Mechanistic Insights into the Antioxidant and Pro-oxidant Activities of Bromophenols from Marine Algae: A DFT Investigation.

Marine algae are a rich source of aromatic secondary metabolites, with bromophenols (BPs) receiving particular attention due to their health benefits. Despite extensive research on BPs, the understanding of their antioxidant potential, as well as their mechanisms of action at the molecular level, remains incomplete. This study utilized density functional theory (DFT) to systematically elucidate the antioxidant and pro-oxidant mechanisms of the main BP scaffolds under physiological conditions. It was found that BPs exhibit potent antioxidant capacity in both polar and lipid environments. In lipid media, the formal hydrogen transfer mechanism has been identified as the exclusive antiradical pathway. The position of bromine atoms significantly influenced the activity, particularly in scaffolds containing one hydroxyl group. However, no significant effect was observed in scaffolds with two hydroxyl groups. In water, monodeprotonated BPs showed key radical scavenging activity, with different mechanisms favored depending on the configuration of the hydroxyl groups. Additionally, BPs, particularly those bearing a catechol moiety, exhibit secondary antioxidant activity by reducing the production of hydroxyl radicals via the ascorbic acid anion pathway. These findings provide further validation of the potent antioxidant properties of BPs and shed light on their mechanism of action in physiological environments.

Unveiling potent Schiff base derivatives with selective xanthine oxidase inhibition: In silico and in vitro approach.

This research describes the synthesis by an environmentally-friendly method, microwave irradiation, development and analysis of three novel and one previously identified Schiff base derivative as a potential inhibitor of bovine xanthine oxidase (BXO), a key enzyme implicated in the progression of gout. Meticulous experimentation revealed that these compounds (10, 9, 4, and 7) have noteworthy inhibitory effects on BXO, with IC50 values ranging from 149.56 µM to 263.60 µM, indicating their good efficacy compared to that of the standard control. The validation of these results was further enhanced through comprehensive in silico studies, which revealed the pivotal interactions between the inhibitors and the catalytic sites of BXO, with a particular emphasis on the imine group (-C = N-) functionalities. Intriguingly, the compounds exhibiting the highest inhibition rates also showcase advantageous ADMET profiles, alongside encouraging initial assessments via PASS, hinting at their broad-spectrum potential. The implications of these findings are profound, suggesting that these Schiff base derivatives not only offer a new vantage point for the inhibition of BXO but also hold considerable promise as innovative therapeutic agents in the management and treatment of gout, marking a significant leap forward in the quest for more effective gout interventions.

Exploring the Anti-Cancer Potential of Hispidin: A Comprehensive in Silico and in Vitro Study on Human Osteosarcoma Saos2 Cells.

Hispidin was initially discovered in basidiomycete Inonotus hispidus (Bull.) P. Karst and this extraordinary compound possesses immense potency and can be extracted from the wild mushroom through specialized bioreactor cultivation techniques. In our study, we isolated it from Inonotus hispidus (Bull.) P. Karst., with a yield of 3.6 %. We identified and characterized hispidin through the implementation of spectroscopic techniques such as FTIR, NMR, and MS. Additionally, we utilized Thermogravimetric Analysis for thermal characterization of the compound. Computational studies based on DFT were performed to investigate the molecular structure, electronic properties, and chemical reactivity of hispidin. PASS analysis for hispidin demonstrated that 19 of them are anti-neoplastic activities. The Pharmacology prediction of hispidin confirm that it is not toxic, non-carcinogenesis with a good human intestinal absorption. The effect of hispidin on the viability of bone cancer cells was evaluated by MTT assay. The results showed that hispidin significantly reduced SaoS2 cell viability in a dose-dependent manner. Molecular docking was carried out using five targets related to bone cancer to determine the interactions between hispidin and the studied proteins. The results demonstrate that hispidin is a good inhibitor for the five targets. Dynamic simulation shows a good stability of the complex hispidin-protein.

A Comprehensive Study of the Radical Scavenging Activity of Rosmarinic Acid.

