Microencapsulation of Theobroma cacao L polyphenols: A high-value approach with in vitro anti-Trypanosoma cruzi, immunomodulatory and antioxidant activities.

Chagas disease (CHD) is the highest economic burden parasitosis worldwide and the most important cardiac infection, without therapeutic alternatives to halt or reverse its progression. In CHD-experimental models, antioxidant and anti-inflammatory compounds have demonstrated therapeutic potential in cardiac dysfunction. Theobroma cacao polyphenols are potent natural antioxidants with cardioprotective and anti-inflammatory action, which are susceptible to degradation, requiring technological approaches to guarantee their protection, stability, and controlled release. Here, 21 cocoa polyphenol-rich microencapsulates were produced by spray-drying and freeze-drying techniques using two wall materials (maltodextrin and gum arabic). Chemical (total and individual phenolic content and antioxidant activity), structural (morphology), and biological parameters (cytotoxicity, trypanocidal, antioxidant, and immunomodulatory activities) were assessed to determine the most efficient microencapsulation conditions on Trypanosoma cruzi-infected myocardioblast and macrophage cells. Significant antiproliferative properties against infected cells (superior to benznidazole) were found in two microencapsulates which also exhibited cardioprotective properties against oxidative stress, inflammation, and cell death.

Photophysical Analysis of Aggregation-Induced Emission (AIE) Luminogens Based on Triphenylamine and Thiophene: Insights into Emission Behavior in Solution and PMMA Films.

Aggregation-Induced Emission (AIE) luminogens have garnered significant interest due to their distinctive applications in different applications. Among the diverse molecular architectures, those based on triphenylamine and thiophene hold prominence. However, a comprehensive understanding of the deactivation mechanism both in solution and films remains lacking. In this study, we synthesized and characterized spectroscopically two AIE luminogens: 5-(4-(bis(4-methoxyphenyl)amino)phenyl)thiophene-2-carbaldehyde (TTY) and 5'-(4-(bis(4-methoxyphenyl)amino)phenyl)-[2,2'-bithiophene]-5-carbaldehyde (TTO). Photophysical and theoretical analyses were conducted in both solution and PMMA films to understand the deactivation mechanism of TTY and TTO. In diluted solutions, the emission behavior of TTY and TTO is influenced by the solvent, and the deactivation of the excited state can occur via locally excited (LE) or twisted intramolecular charge transfer (TICT) state. In PMMA films, rotational and translational movements are constrained, necessitating emission solely from the LE state. Nevertheless, in the PMMA film, excimers-like structures form, resulting in the emergence of a longer wavelength band and a reduction in emission intensity. The zenith of emission intensity occurs when molecules are dispersed at higher concentrations within PMMA, effectively diminishing the likelihood of excimer-like formations. Luminescent Solar Concentrators (LSC) were fabricated to validate these findings, and the optical efficiency was studied at varying concentrations of luminogen and PMMA.

On the Chemical and Biological Characteristics of Multifunctional Compounds for the Treatment of Parkinson's Disease.

Protein aggregation, mitochondrial dysfunction, iron dyshomeostasis, increased oxidative damage and inflammation are pathognomonic features of Parkinson's disease (PD) and other neurodegenerative disorders characterized by abnormal iron accumulation. Moreover, the existence of positive feed-back loops between these pathological components, which accelerate, and sometimes make irreversible, the neurodegenerative process, is apparent. At present, the available treatments for PD aim to relieve the symptoms, thus improving quality of life, but no treatments to stop the progression of the disease are available. Recently, the use of multifunctional compounds with the capacity to attack several of the key components of neurodegenerative processes has been proposed as a strategy to slow down the progression of neurodegenerative processes. For the treatment of PD specifically, the necessary properties of new-generation drugs should include mitochondrial destination, the center of iron-reactive oxygen species interaction, iron chelation capacity to decrease iron-mediated oxidative damage, the capacity to quench free radicals to decrease the risk of ferroptotic neuronal death, the capacity to disrupt α-synuclein aggregates and the capacity to decrease inflammatory conditions. Desirable additional characteristics are dopaminergic neurons to lessen unwanted secondary effects during long-term treatment, and the inhibition of the MAO-B and COMPT activities to increase intraneuronal dopamine content. On the basis of the published evidence, in this work, we review the molecular basis underlying the pathological events associated with PD and the clinical trials that have used single-target drugs to stop the progress of the disease. We also review the current information on multifunctional compounds that may be used for the treatment of PD and discuss the chemical characteristics that underlie their functionality. As a projection, some of these compounds or modifications could be used to treat diseases that share common pathology features with PD, such as Friedreich's ataxia, Multiple sclerosis, Huntington disease and Alzheimer's disease.

