RESUMEN

A theoretical thermodynamic study was conducted to investigate the antioxidant activity and mechanism of 1,3,4-oxadiazol-2-ylthieno[2,3-d]pyrimidin-4-amine derivatives (OTP) using a Density Functional Theory (DFT) approach. The study assessed how solvent environments influence the antioxidant properties of these derivatives. With the increasing prevalence of diseases linked to oxidative stress, such as cancer and cardiovascular diseases, antioxidants are crucial in mitigating the damage caused by free radicals. Previous research has demonstrated the remarkable scavenging abilities of 1,3,4-oxadiazole derivatives, prompting this investigation into their potential using computational methods. DFT calculations were employed to analyze key parameters, including bond dissociation enthalpy (BDE), ionization potential (IP), proton dissociation enthalpy (PDE), and electron transfer enthalpy (ETE), to delineate the antioxidant mechanisms of these compounds. Our findings indicate that specific electron-donating groups such as amine on the phenyl rings significantly enhance the antioxidant activities of these derivatives. The study also integrates global and local reactivity descriptors, such as Fukui functions and HOMO-LUMO energies, to predict the stability and reactivity of these molecules, providing insights into their potential as effective synthetic antioxidants in pharmaceutical applications.

RESUMEN

The radical Truce-Smiles rearrangement is a straightforward strategy for incorporating aryl groups into organic molecules for which asymmetric processes remains rare. By employing a readily available and non-expensive chiral auxiliary, we developed a highly efficient asymmetric photocatalytic acyl and alkyl radical Truce-Smiles rearrangement of α-substituted acrylamides using tetrabutylammonium decatungstate (TBADT) as a hydrogen atom-transfer photocatalyst, along with aldehydes or C-H containing precursors. The rearranged products exhibited excellent diastereoselectivities (7 : 1 to >98 : 2 d.r.) and chiral auxiliary was easily removed. Mechanistic studies allowed understanding the transformation in which density functional theory (DFT) calculations provided insights into the stereochemistry-determining step.

RESUMEN

We report the Cu(II) catalyzed synthesis of ß-disubstituted ketones from styrene via oxo-alkylation with unactivated cycloalkanes as the alkylating agent in presence of tert-butylhydroperoxide (TBHP) and 1-methylimidazole as oxidant and base respectively. ß-disubstituted ketones are known to be synthesized by using either expensive Ru/Ir complexes, or low-cost metal complexes (e. g., Fe, Mn) with activated species like aldehyde, acid, alcohol, or phthalimide derivatives as the alkylating agent, however, use of unactivated cycloalkanes directly as the alkylating agent remains challenging. A wide range of aliphatic C-H substrates as well as various olefinic arenes and heteroarene (35 substrates including 14 new substrates) are well-tolerated in this method. Hammett analysis shed more light on the substitution effect in the olefinic part on the overall mechanism. Furthermore, the controlled experiments, kinetic isotope effect study, and theoretical calculations (DFT) enable us to gain deeper insight of mechanistic intricacies of this new simple and atom-economic methodology.

RESUMEN

Oxidants are very active compounds that can cause damage to biological systems under specific environmental conditions. One effective way to counterbalance these adverse effects is the use of anti-oxidants. At low concentrations, an antioxidant is defined as a compound that can delay, control, or prevent an oxidative process. Antioxidants exist in plants, soil, and minerals; therefore, nature is a rich source of natural antioxidants, such as tocopherols and polyphenols. In nature, antioxidants perform in tandem with their bio-environment, which may tune their activity and protect them from degradation. In vitro use of antioxidants, i.e., out of their biomatrix, may encounter several drawbacks, such as auto-oxidation and polymerization. Artificial nanoantioxidants can be developed via surface modification of a nanoparticle with an antioxidant that can be either natural or synthetic, directly mimicking a natural antioxidant system. In this direction, state-of-the-art nanotechnology has been extensively incorporated to overcome inherent drawbacks encountered in vitro use of antioxidants, i.e., out of their biomatrix, and facilitate the production and use of antioxidants on a larger scale. Biomimetic nanoengineering has been adopted to optimize bio-medical antioxidant systems to improve stability, control release, enhance targeted administration, and overcome toxicity and biocompatibility issues. Focusing on biotechnological sciences, this review highlights the importance of nanoengineering in developing effective antioxidant structures and comparing the effectiveness of different nanoengineering methods. Additionally, this study gathers and clarifies the different antioxidant mechanisms reported in the literature and provides a clear picture of the existing evaluation methods, which can provide vital insights into bio-medical applications.

