Biological and Medicinal Properties of Natural Chromones and Chromanones.

Emerging threats to human health require a concerted effort to search for new treatment therapies. One of the biggest challenges is finding medicines with few or no side effects. Natural products have historically contributed to major advances in the field of pharmacotherapy, as they offer special characteristics compared to conventional synthetic molecules. Interest in natural products is being revitalized, in a continuous search for lead structures that can be used as models for the development of new medicines by the pharmaceutical industry. Chromone and chromanones are recognized as privileged structures and useful templates for the design of diversified therapeutic molecules with potential pharmacological interest. Chromones and chromanones are widely distributed in plants and fungi, and significant biological activities, namely antioxidant, anti-inflammatory, antimicrobial, antiviral, etc., have been reported for these compounds, suggesting their potential as lead drug candidates. This review aims to update the literature published over the last 6 years (2018-2023) regarding the natural occurrence and biological activity of chromones and chromanones, highlighting the recent findings and the perspectives that they hold for future research and applications namely in health, cosmetic, and food industries.

Isothiazolinone Biocides: Chemistry, Biological, and Toxicity Profiles.

The importance of isothiazole and of compounds containing the isothiazole nucleus has been growing over the last few years. Isothiazolinones are used in cosmetic and as chemical additives for occupational and industrial usage due to their bacteriostatic and fungiostatic activity. Despite their effectiveness as biocides, isothiazolinones are strong sensitizers, producing skin irritations and allergies and may pose ecotoxicological hazards. Therefore, their use is restricted by EU legislation. Considering the relevance and importance of isothiazolinone biocides, the present review describes the state-of-the-art knowledge regarding their synthesis, antibacterial components, toxicity (including structure-activity-toxicity relationships) outlines, and (photo)chemical stability. Due to the increasing prevalence and impact of isothiazolinones in consumer's health, analytical methods for the identification and determination of this type of biocides were also discussed.

Microencapsulation of caffeic acid phenethyl ester and caffeic acid phenethyl amide by inclusion in hydroxypropyl-ß-cyclodextrin.

Caffeic acid phenethyl ester (CAPE) is a bioactive polyphenolic compound obtained from propolis extract. Although it has a broad therapeutic potential, the bioavailability of CAPE is limited, due to reduced solubility and poor plasmatic stability. Efforts to reduce these pharmacokinetic drawbacks resulted in the synthesis of caffeic acid phenethyl amide (CAPA). Cyclodextrins have been proved as promising excipients for the formulation of active ingredients. Herein, we report the inclusion complexation behavior and binding ability of CAPE and CAPA with hydroxypropyl-ß-cyclodextrin (HP-ß-CD). The supramolecular interactions were examined through UV and FTIR spectroscopy, DSC, 1H NMR and 2D ROESY. The CAPE/HP-ß-CD and CAPA/HP-ß-CD inclusion complexes stability constants were determined to be, respectively, 2911.6 and 584.6 M-1 in water and 2866.2 and 700.1 M-1 at physiological pH. The aqueous solubility increased notably, proving that HP-ß-CD can be potentially useful to improve the biological, chemical and physical properties of CAPE and CAPA.

ß-Cyclodextrin carbon nanotube-enhanced sensor for ciprofloxacin detection.

A simple and expedite electrochemical methodology was developed for the determination of ciprofloxacin, based on a glassy carbon (GC) electrode modified by a combination of multi-walled carbon nanotubes (MWCNT) with ß-cyclodextrin (ß-CD) incorporated in a polyaniline film. The combined use of ß-CD and MWCNT in the electrochemical sensor leads to a significant signal improvement. The ß-CD/MWCNT modified GC electrode exhibited efficient electrocatalytic behavior in the oxidation of ciprofloxacin with relatively high sensitivity, stability and lifetime. Molecular modeling studies showed that ciprofloxacin binds preferably to ß-CD rather than to CNT edges, leading to an improved sensitivity of the sensor. Under optimized conditions, a linear calibration curve was obtained for ciprofloxacin in the concentration range 10-80 µM with a detection limit of 50 nM. The analytical performance of this sensor was evaluated for the detection of ciprofloxacin in a wastewater treatment plant effluent.