Antioxidant activity and enzymatic of lichen substances: A study based on cyclic voltammetry and theoretical.

The antioxidant activity of nine lichen substances, including methylatrarate (1), methyl haematommate (2), lobaric acid (3), fumarprotocetraric acid (4), sphaerophorin (5), subsphaeric acid (6), diffractaic acid (7), barbatolic acid (8) and salazinic acid (9) has been determined through cyclic voltammetry. The compounds 1-4 presented slopes close to the Nernst constant of 0.059 V, indicating a 2H+/2e- relation between protons and electrons, as long as the compounds 5, 6, 7, 8, and 9 present slopes between 0.037 V and 0.032 V, indicating a 1H+/2e- relation between protons and electrons. These results show a high free radical scavenging activity by means of the release of H+, suggesting an important antioxidant capacity of these molecules. Theoretical calculations of hydrogen bond dissociation enthalpies (BDE), proton affinities (PA), and Proton Transfer (PT) mechanisms, at M06-2x/6-311+G(d,p) level complement the experimental results. Computations support that the best antioxidant activity is obtained for the molecules (3, 4, 5, 6, 7 and 8), that have a carboxylic acid group close to a phenolic hydroxyl group, through hydrogen atomic transfer (HAT) and sequential proton loss electron transfer (SPLET) mechanisms. Additional computations were performed for modelling binding affinity of the lichen substances with CYPs enzymes, mainly CYP1A2, CYP51, and CYP2C9*2 isoforms, showing strong affinity for all the compounds described in this study.

Green ultrasound-assisted extraction of lichen substances from Hypotrachyna cirrhata. Ethyl lactate, a better extracting agent than methanol toxic organic solvent?

For the first time, we report a green extraction of lichen substances assisted by high power ultrasounds from Hypotrachyna cirrhata using ethyl lactate. This sustainable alternative was comparable, both in isolation and detection of lichen substances, to methanol. In the metabolomic analysis, a total of 77 lichen substances were detected comprising depsides, depsidones, dibenzofurans, organic acids, and lipids. Although the UHPLC/ESI/MS profiles were similar, the antioxidant activity was higher for the ethyl lactate extract. Ethyl lactate can replace toxic organic solvents, such as methanol, in order to provide more sustainable green chemistry methods.

A sustainable application for the extraction of lichen metabolites from Usnea cornuta: nontargeted metabolomics and antioxidant activity.

In this study, isolation and purification of lichen substances from Usnea cornuta were performed using conventional solvents, green solvents and green technologies. In addition, several lichen compounds were tentatively identified by UHPLC/ESI/MS/MS and usnic acid, diffractaic and galbinic acids were quantified as well. Limonene, ethyl lactate and methanol, were compared regarding their extraction properties and antioxidant capacities, determined by DPPH, ORAC, and FRAP assays. In the ethyl lactate, methanol and limonene extracts, 28 compounds in all, were detected for the first time by high resolution UHPLC-MS/MS fingerprinting. Untargeted metabolomics tentatively identified 14 compounds from the methanolic extract, 4 from limonene extract, and 20 metabolites from ethyl lactate extract. The green extract of ethyl lactate showed a similar antioxidant capacity to toxic methanol extract, except at ORAC assay where it was higher. Therefore, ethyl lactate can replace methanol, to provide more sustainable green chemistry methods.