Rosmarinic acid (RA) is reported in separate studies to be either an inducer or reliever of oxidative stress, and this contradiction has not been resolved. In this study, we present a comprehensive examination of the radical scavenging activity of RA using density functional theory calculations in comparison with experimental data. In model physiological media, RA exhibited strong HO• radical scavenging activity with overall rate constant values of 2.89 × 1010 and 3.86 × 109 M-1 s-1. RA is anticipated to exhibit excellent scavenging properties for HOO• in an aqueous environment (koverall = 3.18 × 108 M-1 s-1, ≈2446 times of Trolox) following the hydrogen transfer and single electron transfer pathways of the dianion state. The neutral form of the activity is equally noteworthy in a lipid environment (koverall = 3.16 × 104 M-1 s-1) by the formal hydrogen transfer mechanism of the O6(7,15,16)-H bonds. Chelation with RA may prevent Cu(II) from reduction by the ascorbic acid anion (AA-), hence blocking the OIL-1 pathway, suggesting that RA in an aqueous environment also serves as an OIL-1 antioxidant. The computational findings exhibit strong concurrence with the experimental observations, indicating that RA possesses a significant efficacy as a radical scavenger in physiological environments.

Computational assessment of the primary and secondary antioxidant potential of alkylresorcinols in physiological media.

Alkylresorcinols are a group of natural phenolic compounds found in various foods such as whole grain cereals, bread, and certain fruits. They are known for their beneficial health effects, such as anti-inflammatory and anti-cancer properties. This study aimed to evaluate the antioxidant activity of two typical alkylresorcinols namely olivetol and olivetolic acid (Oli and OliA) under physiological conditions. The free radical scavenging capacity of Oli and OliA toward oxygenated free radicals (HO˙ and HOO˙ radicals) was investigated using thermodynamic and kinetic calculations. The results revealed that Oli and OliA are potent scavengers of HO˙ radical in both polar and lipid media, acting exclusively via the FHT (formal hydrogen transfer) mechanism. Moreover, they demonstrated excellent scavenging activity toward HOO˙ radical in water via the SET (single electron transfer) mechanism, outperforming the common antioxidant BHT. In lipid media, Oli and OliA showed moderate scavenging activity toward HOO˙ radical via the FHT mechanism. Significant prooxidant potential of OliA- was also demonstrated through the formation of complexes with copper ions. Additionally, docking studies indicate that the compounds exhibited a good affinity for ROS-producing enzymes, including myeloperoxidase (MP), cytochrome P450 (CP450), lipoxygenase (LOX), and xanthine oxidase (XO), highlighting their potential as natural antioxidants with promising therapeutic applications.

Exploring the Antioxidant Properties of Caffeoylquinic and Feruloylquinic Acids: A Computational Study on Hydroperoxyl Radical Scavenging and Xanthine Oxidase Inhibition.

Caffeoylquinic (5-CQA) and feruloylquinic (5-FQA) acids, found in coffee and other plant sources, are known to exhibit diverse biological activities, including potential antioxidant effects. However, the underlying mechanisms of these phenolic compounds remain elusive. This paper investigates the capacity and mode of action of 5-CQA and 5-FQA as natural antioxidants acting as hydroperoxyl radical scavengers and xanthine oxidase (XO) inhibitors. The hydroperoxyl radical scavenging potential was investigated using thermodynamic and kinetic calculations based on the DFT method, taking into account the influence of physiological conditions. Blind docking and molecular dynamics simulations were used to investigate the inhibition capacity toward the XO enzyme. The results showed that 5-CQA and 5-FQA exhibit potent hydroperoxyl radical scavenging capacity in both polar and lipidic physiological media, with rate constants higher than those of common antioxidants, such as Trolox and BHT. 5-CQA carrying catechol moiety was found to be more potent than 5-FQA in both physiological environments. Furthermore, both compounds show good affinity with the active site of the XO enzyme and form stable complexes. The hydrogen atom transfer (HAT) mechanism was found to be exclusive in lipid media, while both HAT and SET (single electron transfer) mechanisms are possible in water. 5-CQA and 5-FQA may, therefore, be considered potent natural antioxidants with potential health benefits.

