Search

Herein we describe the design of natural curcumin ester and ether derivatives and their application as potential bioplasticizers, to prepare photosensitive phthalate-free PVC-based materials. The preparation of PVC-based films incorporating several loadings of newly synthesized curcumin derivatives along with their standard solid-state characterization is also described. Remarkably, the plasticizing effect of the curcumin derivatives in the PVC material was found to be similar to that observed in previous PVC–phthalate materials. Finally, studies applying these new materials in the photoinactivation of S. aureus planktonic cultures revealed a strong structure/activity correlation, with the photosensitive materials reaching up to 6 log CFU reduction at low irradiation intensities.

In 2021, our research group published the prominent anticancer activity achieved through the successful combination of two redox centres (ortho-quinone/para-quinone or quinone/selenium-containing triazole) through a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The combination of two naphthoquinoidal substrates towards a synergetic product was indicated, but not fully explored. Herein, we report the synthesis of 15 new quinone-based derivatives prepared from click chemistry reactions and their subsequent evaluation against nine cancer cell lines and the murine fibroblast line L929. Our strategy was based on the modification of the A-ring of para-naphthoquinones and subsequent conjugation with different ortho-quinoidal moieties. As anticipated, our study identified several compounds with IC50 values below 0.5 µM in tumour cell lines. Some of the compounds described here also exhibited an excellent selectivity index and low cytotoxicity on L929, the control cell line. The antitumour evaluation of the compounds separately and in their conjugated form proved that the activity is strongly enhanced in the derivatives containing two redox centres. Thus, our study confirms the efficiency of using A-ring functionalized para-quinones coupled with ortho-quinones to obtain a diverse range of two redox centre compounds with potential applications against cancer cell lines. Here as well, it literally takes two for an efficient tango!

The genus Ulex comprises thirteen accepted species of perennial shrubs in the family Fabaceae. In Galicia (Spain) many of these are considered spontaneous colonizing species, which are easy to establish and maintain. Among them, Ulex gallii Planch. is used in traditional medicine for the same anti-infective, hypotensive and diuretic purposes as Ulex europaeus L., which is the most studied species. Likewise, some studies have described the antitumoral properties of several species. However, there are few scientific studies that justify the use of Ulex gallii Planch. and nothing has been reported about its composition to date. In our study, the entire plant was extracted with methanol and the crude extract was subjected to liquid phase extraction with distinct solvents, yielding three fractions: hexane (H), dichloromethane (D) and methanol (M), which were subsequently fractionated. The dichloromethane (D5, D7 and D8) and methanol (M4) sub-fractions showed antiproliferative activity on A549 (lung cancer) and AGS (stomach cancer) cell lines, and caspase 3/7 activity assessment and DNA quantification were also performed. Targeted analysis via UHPLC-QToF, in combination with untargeted analysis via MS-Dial, MS-Finder and Global Natural Products Social Molecular Networking (GNPS), allowed us to tentatively identify different metabolites in these sub-fractions, mostly flavonoids, that might be involved in their antiproliferative activity.

In this study, the health-promoting benefits of different fruits grown in Madeira Island, namely lemon (Citrus limon var. eureka), tangerine (Citrus reticulata var. setubalense), pitanga (Eugenia uniflora var. red), tomato (Solanum lycopersicum var. gordal) and uva-da-serra, an endemic blueberry (Vaccinium padifolium Sm.), were investigated. The phenolic composition (total phenolics and total flavonoids content) and antioxidant capacity (assessed through ABTS and DPPH assays) were measured revealing a high phenolic potential for all fruits, except tomato, while uva-da-serra is particularly rich in flavonoids. In relation to the antioxidant capacity, the highest values were obtained for pitanga and uva-da-serra extracts. The bioactive potential was also assessed through the ability of the extracts to inhibit digestive enzymes linked to diabetes (α-amylase, α- and β-glucosidases) and hypertension (angiotensin-converting enzyme, ACE). The results obtained point to a very high bioactive potential with the selected samples exhibiting very important ACE anti-enzymatic capacities. A statistical analysis of the obtained data reveals a very strong correlation between ABTS and TPC, and a strong contribution of the fruit polyphenols for enzyme inhibition, and thus, presenting high antihypertensive and antidiabetic capacities. Overall, the results obtained clearly show a high bioactive potential of the selected fruits that should be further studied, in terms of specific phenolic composition. Moreover, these results strongly support the valorisation of pitanga seeds usually discarded as a waste, and uva-da-serra, an endemic and wild bush, as potential bioresources of bioactive compounds with impact in human diet.

