Polymorphs of Substituted p-Toluenesulfonanilide: Synthesis, Single-Crystal Analysis, Hirshfeld Surface Exploration, and Theoretical Investigation.

Polymorphism is an exciting feature of chemical systems where a compound can exist in different crystal forms. The present investigation is focused on the two polymorphic forms, triclinic (MSBT) and monoclinic (MSBM), of ethyl 3-iodo-4-((4-methylphenyl)sulfonamido)benzoate prepared from ethyl 4-amino-3-iodobenzoate. The prepared polymorphs were unambiguously confirmed by single-crystal X-ray diffraction (SC-XRD) analysis. According to the SC-XRD results, the molecular configurations of both structures are stabilized by intramolecular N-H···I and C-H···O bonding. The crystal packing of MSBT is different as compared to the crystal packing of MSBM because MSBT is crystallized in the triclinic crystal system with the space group P1̅, whereas MSBM is crystallized in the monoclinic crystal system with the space group P21/c. The molecules of MSBT are interlinked in the form of dimers through N-H···O bonding to form R22(8) loops, while the MSBM molecules are connected with each other in the form of an infinite chain through C-H···O bonding. The crystal packing of both compounds is further stabilized by off-set π···π stacking interactions between phenyl rings, which is found stronger in MSBM as compared to in MSBT. Moreover, Hirshfeld surface exploration of the polymorphs was carried out, and the results were compared with the closely related literature structure. Accordingly, the supramolecular assembly of these polymorphs is mainly stabilized by noncovalent interactions or intermolecular interactions. Furthermore, a density functional theory (DFT) study was also carried out, which provided good support for the SC-XRD and Hirshfeld studies, suggesting the formation of both intramolecular and intermolecular interactions for both compounds.

Effects of Extraction Methods on Phenolic Content, Antioxidant and Antiplatelet Activities of Tomato Pomace Extracts.

Aqueous and ethanolic extracts of tomato pomace were examined with the aim of optimizing the extraction process of compounds with cardioprotective activity. Once the results of the ORAC response variables, total polyphenols, °Brix, and antiplatelet activity of the extracts were obtained, a multivariate statistical analysis was performed using the Statgraphics Centurion XIX software. This analysis showed that the most relevant positive effects in the inhibition of platelet aggregation were 83 ± 2% when using the agonist TRAP-6, when the working conditions were the type of tomato pomace conditioning (drum-drying process at 115 °C), phase ratio (1/8), type of solvent (ethanol 20%), and type of extraction (ultrasound-assisted solid-liquid extraction). The extracts with the best results were microencapsulated and characterized by HPLC. The presence of chlorogenic acid (0.729 mg/mg of dry sample) was found, a compound that has a potential cardioprotective effect documented in various studies, in addition to rutin (2.747 mg/mg of dry sample) and quercetin (0.255 mg/mg of dry sample). These results show that the extraction efficiency of compounds with cardioprotective activity depends largely on the polarity of the solvent, thus playing an important role in the antioxidant capacity of the extracts of tomato pomace.

A Comprehensive Literature Review on Cardioprotective Effects of Bioactive Compounds Present in Fruits of Aristotelia chilensis Stuntz (Maqui).

Some fruits and vegetables, rich in bioactive compounds such as polyphenols, flavonoids, and anthocyanins, may inhibit platelet activation pathways and therefore reduce the risk of suffering from CVD when consumed regularly. Aristotelia chilensis Stuntz (Maqui) is a shrub or tree native to Chile with outstanding antioxidant activity, associated with its high content in anthocyanins, polyphenols, and flavonoids. Previous studies reveal different pharmacological properties for this berry, but its cardioprotective potential has been little studied. Despite having an abundant composition, and being rich in bioactive products with an antiplatelet role, there are few studies linking this berry with antiplatelet activity. This review summarizes and discusses relevant information on the cardioprotective potential of Maqui, based on its composition of bioactive compounds, mainly as a nutraceutical antiplatelet agent. Articles published between 2000 and 2022 in the following bibliographic databases were selected: PubMed, ScienceDirect, and Google Scholar. Our search revealed that Maqui is a promising cardiovascular target since extracts from this berry have direct effects on the reduction in cardiovascular risk factors (glucose index, obesity, diabetes, among others). Although studies on antiplatelet activity in this fruit are recent, its rich chemical composition clearly shows that the presence of chemical compounds (anthocyanins, flavonoids, phenolic acids, among others) with high antiplatelet potential can provide this berry with antiplatelet properties. These bioactive compounds have antiplatelet effects with multiple targets in the platelet, particularly, they have been related to the inhibition of thromboxane, thrombin, ADP, and GPVI receptors, or through the pathways by which these receptors stimulate platelet aggregation. Detailed studies are needed to clarify this gap in the literature, as well as to specifically evaluate the mechanism of action of Maqui extracts, due to the presence of phenolic compounds.