Examination of the Antioxidant Activity of Psoralidin: Computational Mechanistic Study and Impact on the ROS Level in Human Keratinocytes.

Psoralidin (Pso) is a coumestan-type compound found in Psoralea corylifolia L. that exhibits a broad spectrum of pharmacological properties. The current work aimed to study, for the first time, the antioxidant capacities of Pso under physiological circumstances. Tandem experimental and computational approaches were used to fully understand the interaction of Pso with ROS (reactive oxygen species) at the molecular level as well as its impact on the basal ROS level in cells. Pso has been found to be a potent radical scavenger in physiological polar media, acting via the single electron-transfer mechanism rather than the hydrogen-transfer mechanism. In contrast, Pso is a moderate radical scavenger in lipid media, and its reaction is determined by hydrogen transfer from the 7OH group. The in vitro assays revealed that Pso moderately reduces the basal ROS level in human keratinocytes at non-toxic concentrations, which is in agreement with the computational study. These findings indicate that Pso is a promising antioxidant, but in its natural form it has no significant effects on basal cell conditions.

Insights on the antiradical capacity and mechanism of phytocannabinoids: H-abstraction and electron transfer processes in physiological media and the influence of the acid-base equilibrium.

Phytocannabinoids are natural products primarily isolated from Cannabis sativa that exhibit the typical C21 terpenophenolic skeleton. This class of compounds has been shown to be effective in the treatment of various oxidation-related diseases, which has made their antioxidant properties the focus of increasing interest. In the present contribution, the primary antioxidant properties of eight representative phytocannabinoids have been systematically studied against a variety of biologically significant radical species using the density functional theory (DFT) method. The findings demonstrated that phytocannabinoids, in water at physiological pH, exhibit excellent radical scavenging capacity, mainly exerted by the single electron transfer (SET) process from the deprotonated state. In contrast, phytocannabinoids are moderate radical scavengers in non-polar environment via the formal hydrogen atom transfer (fHAT) process. Among the compounds examined, cannabichromene (CBC) and cannabifuran (CBF) had the greatest free radical scavenging capacity in water, surpassing even common antioxidants like BHT and Trolox. CBF is expected to have potent antiradical action toward peroxyl radicals, alkoxy radicals, and nitrogen dioxide in water at physiological pH. These results provide supporting evidence that phytocannabinoids may be useful in scavenging harmful free radicals in physiological environments.

Synthesis and evaluation of the antioxidant and anti-tyrosinase activities of thiazolyl hydrazone derivatives and their application in the anti-browning of fresh-cut potato.

Tyrosinase is a key enzyme in the biosynthesis of melanin, which is responsible for the browning of foods as well as many skin disorders. In order to develop new anti-browning agents with dual antioxidant and anti-tyrosinase capacities, a series of 30 thiazolyl hydrazone derivatives were synthesized. Among the molecules prepared, 6 and 30 were found to be the most potent tyrosinase inhibitors with IC50 values ​​comparable to that of kojic acid. Interestingly, 6 also has the highest radical scavenging activity among the prepared molecules. The inhibition kinetics study indicated that 6 is a non-competitive inhibitor while 30 inhibits tyrosinase competitively. The anti-browning assay of fresh-cut potato slices revealed that 6 and 30 are potent anti-browning agents with a capacity as high as kojic acid. The mechanisms of free radical scavenging and tyrosinase inhibition have been fully investigated in silico using computational kinetics, molecular docking, and molecular dynamics simulations.

Computational design of new tacrine analogs: an in silico prediction of their cholinesterase inhibitory, antioxidant, and hepatotoxic activities.

Tacrine, the first drug approved for the treatment of Alzheimer's disease (AD), is a non-competitive cholinesterase inhibitor withdrawn due to its acute hepatotoxicity. However, new non-hepatotoxic forms of tacrine have been actively researched. Moreover, several recent reports have shown that oxidative stress is the cause of damage and plays a role in the pathogenesis of several neurodegenerative diseases including AD. The aim of the present study is the design of new easily synthesized tacrine analogs with less hepatotoxicity and potent antioxidant activity. In this context, a library of 34 novel tacrine analogs bearing an antioxidant fragment was designed and evaluated for its hepatotoxicity as well as anticholinesterase and antioxidant activities using computational methods. As a result, six new tacrine analogs have been proposed as potential inhibitors of cholinesterase with antioxidant activity and low or no hepatotoxicity. Furthermore, ADME calculations suggest that these compounds are promising oral drug candidates. Communicated by Ramaswamy H. Sarma.