A pharmacophore model for inhibitors of Escherichia coli’s DNA Gyrase B was developed, using computer-aided drug design. Subsequently, docking studies showed that 2,5(6)-substituted benzimidazole derivatives are promising molecules, as they possess key hydrogen bond donor/acceptor groups for an efficient interaction with this bacterial target. Furthermore, 5(6)-bromo-2-(2-nitrophenyl)-1H-benzimidazole, selected as a core molecule, was prepared on a multi-gram scale through condensation of 4-bromo-1,2-diaminobenzene with 2-nitrobenzaldehyde using a sustainable approach. The challenging functionalization of the 5(6)-position was carried out via palladium-catalyzed Suzuki–Miyaura and Buchwald-Hartwig amination cross-coupling reactions between N-protected-5-bromo-2-nitrophenyl-benzimidazole and aryl boronic acids or sulfonylanilines, with yields up to 81%. The final designed molecules (2-(aminophen-2-yl)-5(6)-substituted-1H-benzimidazoles), which encompass the appropriate functional groups in the 5(6)-position according to the pharmacophore model, were obtained in yields up to 91% after acid-mediated N-boc deprotection followed by Pd-catalyzed hydrogenation. These groups are predicted to favor interactions with DNA gyrase B residues Asn46, Asp73, and Asp173, aiming to promote an inhibitory effect.

18 pages, 14 figures.-- This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license, Optosensing chitosan-based membranes have been applied for the detection of heavy metals, especially in drinking water. The novelty of this study is based on the use of sulphated polysaccharides, in such optosensing membranes, aiming at an improved analytical performance. The sulphated polysaccharides, such as ulvan, fucoidan and chondroitin sulfate, were extracted from by-products and wastes of marine-related activities. The membranes were developed for the analysis of aluminum. The variation in the visible absorbance of the sensor membranes after the contact between the chromophore and the aluminum cation was studied. The membranes containing sulphated polysaccharides showed improved signals when compared to the chitosan-only membrane. As for the detection limits for the membranes containing ulvan, fucoidan and chondroitin sulfate, 0.17 mg L−1, 0.21 mg L−1 and 0.36 mg L−1 were obtained, respectively. The values were much lower than that obtained for the chitosan-only membrane, 0.52 mg L−1, which shows the improvement obtained from the sulphated polysaccharides. The results were obtained with the presence of CTAB in analysis solution, which forms a ternary complex with the aluminum cation and the chromophore. This resulted in an hyperchromic and batochromic shift in the absorption band. When in the presence of this surfactant, the membranes showed lower detection limits and higher selectivity, This work was financed by Programa de Cooperação Transfronteiriça Espanha—Portugal through the Fundo Europeu de Desenvolvimento Regional (FEDER) with support from the European Union under the project CVMAR+i. Additional financial support was granted from CIQUP (UIDB/00081/2020 and UIDP/00081/2020) and IMS (LA/P/0056/2020)