Determination of the Bioactive Effect of Custard Apple By-Products by In Vitro Assays.

Annona cherimola fruit, known as cherimoya or custard apple, is an exotic fruit from South America but is strongly produced in Andalusia, Spain. Its by-products (seeds and peel) are recognised as important sources of antioxidants, including phenolic acids, flavonoids and procyanidins. Therefore, the aim of this study was to carry out the characterization of its phenolic composition and to in vitro evaluate the bioactivity of custard apple seed and peel. Therefore, high performance liquid chromatography coupled to mass spectrometry (HPLC-ESI-qTOF-MS) was performed in order to tentatively identify their phenolic composition. In the end, 19 compounds were identified and quantified, some of them for the first time in the custard apple matrix. Then, seed and peel total phenolic content, as well as antioxidant properties, radical scavenging capacity (O2, NO, HOCl) and inhibition of enzymes involved in different pathologies (hyaluronidase, elastase, collagenase, tyrosinase, acetylcholinesterase and xanthine oxidase), were evaluated. Although both extracts showed almost similar antioxidant capacities, custard apple seed stood out slightly more than peel (171 ± 2 vs. 130.0 ± 0.4 µmol TE/g DE, resp.), especially as ·NO scavenger (IC50 1.5 ± 0.2 vs. 11.8 ± 0.3 mg/L, resp.) and hyaluronidase inhibitor (IC50 170 ± 10 vs. 460 ± 20mg/L, resp.). Finally, the application of extracts on a real human model of platelet aggregation was performed, reporting antiaggregatory effects in agonist-promoted platelet thrombus formation. All these results show that custard apple by-products are stated as interesting sources of bioactive compounds with multiple industrial applications for the development of high-added-value products, such as functional foods, nutraceuticals and cosmeceuticals, promoting the circular bioeconomy of these by-products.

Biological Evaluation of Avocado Residues as a Potential Source of Bioactive Compounds.

Avocado seed and peel are the main by-products from avocado industrialisation, and account for nearly 30% of fruit weight. Although they are usually discarded, their high phenolic content has been deeply associated with several nutritional and functional benefits. Thus, for a comprehensive analytical evaluation of both semi-industrial extracts, various steps have been developed: tentative characterisation and quantification of the phenolic composition using HPLC-ESI-qTOF-MS, determination of TPC and antioxidant activity by Folin-Ciocalteu, FRAP, TEAC and ORAC methods, evaluation of scavenging capacity against different ROS and measurement of the enzymatic inhibitory potential against potentially harmful enzymes. Finally, their bioactive potential was tested in a human platelet model where antiaggregatory activity was measured. Hence, 48 different compounds were identified, where flavonoids and procyanidins were the most representative groups. The higher TPC was found in avocado peel extract (190 ± 3 mg/g), which showed more antioxidant power and more capacity to decrease ROS generation than seed extract (60 ± 2 mg/g). In addition, both extracts showed enzymatic inhibition, especially against hyaluronidase, xanthine oxidase and acetylcholinesterase. Lastly, avocado peel was proven to inhibit platelet aggregation with significant results at 1, 0.75 and 0.5 mg/mL, where the extract showed reducing effects on agonists' expression such as p-selectin or GPIIb/IIIa complex. These results demonstrate that both semi-industrial extracts-above all, avocado peel-have an interesting potential to be exploited as a natural by-product with antioxidant properties with multiple applications for the prevention of different pathologies.

Antioxidant Capacity and Antiplatelet Activity of Aqueous Extracts of Common Bean (Phaseolus vulgaris L.) Obtained with Microwave and Ultrasound Assisted Extraction.

Phaseolus vulgaris L. has beneficial effects on several chronic non-communicable diseases (e.g., cardiovascular diseases) related to oxidative stress. This redox state may influence platelet activation and aggregation; which is crucial in thrombus formation. In this work, the antiplatelet and antioxidant potential of aqueous extracts obtained by green processes, microwave-assisted extraction and ultrasound-assisted extraction, from 25 landraces of common beans were investigated. Phenol content and antioxidant potential were determined using the Folin-Ciocalteu method, total monomeric anthocyanin and ORAC assay, respectively. The antiplatelet potential of the extracts was explored by turbidimetry. Microwave extraction showed higher phenol content and antioxidant activity in most extracts. Soja landrace extract obtained by microwave-assisted extraction showed higher phenol content and antioxidant activity (893.45 ± 87.30 mg GAE/g and 35,642.85 ± 2588.88 ORAC µmolTE/g, respectively). Although most of the extracts obtained by microwave-assisted extraction showed antiplatelet activity, the extract of Hallado Aleman landrace obtained by ultrasound-assisted extraction (IC50 = 0.152 ± 0.018 mg/mL) had the highest antiplatelet potential. The extraction method, MAE and UAE, influences the biological potential of the beans, specifically the antiplatelet activity and antioxidant activity. The functional value of this legume for direct consumption by the population was evidenced, as well as its inclusion in food formulations.