The radical scavenger capacity and mechanism of prenylated coumestan-type compounds: a DFT analysis.

The antiradical capacity and mechanisms of two representative coumestan-type compounds, namely isosojagol (Iso) and phaseoul (Pha), were examined using quantum chemistry calculations and computational kinetics methods. From a thermodynamic point of view, the 18CH groups of the prenyl substituent have been found to be the most suitable sites for radical attacks via the formal hydrogen transfer (FHT) mechanism. However, the kinetic study revealed that the reaction at these CH groups is slow and does not contribute to the overall reactivity of these compounds, which the phenolic groups mainly define. The kinetic study also revealed that the studied compounds are good free radical scavengers with overall rate coefficients as high as recognized antioxidants such as carnosic acid, artepillin C, thymol, and rosefuran.

Preparation, DFT calculations, docking studies, antioxidant, and anticancer properties of new pyrazole and pyridine derivatives.

Seven novel pyrazole derivatives (4a-g) and four novel starting compounds incorporating substituted pyridine moieties were synthesized successfully. Cell viability assay for the tested compounds was performed, and the inhibitory concentrationlogarithmic 50 (LogIC50 ) values of the compounds were calculated after a 24-h treatment. Four of the examined compounds (3d, 3g, 4f, and 4g) showed comparable cytotoxic activity against CaCo-2 compared to the standard drug docetaxel at 0.1 and 1 µM concentrations. Although the LogIC50  of docetaxel was -0.678 µM for CaCo-2 cells at 24 h, the LogIC50 values of compounds were -0.794, -0.567, -0.657, and -0.498 µM, respectively. Five of the compounds (2d, 2g, 3d, 3g, and 4e) showed comparable cytotoxic activity against MCF-7 at 0.1 µM concentration compared to docetaxel (p < 0.05). Docking studies revealed the compounds have a good affinity to the active site of the human topoisomerase II ß enzyme. The antioxidant capacities of all compounds were determined using both 1,1-diphenyl-2-picrylhydrazyl and metal chelation methods. Although the compounds did not show significant antioxidant activity, relatively effective are compounds 3c, 3d, and 3g, which are hydrazine derivatives with approximately 50% antioxidant activity of standard antioxidants at concentrations of 62.5 and 125 µg/ml.

HPLC-DAD-ESI/MS profiles of bioactive compounds, antioxidant and anticholinesterase activities of Ephedra alata subsp. alenda growing in Algeria.

Ephedra (Ephedraceae) is used in medicine for various purposes as having, antioxidant, anticarcinogen, antibacterial, anti-inflammatory hepatoprotective, anti-obesity, antiviral and diuretic activities. In this study the aim was to investigate chemical constituents of Ephedra alata and understand the possible effects of those constituents in antioxidant activity and alzheimer's disease essay. For this purpose, natural compounds from E.alata were characterized by LC-DAD-ESI-MS/MS using negative and positive ionization modes, while the bioactivity was assessed by acetylcholinesterase (AChE) inhibition study and determining of antioxidant activity; DPPH radical scavenging and ß-carotene bleaching assays were used to assess the antioxidant potential. The proposed method of spectrometry provided tentative identification of 27 compounds including alkaloids and phenolic compounds as flavonoids. The methanolic extract showed high contents of total phenolic and exhibited an important antioxidant potential and demonstrated a potent inhibitory effect against acetylcholinesterase (IC50: 11,25 ± 0,25 µg/mL). The results showed that the plant possesses a therapeutic effect.

Structure-activity relationship of antioxidant prenylated (iso)flavonoid-type compounds: quantum chemistry and molecular docking studies.