Effects of chlorophenoxy herbicides and their main transformation products on DNA damage and acetylcholinesterase activity.

Persistent pesticide transformation products (TPs) are increasingly being detected among different environmental compartments, including groundwater and surface water. However, there is no sufficient experimental data on their toxicological potential to assess the risk associated with TPs, even if their occurrence is known. In this study, the interaction of chlorophenoxy herbicides (MCPA, mecoprop, 2,4-D and dichlorprop) and their main transformation products with calf thymus DNA by UV-visible absorption spectroscopy has been assessed. Additionally, the toxicity of the chlorophenoxy herbicides and TPs was also assessed evaluating the inhibition of acetylcholinesterase activity. On the basis of the results found, it seems that AChE is not the main target of chlorophenoxy herbicides and their TPs. However, the results found showed that the transformation products displayed a higher inhibitory activity when compared with the parent herbicides. The results obtained in the DNA interaction studies showed, in general, a slight effect on the stability of the double helix. However, the data found for 4-chloro-2-methyl-6-nitrophenol suggest that this transformation product can interact with DNA through a noncovalent mode.

Hydroxycinnamic acid antioxidants: an electrochemical overview.

Hydroxycinnamic acids (such as ferulic, caffeic, sinapic, and p-coumaric acids) are a group of compounds highly abundant in food that may account for about one-third of the phenolic compounds in our diet. Hydroxycinnamic acids have gained an increasing interest in health because they are known to be potent antioxidants. These compounds have been described as chain-breaking antioxidants acting through radical scavenging activity, that is related to their hydrogen or electron donating capacity and to the ability to delocalize/stabilize the resulting phenoxyl radical within their structure. The free radical scavenger ability of antioxidants can be predicted from standard one-electron potentials. Thus, voltammetric methods have often been applied to characterize a diversity of natural and synthetic antioxidants essentially to get an insight into their mechanism and also as an important tool for the rational design of new and potent antioxidants. The structure-property-activity relationships (SPARs) correlations already established for this type of compounds suggest that redox potentials could be considered a good measure of antioxidant activity and an accurate guideline on the drug discovery and development process. Due to its magnitude in the antioxidant field, the electrochemistry of hydroxycinnamic acid-based antioxidants is reviewed highlighting the structure-property-activity relationships (SPARs) obtained so far.

Exploring nature profits: development of novel and potent lipophilic antioxidants based on galloyl-cinnamic hybrids.

Phenolic acids are ubiquitous antioxidants accounting for approximately one third of the phenolic compounds in our diet. Their importance was supported by epidemiological studies that suggest an inverse relationship between dietary intake of phenolic antioxidants and the occurrence of diseases, such as cancer and neurodegenerative disorders. However, until now, most of natural antioxidants have limited therapeutic success a fact that could be related with their limited distribution throughout the body and with the inherent difficulties to attain the target sites. The development of phenolic antioxidants based on a hybrid concept and structurally based on natural hydroxybenzoic (gallic acid) and hydroxycinnamic (caffeic acid) scaffolds seems to be a suitable solution to surpass the mentioned drawbacks. Galloyl-cinnamic hybrids were synthesized and their antioxidant activity as well as partition coefficients and redox potentials evaluated. The structure-property-activity relationship (SPAR) study revealed the existence of a correlation between the redox potentials and antioxidant activity. The galloyl-cinnamic acid hybrid stands out as the best antioxidant supplementing the effect of a blend of gallic acid plus caffeic acid endorsing the hypothesis that the whole is greater than the sum of the parts. In addition, some hybrid compounds possess an appropriate lipophilicity allowing their application as chain-breaking antioxidant in biomembranes or other type of lipidic systems. Their predicted ADME properties are also in accordance with the general requirements for drug-like compounds. Accordingly, these phenolic hybrids can be seen as potential antioxidants for tackling the oxidative status linked to the neurodegenerative, inflammatory or cancer processes.