RESUMEN

Erlotinib and gefitinib are quinazoline derivatives with antineoplastic properties. Usually, intake of antineoplastic agents results in much a greater degree of oxidative stress, i.e. the production of free radicals, than induced by cancer itself. Hence, anticancerous drugs must also exhibit antioxidant activity but this has not been studied thus far. In this study, the antioxidant activity of erlotinib and gefitinib was examined by experimental and computational studies. It was found that erlotinib and gefitinib exhibit good 2,2-dipheny l-1-picrylhydrazyl (DPPH) radical and hydroxyl radical scavenging (HRS) activities. In DPPH assay, the IC50 for erlotinib and gefitinib were 0.584 and 0.696 mM, respectively, while IC50 for HRS assay were 0.843 and 1.03 mM for erlotinib and gefitinib, respectively. Structural characteristics such as frontier molecular orbitals (FMOs), molecular electrostatic potential maps (MESPs), and global descriptive parameters were calculated at DFT/B3LYP/6-311++G (d,p) on the optimized geometries of erlotinib and gefitinib. UV-visible spectroscopy revealed the possible electronic transitions between the FMOs and their associated excitation energies of both drugs and found that erlotinib has π to π* transitions while gefitinib has π to π* and σ to π* transitions. To elucidate the antioxidant activity of erlotinib and gefitinib, three mechanisms namely hydrogen atom transfer (HAT), single electron transfer proton transfer (SETPT), and sequential proton-loss electron-transfer (SPLET) were employed and articulated the results in arithmetic parameters like bond dissociation energy (BDE), proton affinity (PA), ionization potential (IP), electron transfer enthalpy (ETE), and proton dissociation enthalpy (PDE). Further, molecular docking studies have been carried out to have a better understanding of binding sites and modes of interaction with a well-known antioxidant target protein monoamine oxidase-B (MAO-B) employing docking scores and types of interactions. All the calculated parameters point out that though gefitinib and erlotinib were interchangeable, erlotinib requires a lesser amount of energy for proton transfer and electron transfer, moreover it scavenges radicals easily.

Asunto(s)

RESUMEN

Synthetic nitrone spin-traps are being explored as therapeutic agents for the treatment of a wide range of oxidative stress-related pathologies, including but not limited to stroke, cancer, cardiovascular, and neurodegenerative diseases. In this context, increasing efforts are currently being made to the design and synthesis of new nitrone-based compounds with enhanced efficacy. The most researched nitrones are surely the ones related to α-phenyl-tert-butylnitrone (PBN) and 5,5-dimethyl-1-pyrroline N-oxide (DMPO) derivatives, which have shown to possess potent biological activity in many experimental animal models. However, more recently, nitrones with a benzoxazinic structure (3-aryl-2H-benzo[1,4]oxazin-N-oxides) have been demonstrated to have superior antioxidant activity compared to PBN. In this study, two new benzoxazinic nitrones bearing an electron-withdrawing methoxycarbonyl group on the benzo moiety (in para and meta positions respect to the nitronyl function) were synthesized. Their in vitro antioxidant activity was evaluated by two cellular-based assays (inhibition of AAPH-induced human erythrocyte hemolysis and cell death in human retinal pigmented epithelium (ARPE-19) cells) and a chemical approach by means of the α,α-diphenyl-ß-picrylhydrazyl (DPPH) scavenging assay, using both electron paramagnetic resonance (EPR) spectroscopy and UV spectrophotometry. A computational approach was also used to investigate their potential primary mechanism of antioxidant action, as well as to rationalize the effect of functionalization on the nitrones reactivity toward DPPH, chosen as model radical in this study. Further insights were also gathered by exploring the nitrone electrochemical properties via cyclic voltammetry and by studying their kinetic behavior by means of EPR spectroscopy. Results showed that the introduction of an electron-withdrawing group in the phenyl moiety in the para position significantly increased the antioxidant capacity of benzoxazinic nitrones both in cell and cell-free systems. From the mechanistic point of view, the calculated results closely matched the experimental findings, strongly suggesting that the H-atom transfer (HAT) is likely to be the primary mechanism in the DPPH quenching.

RESUMEN

Selective synthesis of three different bioactive heterocycles; isoxazolines, 5-hydroxy-2-isoxazolines and isoxazoles from the same starting material using TEMPO (2,2,6,6-Tetramethylpiperidin-1-oxyl) as a radical initiator is reported. Selectivity was achieved using different oxidants with TEMPO. The reaction goes through a 1,5-HAT (hydrogen atom transfer) process resulting in products with good yields. This strategy offers a straightforward route to three different heterocycles from oximes via radical-mediated C(sp3 )-H oxidation.