Prenylated (iso)flavonoid-type compounds are a subclass of natural flavonoids that have been reported to exhibit good antioxidant properties. In the present paper, the structure-activity relationship of three typical prenylated (iso)flavonoids namely 8-prenyldaidzein (Per), Licoflavone (Lic), and erysubin F (Ery) have been determined using DFT (density functional theory)-based calculations and molecular docking studies. As result, the CH bond of the prenyl substituent was found to be the most thermodynamically favorable site for trapping free radicals in the gas phase and lipid physiological environments. While the OH bond of the B-ring seems to be more reactive in water. HAT (hydrogen atom transfer) and SPLET (sequential proton loss electron transfer) play a decisive role in the antiradical activity of the studied compounds in lipid and polar physiological environments, respectively. All of the studied compounds exhibit strong binding affinity to both xanthine oxidase and inducible nitric oxide synthase enzymes by forming several hydrogen bonds and hydrophobic interactions with their respective catalytic sites. These results suggest that (iso)flavonoid-type compounds are promising radical scavengers and antioxidants. Communicated by Ramaswamy H. Sarma.

Modeling the peroxyl radical scavenging behavior of Carnosic acid: Mechanism, kinetics, and effects of physiological environments.

Carnosic acid (CA), a phenolic diterpene and abietane-type compound, is a potent natural antioxidant with medical benefits. The present paper elucidates, for the first time, the kinetics and the exact mechanism of the peroxyl radical scavenging activity of CA in the gas phase and under physiological conditions. According to the obtained results, the reaction of CA with HOO• is significantly faster in aqueous solution than in the gas phase and nonpolar environments. The abstraction of the hydrogen atom from 2-OH is the decisive mechanism in the gas phase and nonpolar media, while both hydrogen abstraction (15%) and electron transfer (85%) mechanisms can take place in aqueous solution. The overall rate coefficient in water (4.73 × 106 M-1 s-1) is about 36 times higher than that of the reference antioxidant Trolox (1.30 × 105 M-1 s-1), suggesting that CA is a potent scavenger of peroxyl radicals in polar media.

A detailed DFT-based study of the free radical scavenging activity and mechanism of daphnetin in physiological environments.

Daphnetin, a biologically active coumarin derivative found in plants of the genus Daphne, is a potent antioxidant phenolic compound. The present work describes the mechanisms and kinetics of the HO, NO, HOO, and NO2 scavenging activities of daphnetin in physiological environments using quantum chemistry calculations. The main antiradical mechanisms have been studied: formal hydrogen transfer (FHT), sequential electron transfer proton transfer (SETPT), sequential proton loss electron transfer (SPLET), and radical adduct formation (RAF). Besides its good HO scavenging activity in physiological environments, daphnetin is expected to exhibit good HOO and NO2 scavenging activities in water with koverall = 1.51 × 107 and 4.79 × 108 M-1s-1, respectively. The FHT mechanism decides the HO scavenging activity in aqueous solution, as well as HO, HOO, and NO2 scavenging activities in lipid media, while SPLET is the primary mechanism in water for HOO and NO2 scavenging activities. The theoretical predictions were found to be in good agreement with the available experimental data, which supports the reliability of the calculations.

Are thymol, rosefuran, terpinolene and umbelliferone good scavengers of peroxyl radicals?

DFT-based computational calculations have been used to investigate the hydroperoxyl radical scavenging activity of four essential oil constituents namely thymol (Thy), rosefuran (Ros), terpinolene (Ter), and umbelliferone (Umb). Different reaction mechanisms including formal hydrogen transfer (FHT), radical adduct formation (RAF), sequential proton loss electron transfer (SPLET), and sequential electron transfer proton transfer (SETPT) have been examined in the gas phase and physiological environments. It was found that the HOO radical scavenging activity of these compounds is strongly influenced by the environment, which becomes more important in water than pentyl ethanoate. According to the overall reaction rate constants, the phenolic compounds Thy and Umb are predicted to exhibit excellent activity in aqueous solution. Umb with an overall rate constant of 1.44 × 108M-1s-1 at physiological pH is among the best HOO radical scavengers in water with activity comparable to that of caffeic acid, higher than those of ascorbic acid, guaiacol and eugenol, and much higher than that of Trolox.