The potential of plant extracts as bioinsecticides has been described as a promising field of agricultural development. In this work, the extracts of Punica granatum (pomegranate), Phytolacca americana (American pokeweed), Glandora prostrata (shrubby gromwell), Ulex europaeus (gorce), Tagetes patula (French marigold), Camellia japonica red (camellia), Ruta graveolens (rue or herb-of-grace) were obtained, purified, and their activity against Spodoptera frugiperda (Sf9) insect cells was investigated. From the pool of over twenty extracts obtained, comprising different polarities and vegetable materials, less polar samples were shown to be more toxic towards the insect cell line Sf9. Among these, a dichloromethane extract of R. graveolens was capable of causing a loss of viability of over 50%, exceeding the effect of the commercial insecticide chlorpyrifos. This extract elicited chromatin condensation and the fragmentation in treated cells. Nanoencapsulation assays of the cytotoxic plant extracts in soybean liposomes and chitosan nanostructures were carried out. The nanosystems exhibited sizes lower or around 200 nm, low polydispersity, and generally high encapsulation efficiencies. Release assays showed that chitosan nanoemulsions provide a fast and total extract release, while liposome-based systems are suitable for a more delayed release. These results represent a proof-of-concept for the future development of bioinsecticide nanoformulations based on the cytotoxic plant extracts., This research was funded by COMPETE 2020 program, co-financed by the FEDER and the European Union, PTDC/ASP-AGR/30154/2017 (POCI-01-0145-FEDER-030154). Foundation for Science and Technology (FCT, Portugal), and FEDER-COMPETE-QREN-EU funded research centers CQ-UM(UIDB/00686/2020), CF-UM-UP (UIDB/04650/2020) and REQUIMTE (UIDB/50006/2020).

Isopentyl caffeate (ICaf) is a bioactive ester widely distributed in nature. Our patented work has shown promising results of this molecule against Leishmania. However, ICaf shows poor solubility, which limits its usage in clinical settings. In this work, we have proposed the development of an inclusion complex of ICaf in &beta, cyclodextrin (&beta, CD), with the aim to improve the drug solubility, and thus, its bioavailability. The inclusion complex (ICaf:&beta, CD) was developed applying three distinct methods, i.e., physical mixture (PM), kneading (KN) or co-evaporation (CO) in different molar proportions (0.25:1, 1:1 and 2:1). Characterization of the complexes was carried out by thermal analysis, Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and molecular docking. The ICaf:&beta, CD complex in a molar ratio of 1:1 obtained by CO showed the best complexation and, therefore, was selected for further analysis. Solubility assay showed a marked improvement in the ICaf:&beta, CD (CO, 1:1) solubility profile when compared to the pure ICaf compound. Cell proliferation assay using ICaf:&beta, CD complex showed an IC50 of 3.8 and 2.7 &micro, g/mL against L. amazonesis and L. chagasi promastigotes, respectively. These results demonstrate the great potential of the inclusion complex to improve the treatment options for visceral and cutaneous leishmaniases.

Fostered by the advances in the instrumental and analytical fields, in recent years the analysis of volatile organic compounds (VOCs) has emerged as a new frontier in medical diagnostics. VOCs analysis is a non-invasive, rapid and inexpensive strategy with promising potential in clinical diagnostic procedures. Since cellular metabolism is altered by diseases, the resulting metabolic effects on VOCs may serve as biomarkers for any given pathophysiologic condition. Human VOCs are released from biomatrices such as saliva, urine, skin emanations and exhaled breath and are derived from many metabolic pathways. In this review, the potential of VOCs present in saliva will be explored as a monitoring tool for several oral diseases, including gingivitis and periodontal disease, dental caries, and oral cancer. Moreover, the analytical state-of-the-art for salivary volatomics, e.g., the most common extraction techniques along with the current challenges and future perspectives will be addressed unequivocally.

The synthesis and structural modulation of five pro-ligand salts was achieved using alternative sustainable synthetic strategies, the use of microwaves being the method of choice, with an 81% yield and an E factor of 43 for 3d. After complexation with Fe3(CO)12 by direct reaction with the appropriate pro-ligands at 130 &deg, C, a set of iron(II) N-heterocyclic carbene (NHC) complexes were isolated and fully characterized (via 1H and 13C NMR and IR spectroscopy and elemental analysis). The antibacterial activities of the iron(II)-NHC complexes were tested against standard World Health Organization priority bacterial strains: Staphylococcus aureus ATCC 29213 and Escherichia coli ATCC 25922. The results showed a significant effect of the Fe(II)-NHC side-chain on the antibacterial activity against both Gram-negative and Gram-positive bacteria. Among all compounds, the most lipophilic iron complex, 3b, was found to be the most active one, with a minimum inhibitory concentration of 8 &micro, g/mL. Pioneering mechanistic studies suggested an alternative mechanism of action (OH&middot, formation), which opens the way for the development of a new class of antibiotics.