A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson's Disease.

Coumarins are plant-derived polyphenolic compounds belonging to the benzopyrones family, possessing wide-ranging pharmaceutical applications including cytoprotection, which may translate into therapeutic potential for multiple diseases, including Parkinson's disease (PD). Here we demonstrate the neuroprotective potential of a new polyhydroxyl coumarin, N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide (CT51), against the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+). MPP+'s mechanism of toxicity relates to its ability to inhibit complex I of the mitochondrial electron transport chain (METC), leading to adenosine triphosphate (ATP) depletion, increased reactive oxygen species (ROS) production, and apoptotic cell death, hence mimicking PD-related neuropathology. Dopaminergic differentiated human neuroblastoma cells were briefly pretreated with CT51, followed by toxin exposure. CT51 significantly restored somatic cell viability and neurite processes; hence, the drug targets cell bodies and axons thereby preserving neural function and circuitry against PD-related damage. Moreover, MPP+ emulates the iron dyshomeostasis affecting dopaminergic neurons in PD-affected brains, whilst CT51 was previously revealed as an effective iron chelator that preferentially partitions to mitochondria. We extend these findings by characterising the drug's interactive effects at the METC level. CT51 did not improve mitochondrial coupling efficiency. However, voltammetric measurements and high-resolution respirometry analysis revealed that CT51 acts as an antioxidant agent. Also, the neuronal protection afforded by CT51 associated with downregulating MPP+-induced upregulated expression of hypoxia-inducible factor 1 alpha (HIF-1α), a protein which regulates iron homeostasis and protects against certain forms of oxidative stress after translocating to mitochondria. Our findings support the further development of CT51 as a dual functioning iron chelator and antioxidant antiparkinsonian agent.

Search for Novel Potent Inhibitors of the SARS-CoV-2 Papain-like Enzyme: A Computational Biochemistry Approach.

The rapid emergence and spread of new variants of coronavirus type 2, as well as the emergence of zoonotic viruses, highlights the need for methodologies that contribute to the search for new pharmacological treatments. In the present work, we searched for new SARS-CoV-2 papain-like protease inhibitors in the PubChem database, which has more than 100 million compounds. Based on the ligand efficacy index obtained by molecular docking, 500 compounds with higher affinity than another experimentally tested inhibitor were selected. Finally, the seven compounds with ADME parameters within the acceptable range for such a drug were selected. Next, molecular dynamics simulation studies at 200 ns, ΔG calculations using molecular mechanics with generalized Born and surface solvation, and quantum mechanical calculations were performed with the selected compounds. Using this in silico protocol, seven papain-like protease inhibitors are proposed: three compounds with similar free energy (D28, D04, and D59) and three compounds with higher binding free energy (D60, D99, and D06) than the experimentally tested inhibitor, plus one compound (D24) that could bind to the ubiquitin-binding region and reduce the effect on the host immune system. The proposed compounds could be used in in vitro assays, and the described protocol could be used for smart drug design.

UHPLC-MS Metabolomic Fingerprinting, Antioxidant, and Enzyme Inhibition Activities of Himantormia lugubris from Antarctica.

Himantormia lugubris is a Chilean native small lichen shrub growing in the Antarctica region. In this study, the metabolite fingerprinting and the antioxidant and enzyme inhibitory potential from this species and its four major isolated compounds were investigated for the first time. Using ultra-high performance liquid chromatography coupled to quadrupole-Orbitrap mass spectrometry analysis (UHPLC-Q-Orbitrap-MS), several metabolites were identified including specific compounds as chemotaxonomical markers, while major metabolites were quantified in this species. A good inhibition activity against cholinesterase (acetylcholinesterase (AChE) IC50: 12.38 ± 0.09 µg/mL, butyrylcholinesterase (BChE) IC50: 31.54 ± 0.20 µg/mL) and tyrosinase (22.32 ± 0.21 µg/mL) enzymes of the alcoholic extract and the main compounds (IC50: 28.82 ± 0.10 µg/mL, 36.43 ± 0.08 µg/mL, and 7.25 ± 0.18 µg/mL, respectively, for the most active phenolic atranol) was found. The extract showed a total phenolic content of 47.4 + 0.0 mg of gallic acid equivalents/g. In addition, antioxidant activity was assessed using bleaching of DPPH and ORAC (IC50: 75.3 ± 0.02 µg/mL and 32.7 ± 0.7 µmol Trolox/g lichen, respectively) and FRAP (27.8 ± 0.0 µmol Trolox equivalent/g) experiments. The findings suggest that H. lugubris is a rich source of bioactive compounds with potentiality in the prevention of neurodegenerative or noncommunicable chronic diseases.