Sweet Potato (Ipomoea batatas L.) Phenotypes: From Agroindustry to Health Effects.

Sweet potato (SP; Ipomoea batatas (L.) Lam) is an edible tuber native to America and the sixth most important food crop worldwide. China leads its production in a global market of USD 45 trillion. SP domesticated varieties differ in specific phenotypic/genotypic traits, yet all of them are rich in sugars, slow digestible/resistant starch, vitamins, minerals, bioactive proteins and lipids, carotenoids, polyphenols, ascorbic acid, alkaloids, coumarins, and saponins, in a genotype-dependent manner. Individually or synergistically, SP's phytochemicals help to prevent many illnesses, including certain types of cancers and cardiovascular disorders. These and other topics, including the production and market diversification of raw SP and its products, and SP's starch as a functional ingredient, are briefly discussed in this review.

Role of Phaseolus vulgaris L. in the Prevention of Cardiovascular Diseases-Cardioprotective Potential of Bioactive Compounds.

In terms of safe and healthy food, beans play a relevant role. This crop belongs to the species of Phaseolusvulgaris L., being the most consumed legume worldwide, both for poor and developed countries, the latter seek to direct their diet to healthy feeding, mainly low in fat. Phaseolus vulgaris L. stands out in this area-an important source of protein, vitamins, essential minerals, soluble fiber, starch, phytochemicals, and low in fat from foods. This species has been attributed many beneficial properties for health; it has effects on the circulatory system, immune system, digestive system, among others. It has been suggested that Phaseolus vulgaris L. has a relevant role in the prevention of cardiovascular events, the main cause of mortality and morbidity worldwide. Conversely, the decrease in the consumption of this legume has been related to an increase in the prevalence of cardiovascular diseases. This review will allow us to relate the nutritional level of this species with cardiovascular events, based on the correlation of the main bioactive compounds and their role as cardiovascular protectors, in addition to revealing the main mechanisms that explain the cardioprotective effects regulated by the bioactive components.

Antiplatelet Activity of Cucurbita maxima.

Natural extracts constitute an important source in the prevention of noncommunicable diseases, such as cardiovascular diseases. The pumpkin, Cucurbita maxima, is widely consumed in Chile. Pumpkin seeds, despite having crude protein, lipids, and carbohydrates, are regarded as agro-industrial waste. In this work, we correlated the antiplatelet activity of aqueous, ethanolic, and methanolic extracts from pumpkin seeds with their bioactive compounds. In vitro platelet aggregation and activation studies were performed by turbidimetry and flow cytometry, respectively. Results reveal that the extracts inhibited, in a dose-dependent manner, platelet aggregation induced by adenosine diphosphate, thrombin receptor activator peptide 6 (TRAP-6), and collagen. Pumpkin seed extracts inhibited P-selectin secretion and glycoprotein IIb/IIIa activation on TRAP-6-activated platelets. They were found to be rich in fatty acids and a powerful source of plant-based protein, which could be related to the high antiplatelet potential identified in extracts. This research demonstrated that pumpkin seed extracts could be a candidate in the prevention of thrombotic events.

Antiplatelet Activity of Isorhamnetin via Mitochondrial Regulation.

With the diet, we ingest nutrients capable of modulating platelet function, which plays a crucial role in developing cardiovascular events, one of the leading causes of mortality worldwide. Studies that demonstrate the antiplatelet and antithrombotic potential of bioactive compounds are vital to maintaining good cardiovascular health. In this work, we evaluate the flavonol isorhamnetin's antiplatelet effect on human platelets, using collagen, thrombin receptor activator peptide 6 (TRAP-6), and phorbol myristate acetate (PMA) as agonists. Isorhamnetin induced a significant inhibition on collagen- and TRAP-6-induced platelet aggregation, with half-maximum inhibitory concentration (IC50) values of 8.1 ± 2.6 and 16.1 ± 11.1 µM, respectively; while it did not show cytotoxic effect. Isorhamnetin reduced adenosine triphosphate levels (ATP) in platelets stimulated by collagen and TRAP-6. We also evidenced that isorhamnetin's antiplatelet activity was related to the inhibition of mitochondrial function without effect on reactive oxygen species (ROS) levels. Additionally, we investigated isorhamnetin's effect on thrombus formation in vitro under flow conditions on the damaged vessel wall. In this context, we demonstrate that isorhamnetin at 20 µM induced a significant inhibition on platelet deposition, confirming its antithrombotic effect. Our findings corroborate the antiplatelet and antithrombotic potential of isorhamnetin present in many foods of daily consumption.