Host-guest interaction between herbicide oxadiargyl and hydroxypropyl-ß-cyclodextrin.

In the face of a growing human population and increased urbanization, the demand for pesticides will simply rise. Farmers must escalate yields on increasingly fewer farm acres. However, the risks of pesticides, whether real or perceived, may force changes in the way these chemicals are used. Scientists are working toward pest control plans that are environmentally sound, effective, and profitable. In this context the development of new pesticide formulations which may improve application effectiveness, safety, handling, and storage can be pointed out as a solution. As a contribution to the area, the microencapsulation of the herbicide oxadiargyl (OXA) in (2-hydroxypropyl)-ß-cyclodextrin (HP-ß-CD) was performed. The study was conducted in different aqueous media (ultrapure water and in different pH buffer solutions). In all cases an increment of the oxadiargyl solubility as a function of the HP-ß-CD concentration that has been related to the formation of an inclusion complex was verified. UV-Vis and NMR experiments allowed concluding that the stoichiometry of the OXA/HP-ß-CD complex formed is 1 : 1. The gathered results can be regarded as an important step for its removal from industrial effluents and/or to increase the stabilizing action, encapsulation, and adsorption in water treatment plants.

Alkyl esters of hydroxycinnamic acids with improved antioxidant activity and lipophilicity protect PC12 cells against oxidative stress.

Hydroxycinnamic acids (HCAs) are phenolic compounds present in dietary plants, which possess considerable antioxidant activity. In order to increase the lipophilicity of HCAs, with the aim of improving their cellular absorption and expansion of their use in lipophilic media, methyl, ethyl, propyl and butyl esters of caffeic acid and ferulic acid have been synthesized. All caffeate esters had a slightly lower DPPH IC(50) (13.5-14.5 µM) and higher ferric reducing antioxidant power (FRAP) values (1490-1588 mM quercetin/mole [mMQ/mole]) compared to caffeic acid (16.6 µM and 1398 mMQ/mole, respectively) in antioxidant assays. In contrast, ferulate esters were less active in DPPH (56.3-74.7 µM) and FRAP assays (193-262 mMQ/mole) compared to ferulic acid (44.6 µM and 324 mMQ/mole, respectively). Redox properties of HCAs were in line with their antioxidant capacities, so that compounds with higher antioxidant activities had lower oxidation potentials. Measurement of partition coefficients disclosed the higher lipophilicity of the esters compared to parent compounds. All esters of caffeic acid significantly inhibited hydrogen peroxide-induced neuronal PC12 cell death assessed by MTT assay at 5 and 25 µM. However, caffeic acid, ferulic acid and ferulate esters were not able to protect the cells. In conclusion, these findings suggest that alkyl esterification of some HCAs augments their antioxidant properties as well as their lipophilicity and as a consequence, improves their cell protective activity against oxidative stress. These compounds could have useful applications in conditions where oxidative stress plays a pathogenic role.

Dietary phenolic acids and derivatives. Evaluation of the antioxidant activity of sinapic acid and its alkyl esters.

The action of sinapic acid and its alkyl esters as potential antioxidants has been investigated. For this purpose, a series of sinapic acid ester derivatives was synthesized and their antioxidant activities were evaluated using distinctive analytical methods, namely, 2,2-diphenyl-1-picrylhydrazyl (DPPH) and FRAP UV-vis methods and differential scanning calorimetry. The electron-donating activity and lipophilicity of these phenolic compounds were also evaluated. From the overall results it was concluded that alkyl ester sinapates (linear alkyl esters) present almost the same antioxidant activity, albeit slightly lower, exhibited by the parent compound (sinapic acid). Furthermore, the addition of an alkyl ester side chain has a positive effect on the partition coefficient of sinapic acid, improving its utility as an antioxidant in a more lipophilic medium. The data on the antioxidant activity obtained by different analytical methods correlated well with each other and have revealed interesting antioxidant data of alkyl esters of sinapic acid.

Lipophilic phenolic antioxidants: correlation between antioxidant profile, partition coefficients and redox properties.