In vitro and in silico analysis of galanthine from Zephyranthes carinata as an inhibitor of acetylcholinesterase.

Zephyranthes carinata Herb., a specie of the Amaryllidoideae subfamily, has been reported to have inhibitory activity against acetylcholinesterase. However, scientific evidence related to their bioactive alkaloids has been lacking. Thus, this study describes the isolation of the alkaloids of this plant, and their inhibition of the enzymes acetylcholinesterase (eeAChE) and butyrylcholinesterase (eqBuChE), being galanthine the main component. Additionally, haemanthamine, hamayne, lycoramine, lycorine, tazettine, trisphaeridine and vittatine/crinine were also isolated. The results showed that galanthine has significant activity at low micromolar concentrations for eeAChE (IC50 = 1.96 µg/mL). The in-silico study allowed to establish at a molecular level the high affinity and the way galanthine interacts with the active site of the TcAChE enzyme, information that corroborates the result of the experimental IC50. However, according to molecular dynamics (MD) analysis, it is also suggested that galanthine presents a different inhibition mode that the one observed for galanthamine, by presenting interaction with peripheral anionic binding site of the enzyme, which prevents the entrance and exit of molecules from the active site. Thus, in vitro screening assays plus rapid computer development play an essential role in the search for new cholinesterase inhibitors by identifying unknown bio-interactions between bioactive compounds and biological targets.

Elicitation of isoflavonoids in Colombian edible legume plants with jasmonates and structurally related compounds.

Common bean (Phaseolus vulgaris L.), soybean (Glycine max L.) and mung bean (Vigna radiata L. Wilczek) seedlings were treated with methyl jasmonate (MeJA); then, dose-response and time-course experiments were carried out. Isoflavonoid composition was evaluated by high performance liquid chromatography. As a result of MeJA induction, all leguminous plants increase the amount of isoflavonoids, at levels that depend on the concentration of the elicitor and the time after induction. However, the application of MeJA in concentrations higher than 2.22 mM showed deleterious effects on seedlings and strong decreases in the concentration of isoflavonoids. In addition, a series of compounds structurally related to MeJA, such as jasmonic acid, cis-jasmone, coronatine, and indanoyl derivatives, were evaluated as elicitors. The results show that coronatine and the indanoyl-amino acids conjugates displayed a significant elicitor effect of isoflavonoids in common bean (cvs. Cargamanto Mocho and Corpoica LAS 106) and soybean (cv. Soyica P-34) seedlings, even higher than that found with the recognized elicitors, benzo (1,2,3) thiadiazole-7-carbothioic acid S-methyl ester (acibenzolar S-methyl) and benzo-(1,2,3) thiadiazole-7-carbothioic acid (acibenzolar acid). Leguminous plants can be treated with jasmonates and indanoyl derivatives to increase levels of bioactive isoflavonoids and consequently improve biological and functional properties and resistance against pests.

Phylogenetic Studies and Metabolite Analysis of Sticta Species from Colombia and Chile by Ultra-High Performance Liquid Chromatography-High Resolution-Q-Orbitrap-Mass Spectrometry.