Antiplatelet activity and chemical analysis of leaf and fruit extracts from Aristotelia chilensis.

Aristotelia chilensis (Mol.) Stuntz, also known as maqui, is a plant native to Chile without chemical characterization and quantification of the bioactive compounds present in it. HPLC-UV and HPLC-MS/MS studies have shown the presence, at different concentrations, of phenolic and anthocyanin compounds in fruit and leave extracts of the domesticated maqui clones Luna Nueva, Morena, and Perla Negra. The extracts from leaves and unripe fruits of Luna Nueva and Morena clones significantly inhibit platelet aggregation induced by several agonists; the extracts inhibit platelet granule secretion by decreasing the exposure of P-selectin and CD63 at the platelet membrane. Reactive oxygen species formation in platelets is lower in the presence of maqui extracts. Statistical Pearson analysis supports the levels of phenolic and anthocyanin compounds being responsible for the antiaggregant maqui effects. This work is the first evidence of antiplatelet activity from Aristotelia chilensis giving added value to the use of leaves and unripe fruits from this species.

The Role of Coffee and its Bioactive Components in Platelet Function and Aging.

Cardiovascular diseases (CVD) are known to be the world's leading cause of death and different factors are known to increase the risk of death, including aging, mainly due to increased oxidative stress and inflammation observed in older people. Acute myocardial infarctions and cerebrovascular accidents belong to CVD, and are the ones that cause the most deaths and disabilities, where greater platelet activation plays an important role in pathophysiology. These diseases are more prevalent in older people, which have a clear relationship with increased platelet function and are strongly related to aging. Platelet function is affected by diet, which varies in its requirements and characteristics according to age. Coffee belongs to the family of diet elements that can alter platelet function and an increase in coffee consumption with advancing age, and a U-shaped correlation with the risk of CVD have been reported. However, the effect of coffee consumption and its bioactive compounds on platelet function and aging presents controversial evidence, and therefore, a complex effect is not fully elucidated in the cardiovascular system. This review focuses on the relationship between coffee consumption (and its constituent bioactive compounds), and platelet function, and aging.

Anti-platelet activity and chemical characterization by UPLC-DAD-ESI-QTOF-MS of the main polyphenols in extracts from Psidium leaves and fruits.

In Costa Rica, two species of Psidium fruits, P. guajava and P. friedrichsthalianum, are widely consumed as food and used in folk medicine. Although studies have revealed the health effects of these fruits, there has been little research showing the antiplatelet activity of these species. This work evaluated the antiplatelet potential of aqueous extracts made from leaves and fruits of pink guava and Costa Rican guava. Platelet aggregation was induced by the platelet agonists ADP, TRAP-6, collagen and PMA. Platelet activation and secretion were studied using flow cytometry. The chemical profiles of the four extracts were characterized using UPLC-DAD-ESI-QTOF-MS. The studies revealed that the aqueous extracts of leaves and fruits of P. guajava and P. friedrichsthalianum inhibited platelet aggregation induced by ADP (4 µM), TRAP-6 (5 µM), collagen (1 µg mL-1) and PMA (100 nM), and the effect was dependent on the extract concentration. Extracts of leaves and fruits of pink guava and Costa Rican guava reduced secretion of P-selectin and activation of GP IIb/IIIa. The extracts of leaves and fruits of pink guava and Costa Rican guava proved to be a rich source of phenolic compounds, mainly quercetin aglycones and proanthocyanidins derived from (epi) catechin units. Other compounds such as ellagitannins, and benzophenones were also putatively identified. This research showed that P. guajava and P. friedrichsthalianum could potentially be used for the prevention of thrombotic events.

Functional fermented cherimoya (Annona cherimola Mill.) juice using autochthonous lactic acid bacteria.