Synthesis, biological evaluation, theoretical investigations, docking study and ADME parameters of some 1,4-bisphenylhydrazone derivatives as potent antioxidant agents and acetylcholinesterase inhibitors.

Five 1,4-bisphenylhydrazone derivatives (1-5) were successfully synthesized and evaluated for their antioxidant and acetylcholinesterase inhibitory activities. The antioxidant activity has been carried out using DPPH, ABTS, CUPRAC and superoxide radical scavenging methods. All the compounds showed a very good antioxidant activity compared to that of the standards used. Compound 1 was found to be the best antioxidant agent with IC50 values lower or comparable to that of the standards. The acetylcholinesterase inhibitory activity has been evaluated using a modified Ellman's assay. The obtained results indicate that compound 2 is the best acetylcholinesterase inhibitor with a low IC50 value comparable to that of the galantamine. In addition, DFT calculations have been performed to determine in which mechanism the synthesized hydrazones follow to scavenge free radicals. Molecular docking study was performed for compound 2, and its interaction modes with the enzyme acetylcholinesterase were determined. As a result, a strong interaction between this compound and the active site of AChE enzyme was revealed. Finally, ADME properties of the synthesized compounds were also studied and showed good drug-like properties.

The role of benzylic-allylic hydrogen atoms on the antiradical activity of prenylated natural chalcones: a thermodynamic and kinetic study.

Prenylated chalcones are a family of natural chalcones that have been reported to exhibit a high antioxidant activity. In this paper, the density functional calculations are carried out to study, systematically, the antiradical properties of four prenylated natural chalcones namely isobavachalcone (I), xanthohumol (II), desmethylxanthohumol (III) and broussochalcone (IV). The radical scavenging ability of all the possible CH and OH bonds of chalcones I-IV were discussed in detail thermodynamically and kinetically. The results reveal that the CH bonds of the prenyl substituent are the most thermodynamically preferred sites for free radical attack and thus play an important role on the antiradical activity of the investigated chalcones. For the OH bonds, it has been found that the B ring is more preferred for attacking free radicals than the A ring. Kinetic investigations have revealed that the CH bond and the OH bonds of the B ring can trap HO•/HOO• radicals. These results are of great significance in better understanding the chemical mechanism of the radical-scavenging action and open new perspectives for the design of new potent antioxidant agents.Communicated by Ramaswamy H. Sarma.

Thermodynamic and Kinetic Studies of the Radical Scavenging Behavior of Hydralazine and Dihydralazine: Theoretical Insights.

Hydralazine (HZ) and dihydralazine (DHZ) are phthalazine derivatives substituted at position 1 (HZ) or positions 1 and 4 (DHZ) by a hydrazinyl substituent. These compounds are widely used for treating hypertension and heart failure, essentially acting as vasodilators on the arteries and arterioles. In this study, the antioxidant activity of HZ and DHZ in the gas phase and in physiological environments was investigated by thermodynamic and kinetic calculations. It was found that the HOO• radical scavenging activity of these compounds follows the formal hydrogen transfer (FHT) mechanism. The H abstraction of the N9-H bond plays a deciding role in the HOO• radical scavenging of HZ-1 and DHZ-1, whereas the HOO• radical scavenging activities of HZ-2 and DHZ-2 are defined by the dissociation of the N10-H and N11-H bonds, respectively. The rate constants for the HOO• radical scavenging of the HZ and DHZ in the gas phase are in the range of 9.64 × 106 to 4.52 × 108 M-1 s-1, whereas in aqueous solutions and the lipid medium they are in the range of 2.62 × 104 to 5.13 × 107 M-1 s-1 and 5.75 × 104 to 6.66 × 106 M-1 s-1, respectively. The HOO• radical scavenging of DHZ-1 and DHZ-2 is thus faster than that of the reference antioxidant compound Trolox in all the studied environments. Consistently, DHZs are not only vasodilators but also potent antioxidants.