Eleven species of lichens of the genus Sticta, ten of which were collected in Colombia (S. pseudosylvatica S. luteocyphellata S. cf. andina S. cf. hypoglabra, S. cordillerana, S. cf. gyalocarpa S. leucoblepharis, S. parahumboldtii S. impressula, S. ocaniensis) and one collected in Chile (S. lineariloba), were analyzed for the first time using hyphenated liquid chromatography with high-resolution mass spectrometry. In the metabolomic analysis, a total of 189 peaks were tentatively detected; the analyses were divided in five (5) groups of compounds comprising lipids, small phenolic compounds, saturated acids, terpenes, and typical phenolic lichen compounds such as depsides, depsidones and anthraquinones. The metabolome profiles of these eleven species are important since some compounds were identified as chemical markers for the fast identification of Sticta lichens for the first time. Finally, the usefulness of chemical compounds in comparison to traditional morphological traits to the study of ancestor-descendant relationships in the genus was assessed. Chemical and morphological consensus trees were not consistent with each other and recovered different relationships between taxa.

Theobroma cacao L. compounds: Theoretical study and molecular modeling as inhibitors of main SARS-CoV-2 protease.

Cocoa beans contain antioxidant molecules with the potential to inhibit type 2 coronavirus (SARS-CoV-2), which causes a severe acute respiratory syndrome (COVID-19). In particular, protease. Therefore, using in silico tests, 30 molecules obtained from cocoa were evaluated. Using molecular docking and quantum mechanics calculations, the chemical properties and binding efficiency of each ligand was evaluated, which allowed the selection of 5 compounds of this series. The ability of amentoflavone, isorhoifolin, nicotiflorin, naringin and rutin to bind to the main viral protease was studied by means of free energy calculations and structural analysis performed from molecular dynamics simulations of the enzyme/inhibitor complex. Isorhoifolin and rutin stand out, presenting a more negative binding ΔG than the reference inhibitor N-[(5-methylisoxazol-3-yl)carbonyl]alanyl-l-valyl-N~1~-((1R,2Z)-4-(benzyloxy)-4-oxo-1-{[(3R)-2-oxopyrrolidin-3-yl]methyl}but-2-enyl)-L-leucinamide (N3). These results are consistent with high affinities of these molecules for the major SARS-CoV-2. The results presented in this paper are a solid starting point for future in vitro and in vivo experiments aiming to validate these molecules and /or test similar substances as inhibitors of SARS-CoV-2 protease.

Coumarin-Chalcone Hybrids as Inhibitors of MAO-B: Biological Activity and In Silico Studies.

Fourteen coumarin-derived compounds modified at the C3 carbon of coumarin with an α,ß-unsaturated ketone were synthesized. These compounds may be designated as chalcocoumarins (3-cinnamoyl-2H-chromen-2-ones). Both chalcones and coumarins are recognized scaffolds in medicinal chemistry, showing diverse biological and pharmacological properties among which neuroprotective activities and multiple enzyme inhibition, including mitochondrial enzyme systems, stand out. The evaluation of monoamine oxidase B (MAO-B) inhibitors has aroused considerable interest as therapeutic agents for neurodegenerative diseases such as Parkinson's. Of the fourteen chalcocumarins evaluated here against MAO-B, ChC4 showed the strongest activity in vitro, with IC50 = 0.76 ± 0.08 µM. Computational docking, molecular dynamics and MM/GBSA studies, confirm that ChC4 binds very stably to the active rMAO-B site, explaining the experimental inhibition data.

In Vitro Anthelmintic Evaluation of Gliricidia sepium, Leucaena leucocephala, and Pithecellobium dulce: Fingerprint Analysis of Extracts by UHPLC-Orbitrap Mass Spectrometry.