Green extraction techniques (GreETs) emerged in the last decade as greener and sustainable alternatives to classical sample preparation procedures aiming to improve the selectivity and sensitivity of analytical methods, simultaneously reducing the deleterious side effects of classical extraction techniques (CETs) for both the operator and the environment. The implementation of improved processes that overcome the main constraints of classical methods in terms of efficiency and ability to minimize or eliminate the use and generation of harmful substances will promote more efficient use of energy and resources in close association with the principles supporting the concept of green chemistry. The current review aims to update the state of the art of some cutting-edge GreETs developed and implemented in recent years focusing on the improvement of the main analytical features, practical aspects, and relevant applications in the biological, food, and environmental fields. Approaches to improve and accelerate the extraction efficiency and to lower solvent consumption, including sorbent-based techniques, such as solid-phase microextraction (SPME) and fabric-phase sorbent extraction (FPSE), and solvent-based techniques (μQuEChERS; micro quick, easy, cheap, effective, rugged, and safe), ultrasound-assisted extraction (UAE), and microwave-assisted extraction (MAE), in addition to supercritical fluid extraction (SFE) and pressurized solvent extraction (PSE), are highlighted., This research was funded by FCT (Fundação para a Ciência e a Tecnologia) through the CQM Base Fund, UIDB/00674/2020, Programmatic Fund, UIDP/00674/2020, and CEB—Centre of Biological Engineering, and by ARDITI (Agência Regional para o Desenvolvimento da Investigação Tecnologia e Inovação) through the project M1420-01-0145-FEDER-000005, Centro de Química da Madeira (CQM+; Madeira 14-20 Program). The authors also acknowledge FCT and the Madeira 14–20 Program to the Portuguese Mass Spectrometry Network (RNEM) through the PROEQUIPRAM program, M14-20 M1420-01-0145-FEDER-000008). ARDITI is also acknowledged for the postdoctoral fellowship granted to J.A.M.P. (Project M1420-09-5369-FSE-000001)., info:eu-repo/semantics/publishedVersion

A series of β-amino alcohols were prepared by the reaction of eugenol epoxide with aliphatic and aromatic amine nucleophiles. The synthesized compounds were fully characterized and evaluated as potential insecticides through the assessment of their biological activity against Sf9 insect cells, compared with a commercial synthetic pesticide (chlorpyrifos, CHPY). Three derivatives bearing a terminal benzene ring, either substituted or unsubstituted, were identified as the most potent molecules, two of them displaying higher toxicity to insect cells than CHPY. In addition, the most promising molecules were able to increase the activity of serine proteases (caspases) pivotal to apoptosis and were more toxic to insect cells than human cells. Structure-based inverted virtual screening and molecular dynamics simulations demonstrate that these molecules likely target acetylcholinesterase and/or the insect odorant-binding proteins and are able to form stable complexes with these proteins. Encapsulation assays in liposomes of DMPG and DPPC/DMPG (1:1) were performed for the most active compound, and high encapsulation efficiencies were obtained. A thermosensitive formulation was achieved with the compound release being more efficient at higher temperatures., This research was funded by project PTDC/ASP-AGR/30154/2017 (POCI-01-0145-FEDER-030154) of the COMPETE 2020 program, co-financed by the FEDER and the European Union. The authors acknowledge also the Foundation for Science and Technology (FCT, Portugal) and FEDER-COMPETE-QREN-EU for financial support to the research centers CQ-UM (UID/QUI/00686/2020), CF-UM-UP (UIDB/04650/2020) and REQUIMTE (UIDB/50006/2020). The NMR spectrometer Bruker Avance III 400 is part of the National NMR Network and was purchased within the framework of the National Program for Scientific Re-equipment, contract REDE/1517/RMN/2005 with funds from POCI 2010 (FEDER) and FCT.

