin-Hydroxybenzohydrazide Hybrids and Their Antioxidant Potency

Antioxidants ◽

10.3390/antiox10071106 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1106

Author(s):

Marko R. Antonijević ◽

Dušica M. Simijonović ◽

Edina H. Avdović ◽

Andrija Ćirić ◽

Zorica D. Petrović ◽

...

Keyword(s):

Antioxidant Activity ◽

Electron Transfer ◽

Density Functional ◽

Electron Transfer Reaction ◽

Hydrogen Atom Transfer ◽

Special Importance ◽

Theory Approach ◽

One Pot ◽

Antioxidant Potency

Compounds from the plant world that possess antioxidant abilities are of special importance for the food and pharmaceutical industry. Coumarins are a large, widely distributed group of natural compounds, usually found in plants, often with good antioxidant capacity. The coumarin-hydroxybenzohydrazide derivatives were synthesized using a green, one-pot protocol. This procedure includes the use of an environmentally benign mixture (vinegar and ethanol) as a catalyst and solvent, as well as very easy isolation of the desired products. The obtained compounds were structurally characterized by IR and NMR spectroscopy. The purity of all compounds was determined by HPLC and by elemental microanalysis. In addition, these compounds were evaluated for their in vitro antioxidant activity. Mechanisms of antioxidative activity were theoretically investigated by the density functional theory approach and the calculated values of various thermodynamic parameters, such as bond dissociation enthalpy, proton affinity, frontier molecular orbitals, and ionization potential. In silico calculations indicated that hydrogen atom transfer and sequential proton loss–electron transfer reaction mechanisms are probable, in non-polar and polar solvents respectively. Additionally, it was found that the single-electron transfer followed by proton transfer was not an operative mechanism in either solvent. The conducted tests indicate the excellent antioxidant activity, as well as the low potential toxicity, of the investigated compounds, which makes them good candidates for potential use in food chemistry.

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Crystal structure of atazanavir, C38H52N6O7

Powder Diffraction ◽

10.1017/s0885715620000135 ◽

2020 ◽

Vol 35 (2) ◽

pp. 129-135

Author(s):

James A. Kaduk ◽

Amy M. Gindhart ◽

Thomas N. Blanton

Keyword(s):

Crystal Structure ◽

Hydrogen Bonds ◽

Powder Diffraction ◽

Density Functional ◽

Carbonyl Oxygen ◽

Hydroxyl Group ◽

Amide Nitrogen ◽

Classical Hydrogen Bond ◽

Intramolecular Hydrogen ◽

Atazanavir Sulfate

The crystal structure of atazanavir has been solved and refined using synchrotron X-ray powder diffraction data and optimized using density functional techniques. Atazanavir crystallizes in space group P21 (#4) with a = 15.33545(7), b = 5.90396(3), c = 21.56949(13) Å, β = 96.2923(4)°, V = 1941.134(11) Å3, and Z = 2. Despite being labeled as “atazanavir sulfate”, the commercial reagent sample consisted of atazanavir free base. The structure consists of an array of extended-conformation molecules parallel to the ac-plane. Although the atazanavir molecule contains only four classical hydrogen bond donors, hydrogen bonding is, surprisingly, important to the crystal energy. Both intra- and intermolecular hydrogen bonds are significant. The hydroxyl group forms bifurcated intramolecular hydrogen bonds to a carbonyl oxygen atom and an amide nitrogen. Several amide nitrogens act as donors to the hydroxyl group and carbonyl oxygen atoms. An amide nitrogen acts as a donor to another amide nitrogen. Several methyl, methylene, methyne, and phenyl hydrogens participate in hydrogen bonds to carbonyl oxygens, an amide nitrogen, and the pyridine nitrogen. The powder pattern is included in the Powder Diffraction File™ as entry 00-065-1426.

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Complexation of Cu(BF4)2 with 3-hydroxyflavone in acetonitrile: quantum chemical calculation

Kharkov University Bulletin Chemical Series ◽

10.26565/2220-637x-2018-31-05 ◽

2018 ◽

Keyword(s):

Hydrogen Bond ◽

Hydrogen Atom ◽

Intramolecular Hydrogen Bond ◽

Quantum Chemical ◽

Phenyl Ring ◽

Fluorine Atom ◽

Quantum Chemical Study ◽

Hydroxyl Group ◽

Chemical Calculation ◽

Intramolecular Hydrogen

In the article the results of the quantum chemical study of copper (II) solvato-complexes with acetonitrile (AN), tetrafluoroborate anion (BF4–) and 3-hydroxyflavone (flv) of the composition [Cu(AN)6]2+, [Cu(BF4)(AN)5]+, [Cu(flv)(AN)5]2+, [Cu(flv)(BF4)(AN)4]+ are presented. Calculations were done using density function theory (DFT) on the M06-2X/6-311++G(d,p) level of theory. Obtained results were interpreted in terms of complexes geometry and topology of electron density distribution using non-covalent interactions (NCI) approach. It was shown that flv molecule is a monodentate ligand in copper (II) complexes and coordinates central atom via carbonyl oxygen. Intramolecular hydrogen bond that exists in an isolated flv molecule was found to be broken upon [Cu(flv)(AN)5]2+ complex formation. In [Cu(flv)(AN)5]2+ complex, a significant rotation of phenyl ring over the planar chromone fragment was spotted as a consequence of intramolecular hydrogen bond breaking. Upon inclusion of BF4– anion to the first solvation shell of Cu2+, an intracomplex hydrogen bond was formed between hydrogen atom of hydroxyl group of flv molecule and the closest fluorine atom of BF4– anion. NCI analysis had shown that a hydrogen bond between hydrogen atom of hydroxyl group of flv molecule and the closest fluorine atom of BF4– anion is significantly stronger than intramolecular hydrogen bond in an isolated flv molecule. In addition, flexible phenyl ring of flv molecule in [Cu(flv)(BF4)(AN)4]+ complex was found to be internally stabilized by the weak van der Waals attraction between oxygen atoms of chromone ring and phenyl hydrogens. These evidences led to a conclusion that [Cu(flv)(BF4)(AN)4]+ complex is more stable, comparing to the in [Cu(flv)(AN)5]2+ complex.