In the present work, the anthelmintic activity (AA) of ethanolic extracts obtained from Gliricidia sepium, Leucaena leucocephala, and Pithecellobium dulce was evaluated using the third-stage-larval (L3) exsheathment inhibition test (LEIT) and egg hatch test (EHT) on Haemonchus contortus. Extracts were tested at concentrations of 0.3, 0.6, 1.2, 2.5, 5.0, 10, 20, and 40 mg/mL. The larval exsheathment inhibition (LEI) results showed that G. sepium achieved the highest average inhibition of 91.2%, compared with 44.6% for P. dulce and 41.0% for L. leucocephala at a concentration of 40 mg/mL; the corresponding IC50 values were 22.4, 41.7, and 43.3 mg/mL, respectively. The rates of egg hatching inhibition (EHI) at a concentration of 5 mg/mL were 99.5% for G. sepium, 64.2% for P. dulce, and 54% for L. leucocephala; the corresponding IC50 values were 1.9 mg/mL for G. sepium, 3.9 mg/mL for P. dulce, and 4.3 mg/mL for L. leucocephala. The species extracts studied here were also analyzed by ultra-high performance liquid chromatography and Orbitrap high resolution mass spectrometry (UHPLC-Q/Orbitrap/MS/MS), resulting in the compounds' identification associated with AA. Glycosylated flavonoids and methoxyphenols were observed in all three species: fatty acids in G. sepium and P. dulce; phenylpropanoids, anthraquinone glycosides, amino acids and glycosylated phenolic acids in G. sepium; and flavonoids in L. leucocephala. Comparatively, G. sepium presented a greater diversity of compounds potentially active against the control of gastrointestinal nematodes, which was associated with the results obtained in the applied tests.

Biosystem Analysis of the Hypoxia Inducible Domain Family Member 2A: Implications in Cancer Biology.

The expression of HIGD2A is dependent on oxygen levels, glucose concentration, and cell cycle progression. This gene encodes for protein HIG2A, found in mitochondria and the nucleus, promoting cell survival in hypoxic conditions. The genomic location of HIGD2A is in chromosome 5q35.2, where several chromosomal abnormalities are related to numerous cancers. The analysis of high definition expression profiles of HIGD2A suggests a role for HIG2A in cancer biology. Accordingly, the research objective was to perform a molecular biosystem analysis of HIGD2A aiming to discover HIG2A implications in cancer biology. For this purpose, public databases such as SWISS-MODEL protein structure homology-modelling server, Catalogue of Somatic Mutations in Cancer (COSMIC), Gene Expression Omnibus (GEO), MethHC: a database of DNA methylation and gene expression in human cancer, and microRNA-target interactions database (miRTarBase) were accessed. We also evaluated, by using Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR), the expression of Higd2a gene in healthy bone marrow-liver-spleen tissues of mice after quercetin (50 mg/kg) treatment. Thus, among the structural features of HIG2A protein that may participate in HIG2A translocation to the nucleus are an importin -dependent nuclear localization signal (NLS), a motif of DNA binding residues and a probable SUMOylating residue. HIGD2A gene is not implicated in cancer via mutation. In addition, DNA methylation and mRNA expression of HIGD2A gene present significant alterations in several cancers; HIGD2A gene showed significant higher expression in Diffuse Large B-cell Lymphoma (DLBCL). Hypoxic tissues characterize the "bone marrow-liver-spleen" DLBCL type. The relative quantification, by using RT-qPCR, showed that Higd2a expression is higher in bone marrow than in the liver or spleen. In addition, it was observed that quercetin modulated the expression of Higd2a gene in mice. As an assembly factor of mitochondrial respirasomes, HIG2A might be unexpectedly involved in the change of cellular energetics happening in cancer. As a result, it is worth continuing to explore the role of HIGD2A in cancer biology.

Development of a Low-Cost UV-Vis Spectrophotometer and Its Application for the Detection of Mercuric Ions Assisted by Chemosensors.

Detection of an environmental contaminant requires the use of expensive measurement equipment, which limits the realization of in situ tests because of their high cost, their limited portability, or the extended time duration of the tests. This paper presents in detail the development of a portable low-cost spectrophotometer which, by using a specialized chemosensor, allows detection of mercuric ions (Hg2+), providing effective and accurate results. Design specifications for all the stages assembling the spectrophotometer and the elements selected to build them are presented along with the process to synthesize the chemosensor and the tests developed to validate its performance in comparison with a high-precision commercial laboratory spectrophotometer.