The biochemical and functional properties of fermented Annona cherimola Mill. (cherimoya) juice using five lactic acid bacteria (LAB) isolated from autochthonous fruits from Northwestern Argentina were studied in this work. Fermentation was carried out at 30 °C for 48 h followed by a 21 day-storage period at 4 °C. The assayed LAB grew well during fermentation (final count of 108 CFU/mL, ΔpH ca. 1 U) and survived after the storage period. All strains consumed fructose and glucose present in cherimoya juice as energy sources, with the consequent synthesis of lactic and/or acetic acids as final metabolic products. However, only two of the five evaluated strains were capable to produce fermented cherimoya juices with a perceptible color change. Due to lactic acid fermentation, a moderate reduction in the total phenolic content (between 13% and 43%) was observed in the majority of the samples, although no change in the antioxidant capacity was detected. The fermented cherimoya juices showed a weak antiplatelet activity when adenosine diphosphate agonist was used. The findings of this study evidenced the potential use of Annona cherimola Mill. fermented juice as a novel matrix for the formulation of stable functional beverages with appealing nutritional and functional properties.

Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes.

Nef is an HIV-encoded accessory protein that enhances pathogenicity by down-regulating major histocompatibility class I (MHC-I) expression to evade killing by cytotoxic T lymphocytes (CTLs). A potent Nef inhibitor that restores MHC-I is needed to promote immune-mediated clearance of HIV-infected cells. We discovered that the plecomacrolide family of natural products restored MHC-I to the surface of Nef-expressing primary cells with variable potency. Concanamycin A (CMA) counteracted Nef at subnanomolar concentrations that did not interfere with lysosomal acidification or degradation and were nontoxic in primary cell cultures. CMA specifically reversed Nef-mediated down-regulation of MHC-I, but not CD4, and cells treated with CMA showed reduced formation of the Nef:MHC-I:AP-1 complex required for MHC-I down-regulation. CMA restored expression of diverse allotypes of MHC-I in Nef-expressing cells and inhibited Nef alleles from divergent clades of HIV and simian immunodeficiency virus, including from primary patient isolates. Lastly, we found that restoration of MHC-I in HIV-infected cells was accompanied by enhanced CTL-mediated clearance of infected cells comparable to genetic deletion of Nef. Thus, we propose CMA as a lead compound for therapeutic inhibition of Nef to enhance immune-mediated clearance of HIV-infected cells.

Adipostatins E-J, New Potent Antimicrobials Identified as Inhibitors of Coenzyme-A Biosynthesis.

Phosphopantetheine is a key structural element in biological acyl transfer reactions found embedded within coenzyme A (CoA). Phosphopantothenoylcysteine synthetase (PPCS) is responsible for installing a cysteamine group within phosphopantetheine. Therefore, it holds considerable potential as a drug target for developing new antimicrobials. In this study, we adapted a biochemical assay specific for bacterial PPCS to screen for inhibitors of CoA biosynthesis against a library of marine microbial derived natural product extracts (NPEs). Analysis of the NPE derived from Streptomyces blancoensis led to the isolation of novel antibiotics (10-12, and 14) from the adipostatin class of molecules. The most potent molecule (10) displayed in vitro activity with IC50= 0.93 µM, against S. pneumoniae PPCS. The whole cell antimicrobial assay against isolated molecules demonstrated their ability to penetrate bacterial cells and inhibit clinically relevant pathogenic strains. This establishes the validity of PPCS as a pertinent drug target, and the value of NPEs to provide new antibiotics.

Antiplatelet Activity of Natural Bioactive Extracts from Mango (Mangifera Indica L.) and its By-Products.

The potential antiplatelet aggregation effects of mango pulp and its by-products (peel, husk seed, and seed) due to the presence of bioactive compounds were explored. Among them, mango seed exhibited a 72% percentage inhibition of platelet aggregation induced by adenosine 5'-diphosphate (ADP) agonist with a demonstrated dose-dependent effect. This biological feature could be caused by the chemical differences in phenolic composition. Mango seed was especially rich in monogalloyl compounds, tetra- and penta-galloylglucose, ellagic acid, mangiferin, and benzophenones such as maclurin derivatives and iriflophenone glucoside. Mangiferin showed an inhibitory effect of 31%, suggesting its key role as one of the main contributors to the antiplatelet activity of mango seed. Therefore, mango seed could be postulated as a natural source of bioactive compounds with antiplatelet properties to design functional foods or complementary therapeutic treatments.

Chemoselective ratiometric imaging of protein S-sulfenylation.

Here we report a ratiometric fluorescent probe for chemoselective conjugation to sulfenic acids in living cells. Our approach couples an α-fluoro-substituted dimedone to an aminonaphthalene fluorophore (F-DiNap), which upon sulfenic acid conjugation is locked as the 1,3-diketone, changing the fluorophore excitation. F-DiNap reacts with S-sulfenylated proteins at equivalent rates to current probes, but the α-fluorine substitution blocks side-reactions with biological aldehydes.