Lipophilic compounds structurally based on caffeic, hydrocaffeic, ferulic and hydroferulic acids were synthesized. Subsequently, their antioxidant activity was evaluated as well as their partition coefficients and redox potentials. The structure-property-activity relationship (SPAR) results revealed the existence of a clear correlation between the redox potentials and the antioxidant activity. In addition, some compounds showed a proper lipophilicity to cross the blood-brain barrier. Their predicted ADME properties are also in accordance with the general requirements for potential CNS drugs. Accordingly, one can propose these phenolic compounds as potential antioxidants for tackling the oxidative status linked to the neurodegenerative processes.

Structure-property-activity relationship of phenolic acids and derivatives. Protocatechuic acid alkyl esters.

The esterification of hydrophilic phenolic antioxidants is an efficient approach to enhance their solubility in apolar media. Herein, structure-property studies on the antiradical activity of a series of protocatechuic acid alkyl esters have been accomplished. The increase of the lipophilicity was shown to significantly improve the antioxidant activity of protocatechuic esters. Their efficiency as radical scavengers was evaluated using distinctive analytical methods, namely, 2,2-diphenyl-1-picrylhydrazyl (DPPH) UV/visible method, electrochemistry, and differential scanning calorimetry. All the new alkyl protocatechuate antioxidants studied possessed better radical-scavenging capacity than the natural antioxidant protocatechuic acid. This work has shown that the alkyl ester side chain markedly influences the lipophilicity of this type of phenolic system without disturbing the core of the molecule responsible for antioxidant activity. The data on the antioxidant activity obtained using the different analytical methods correlated well with each other and have revealed the interesting antioxidant potential of alkyl esters of protocatechuic acid.

Fluoxetine and norfluoxetine revisited: new insights into the electrochemical and spectroscopic properties.

The extent to which humans and wildlife are exposed to the vast array of anthropogenic chemicals and their degradation products, along with related naturally occurring compounds, is nowadays an important issue. The study of the physical-chemical properties of the compounds and/or degradation products is an important subject because some of them are intrinsically related to its resistance to degradation and/or bioaccumulation. Accordingly, the study of the electrochemical behavior of the selective serotonin reuptake inhibitor fluoxetine and its main metabolite norfluoxetine was investigated. The identification of the oxidation processes was done via two fluoxetine analogues, 1-(benzyloxy)-4-(trifluoromethyl)benzene and N-methyl-3-phenylpropan-1-amine hydrochloride. The oxidative processes occurring in fluoxetine are pH-dependent and were ascribed to the chemical moieties present in the molecule: the secondary amine group and the substituted aromatic nucleus. To perform an unequivocal ascription, the structural preferences of the drug and metabolite were also determined, by Raman spectroscopy coupled to quantum mechanical calculations (at the DFT level). The analytical data obtained in this work will allow the development of a rapid and unequivocal spectroscopic procedure suitable for fluoxetine identification, as well as to distinguish between the drug and its main metabolite.

New insights into the antioxidant activity of hydroxycinnamic acids: Synthesis and physicochemical characterization of novel halogenated derivatives.

An interdisciplinary research project was developed combining the synthesis of a series of hydroxycinnamic acid derivatives and the evaluation of their physicochemical parameters (namely redox potentials and partition coefficients), along with the corresponding antioxidant activity. A structure-property-activity relationship (SPAR) approach was then applied aiming at establishing a putative relation between the physicochemical parameters of the compounds under study and their antioxidant activity. The results gathered allow concluding that the redox potentials could contribute to the understanding of the antioxidant activity and that the presence of an electron withdrawing group (EWG) of halogen type, namely a bromo atom, in an ortho position to a phenolic group of the cinnamic scaffold does not influence the antioxidant activity. On the other hand after the introduction of this type of substituent a significant increase on the lipophilicity of cinnamic derivatives was observed, which is a feature of extreme importance in the development of novel lipophilic antioxidants. The SPAR results revealed a relation between the redox potentials and the antioxidant activity of hydroxycinnamic acids and derivatives. The data obtained operate as a positive reinforce of the tendency to use redox properties as a guideline of the rational design of this type of compounds.