In Silico Study of Coumarins and Quinolines Derivatives as Potent Inhibitors of SARS-CoV-2 Main Protease.

The pandemic that started in Wuhan (China) in 2019 has caused a large number of deaths, and infected people around the world due to the absence of effective therapy against coronavirus 2 of the severe acute respiratory syndrome (SARS-CoV-2). Viral maturation requires the activity of the main viral protease (Mpro), so its inhibition stops the progress of the disease. To evaluate possible inhibitors, a computational model of the SARS-CoV-2 enzyme Mpro was constructed in complex with 26 synthetic ligands derived from coumarins and quinolines. Analysis of simulations of molecular dynamics and molecular docking of the models show a high affinity for the enzyme (∆E binding between -5.1 and 7.1 kcal mol-1). The six compounds with the highest affinity show K d between 6.26 × 10-6 and 17.2 × 10-6, with binding affinity between -20 and -25 kcal mol-1, with ligand efficiency less than 0.3 associated with possible inhibitory candidates. In addition to the high affinity of these compounds for SARS-CoV-2 Mpro, low toxicity is expected considering the Lipinski, Veber and Pfizer rules. Therefore, this novel study provides candidate inhibitors that would allow experimental studies which can lead to the development of new treatments for SARS-CoV-2.

A selective thioxothiazolidin-coumarin probe for Hg2+ based on its desulfurization reaction. Exploring its potential for live cell imaging.

Sensing the most toxic heavy metal (mercury) has attracted a lot of attention in recent years due to its extreme harmfulness to both human health and the environment. Thus, we reported herein the synthesis, spectroscopic and kinetic characterization, and biological evaluation of a new thioxothiazolidin coumarin derivative (ILA92), which undergoes a desulfurization reaction induced by mercuric ions (Hg2+). This process is the origin of a selective sensing of Hg2+ ions in aqueous solution by colorimetric and fluorescent methods. Furthermore, the probe showed great potential for imaging Hg2+ in living cells.

Theoretical Study of the Antioxidant Activity of Quercetin Oxidation Products.

It was recently shown that, when tested in cellular systems, quercetin oxidized products (Qox) have significantly better antioxidant activity than quercetin (Q) itself. The main Qox identified in the experiments are either 2,5,7,3',4'-pentahydroxy-3,4-flavandione (Fl) or its tautomer, 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H)-benzofuranone (Bf). We have now performed a theoretical evaluation of different physicochemical properties using density functional theory (DFT) calculations on Q and its main Qox species. The most stable structures (for Q and Qox) were identified after a structural search on their potential energy surface. Since proton affinities (PAs) are much lower than the bond dissociation enthalpies (BDEs) of phenolic hydrogens, we consider that direct antioxidant activity in these species is mainly due to the sequential proton loss electron transfer (SPLET) mechanism. Moreover, our kinetic studies, according to transition state theory, show that Q is more favored by this mechanism. However, Qox have lower PAs than Q, suggesting that antioxidant activity by the SPLET mechanism should be a result of a balance between proclivity to transfer protons (which favors Qox) and the reaction kinetics of the conjugated base in the sequential electron transfer mechanism (which favors Q). Therefore, our results support the idea that Q is a better direct antioxidant than its oxidized derivatives due to its kinetically favored SPLET reactions. Moreover, our molecular docking calculations indicate a stabilizing interaction between either Q or Qox and the kelch-like ECH-associated protein-1 (Keap1), in the nuclear factor erythroid 2-related factor 2 (Nrf2)-binding site. This should favor the release of the Nrf2 factor, the master regulator of anti-oxidative responses, promoting the expression of the antioxidant responsive element (ARE)-dependent genes. Interestingly, the computed Keap1-metabolite interaction energy is most favored for the Bf compound, which in turn is the most stable oxidized tautomer, according to their computed energies. These results provide further support for the hypothesis that Qox species may be better indirect antioxidants than Q, reducing reactive oxygen species in animal cells by activating endogenous antioxidants.