Predominantly spread in West Tropical Africa, the shrub Salacia senegalensis (Lam.) DC. is known because of its medicinal properties, the leaves being used in the treatment of skin diseases. Prompted by the ethnomedicinal use, a hydroethanolic extract obtained from the leaves of the plant was screened against a panel of microbial strains, the majority of which involved in superficial infections. The extract was found to be active against the dermatophytes Trichophyton rubrum and Epidermophyton floccosum. Notable results were also recorded regarding the attenuation of the inflammatory response, namely the inhibitory effects observed against soybean 5-lipoxygenase (IC50 = 71.14 &mu, g mL&minus, 1), no interference being recorded in the cellular viability of RAW 264.7 macrophages and NO levels. Relevantly, the extract did not lead to detrimental effects against the keratinocyte cell line HaCaT, at concentrations displaying antidermatophytic and anti-inflammatory effects. Flavonoid profiling of S. senegalensis leaves was achieved for the first time, allowing the identification and quantitation of myricitrin, three 3-O-substituted quercetin derivatives, and three other flavonoid derivatives, which may contribute, at least partially, to the observed antidermatophytic and anti-inflammatory effects. In the current study, the plant S. senegalensis is assessed concerning its antidermatophytic and anti-inflammatory properties.

There is an urgent need for the discovery of new antileishmanial drugs with a new mechanism of action. Type 2 NADH dehydrogenase from Leishmania infantum (LiNDH2) is an enzyme of the parasite’s respiratory system, which catalyzes the electron transfer from NADH to ubiquinone without coupled proton pumping. In previous studies of the related NADH: ubiquinone oxidoreductase crystal structure from Saccharomyces cerevisiae, two ubiquinone-binding sites (UQI and UQII) were identified and shown to play an important role in the NDH-2-catalyzed oxidoreduction reaction. Based on the available structural data, we developed a three-dimensional structural model of LiNDH2 using homology detection methods and performed an in silico virtual screening campaign to search for potential inhibitors targeting the LiNDH2 ubiquinone-binding site 1–UQI. Selected compounds displaying favorable properties in the computational screening experiments were assayed for inhibitory activity in the structurally similar recombinant NDH-2 from S. aureus and leishmanicidal activity was determined in the wild-type axenic amastigotes and promastigotes of L. infantum. The identified compound, a substituted 6-methoxy-quinalidine, showed promising nanomolar leishmanicidal activity on wild-type axenic promastigotes and amastigotes of L. infantum and the potential for further development. Acknowledgments: The authors would like to gratefully acknowledge COST Action CM1307 “Targeted chemotherapy towards diseases caused by endoparasites” and COST Action CM1306–Understanding Movement and Mechanism in Molecular Machines. This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant no. 173001) and Ministry of Higher Education, Science and Technology of the Republic of Slovenia through Grant P1-0012. FVS and FMS are recipients of fellowships from Fundação para a Ciência e a Tecnologia (PD/BD/113985/2015, PD/BD/128213/2016, respectively, within the scope of the PhD program Molecular Biosciences PD/00133/2012). The work was also funded by Fundação para a Ciência e a Tecnologia FCT (IF/01507/2015 to MMP) and the Norte-01-0145-FEDER-000012-Structured program on bioengineered therapies for infectious diseases and tissue regeneration, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). We thank Kaja Bergant for her kind assistance with Figure preparations.

In recent years, few classes of natural products have received as much attention as phenolics and polyphenols. This special issue of Molecules, “Phenolics and Polyphenolics”, is a remarkable confirmation of this trend. Several aspects related to phenolics chemistry, comprising the several classes, will be discussed. In addition, the increasing interest in phenolics’ biological activities is covered, and several works addressing this matter are referred.

Herein we report the synthesis of unsymmetrical meso-aryl substituted porphyrins, using NaY zeolite as an inorganic acid catalyst. A comparative study between this method and the several synthetic strategies available in the literature was carried out. Our method presented a better, more cost-efficient rationale and displayed a significantly lower environmental impact. Furthermore, it was possible to verify the scalability of the process as well as the reutilization of the inorganic catalyst NaY (up to 6 times) without significant yield decrease. In addition, this method was applied to the synthesis of several other unsymmetrical porphyrins, from a low melting point porphyrin to mono-carboxylated halogenated unsymmetrical porphyrins, in yields higher than those found in the literature. Additionally, for the first time, two acetamide functionalized halogenated porphyrins were prepared in high yields. This methodology opens the way to the preparation of high yielding functionalized porphyrins, which can be easily immobilized for a variety of applications, either in catalysis or in biomedicine.