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Molecular and crystal structure of azadirachtin-H

Acta Crystallographica Section B Structural Science ◽

10.1107/s0108768195010056 ◽

1996 ◽

Vol 52 (1) ◽

pp. 145-150 ◽

Cited By ~ 6

Author(s):

T. R. Govindachari ◽

Geetha Gopalakrishnan ◽

S. S. Rajan ◽

V. Kabaleeswaran ◽

L. Lessinger

Keyword(s):

Molecular Structure ◽

Crystal Structure ◽

Hydrogen Bonding ◽

Intramolecular Hydrogen Bonding ◽

Hydroxyl Group ◽

Inhibiting Activity ◽

Nmr Studies ◽

Rotation Axes ◽

Intramolecular Hydrogen ◽

Azadirachtin A

Azadirachtin-H, isolated from the seed kernels of Azadirachta indica (neem), crystallizes in space group I4, Z = 8, with disordered ethyl acetate solvent filling channels along the fourfold rotation axes. The crystal structure determination showed that the previously reported molecular structure deduced from NMR studies was correct except for the stereochemistry at C(11). Azadirachtin-H, which belongs to a group of C-seco-tetranortriterpenoids (C-seco-limonoids) of great interest for their insect antifeedant and ecdysis-inhibiting activity, has some unusual features: the absence of a carbomethoxy group at C(11); the presence of a cyclic hemiacetal function at C(11); the α-orientation of the hydroxyl group on C(11), opposite to that in all other known azadirachtins with a hydroxyl group on C(11), except azadirachtin-I. There is no intramolecular hydrogen bonding. In this crystal the rotation of the two major moieties of the azadirachtin-H molecule about the single connecting C(8)—C(14) bond is quite different from that in azadirachtin-A, whose crystal structure has recently been determined.

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2-Substituted and 2,6-disubstituted 1,4-benzoquinone 4-oximes ('p-nitrosophenols')

Australian Journal of Chemistry ◽

10.1071/ch9690935 ◽

1969 ◽

Vol 22 (5) ◽

pp. 935 ◽

Cited By ~ 13

Author(s):

RK Norris ◽

S Sternhell

Keyword(s):

Hydrogen Bonding ◽

Physical Properties ◽

Intramolecular Hydrogen Bonding ◽

Tautomeric Equilibrium ◽

Phenolic Hydroxyl ◽

Hydroxyl Group ◽

Electronic Effects ◽

Intramolecular Hydrogen

The preparation and physical properties of 27 compounds in the title series are described. Tautomerism, syn-anti isomerism, N.M.R. parameters, and the mechanism of isomerization are discussed. In this series of derivatives, the tautomeric equilibrium in dioxan solutions lies heavily towards the oxime form unless intramolecular hydrogen bonding between the substituent at C2 (or C6) and the phenolic hydroxyl group of the nitroso form is possible. The substituents at C2 (and C6) influence the position of the syn-anti equilibrium in the quinone monoxime forms through electronic effects.

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Salicylaldehyde Hydrazones: Buttressing of Outer-Sphere Hydrogen-Bonding and Copper Extraction Properties

Australian Journal of Chemistry ◽

10.1071/ch16639 ◽

2017 ◽

Vol 70 (5) ◽

pp. 556 ◽

Cited By ~ 2

Author(s):

Benjamin D. Roach ◽

Tai Lin ◽

Heiko Bauer ◽

Ross S. Forgan ◽

Simon Parsons ◽

...

Keyword(s):

Hydrogen Bond ◽

Hydrogen Bonding ◽

Density Functional ◽

Density Functional Theory Calculations ◽

Outer Sphere ◽

Copper Extraction ◽

Hydrogen Bond Acceptor ◽

Hydrogen Bond Formation ◽

Oxime Derivatives ◽

Intramolecular Hydrogen

Salicylaldehyde hydrazones are weaker copper extractants than their oxime derivatives, which are used in hydrometallurgical processes to recover ~20 % of the world’s copper. Their strength, based on the extraction equilibrium constant Ke, can be increased by nearly three orders of magnitude by incorporating electron-withdrawing or hydrogen-bond acceptor groups (X) ortho to the phenolic OH group of the salicylaldehyde unit. Density functional theory calculations suggest that the effects of the 3-X substituents arise from a combination of their influence on the acidity of the phenol in the pH-dependent equilibrium, Cu2+ + 2Lorg ⇌ [Cu(L–H)2]org + 2H+, and on their ability to ‘buttress’ interligand hydrogen bonding by interacting with the hydrazone N–H donor group. X-ray crystal structure determination and computed structures indicate that in both the solid state and the gas phase, coordinated hydrazone groups are less planar than coordinated oximes and this has an adverse effect on intramolecular hydrogen-bond formation to the neighbouring phenolate oxygen atoms.

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