RESUMEN

Antioxidants are an important component of our ability to combat free radicals-an excess of which leads to oxidative stress, which is related to aging and numerous human diseases. Oxidative damage also shortens the shelf-life of foods and other commodities. Understanding the structure-activity relationship of antioxidants and their mechanisms of action is important for designing more potent antioxidants for potential use as therapeutic agents as well as preservatives. We report the first computational study on the electronic effects of ortho-substituents in dendritic tri-phenolic antioxidants, comprising a common phenol moiety and two other phenol units with electron-donating or electron-withdrawing substituents. Among the three proposed antioxidant mechanisms, sequential proton loss electron transfer (SPLET) was found to be the preferred mechanism in methanol for the dendritic antioxidants based on calculations using Gaussian 16. We then computed the total enthalpy values by cumulatively running SPLET for all three rings to estimate electronic effects of substituents on overall antioxidant activity of each dendritic antioxidant and establish their structure-activity relationships. Our results show that the electron-donating o-OCH3 group has a beneficial effect while the electron-withdrawing o-NO2 group has a negative effect on the antioxidant activity of the dendritic antioxidant. The o-Br and o-Cl groups did not show any appreciable effects. These results indicate that electron-donating groups such as o-methoxy are useful for designing potent dendritic antioxidants while the nitro and halogens do not add value to the radical scavenging antioxidant activity. We also found that the half-maximal inhibitory concentration (IC50) values of 2,2-diphenyl-1-picrylhydrazyl (DPPH) better correlate with the second step (electron transfer enthalpy, ETE) than the first step (proton affinity, PA) of the SPLET mechanism, implying that ETE is the better measure for estimating overall radical scavenging antioxidant activities.

RESUMEN

Oxoiron(IV) units are often implicated as intermediates in the catalytic cycles of non-heme iron oxygenases and oxidases. The most reactive synthetic analogues of these intermediates are supported by tetradentate tripodal ligands with N-methylbenzimidazole or quinoline donors, but their instability precludes structural characterization. Herein we report crystal structures of two [FeIV (O)(L)]2+ complexes supported by pentadentate ligands incorporating these heterocycles, which show longer average Fe-N distances than the complex with only pyridine donors. These longer distances correlate linearly with log k2 ' values for O- and H-atom transfer rates, suggesting that weakening the ligand field increases the electrophilicity of the Fe=O center. The sterically bulkier quinoline donors are also found to tilt the Fe=O unit away from a linear N-Fe=O arrangement by 10°.

RESUMEN

Mango "Ataulfo" peel is a rich source of polyphenols (PP), with antioxidant and anti-cancer properties; however, it is unknown whether such antiproliferative activity is related to PP's antioxidant activity. The content (HPLC-DAD), antioxidant (DPPH, FRAP, ORAC), and antiproliferative activities (MTT) of free (FP) and chemically-released PP from mango 'Ataulfo' peel after alkaline (AKP) and acid (AP) hydrolysis, were evaluated. AKP fraction was higher (µg/g DW) in gallic acid (GA; 23,816 ± 284) than AP (5610 ± 8) of FR (not detected) fractions. AKP fraction and GA showed the highest antioxidant activity (DPPH/FRAP/ORAC) and GA's antioxidant activity follows a single electron transfer (SET) mechanism. AKP and GA also showed the best antiproliferative activity against human colon adenocarcinoma cells (LS180; IC50 (µg/mL) 138.2 ± 2.5 and 45.7 ± 5.2) and mouse connective cells (L929; 93.5 ± 7.7 and 65.3 ± 1.2); Cheminformatics confirmed the hydrophilic nature (LogP, 0.6) and a good absorption capacity (75%) for GA. Data suggests that GA's antiproliferative activity appears to be related to its antioxidant mechanism, although other mechanisms after its absorption could also be involved.

Asunto(s)

RESUMEN

Maclurin, an exceptional member of phytophenol family, was found to effectively protect against mesenchymal stem cells (MSCs) oxidative damage induced by hydroxyl radical (OH) at 62.1-310.5 µM. Antioxidant assays indicated that maclurin could efficiently protect DNA from OH-induced damage at 114.6-382.2 µM, and scavenge OH, DPPH (1,1-diphenyl-2-picrylhydrazyl radical), ABTS(+) (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid radical), and bind Cu(2+) (IC50 values were respectively 122.87 ± 10.14, 10.15 ± 0.85, 0.97 ± 0.07, and 133.95 ± 11.92 µM). HPLC-DAD and HPLC-ESI-MS/MS analyses of the end-product of maclurin reaction with DPPH clearly suggested that maclurin (m/z = 261.12 [M-H](-)) donated two hydrogen atoms to DPPH (m/z = 394.06 [M](+)) to form ortho-benzoquinone moiety (λmax = 364 nm; m/z = 259.06 [M-H](-), loss of m/z = 28) and DPPH2 molecule (m/z = 395.03, 396.01), via hydrogen atom transfer (HAT) or sequential electron (e) proton transfer (SEPT), not radical adduct formation (RAF) mechanisms. Therefore, we concluded that: (i) maclurin can effectively protect against OH-induced damages to DNA and MSCs, thereby it may have a therapeutic potential in prevention of many diseases or MSCs transplantation; (ii) a possible mechanism for maclurin to protect against oxidative damages is OH radical-scavenging; (iii) maclurin scavenges OH possibly through metal-chelating, and direct radical-scavenging which is mainly via HAT or SEPT mechanisms; and (iv) the protective and antioxidant effects of maclurin can be primarily attributed to ortho-dihydroxyl groups, and ultimately to the relative stability of the ortho-benzoquinone form.

Asunto(s)