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Concerned about weed infestation, a major threat to food production and herbicide resistance that interferes in the mechanism of action of the main herbicides, we have synthesized eight isatin derivatives using the "Click Chemistry" approach through copper-catalyzed azide-alkyne cycloadditions (CuAAC). Sixteen isatin derivatives were evaluated for their phytotoxic activity against the seed culture of the model plants

The high morbidity and mortality rates of Candida infections, especially among immunocompromised patients, are related to the increased resistance rate of these species and the limited therapeutic arsenal. In this context, we evaluated the anti-Candida potential and the cytotoxic profile of eugenol derivatives. Anti-Candida activity was evaluated on C. albicans and C. parapsilosis strains by minimum inhibitory concentration (MIC), scanning electron microscopy (SEM), and molecular docking calculations at the site of the enzyme lanosterol-14-α-demethylase active site, responsible for ergosterol formation. The cytotoxic profile was evaluated in HepG2 cells, in the presence and absence of the metabolizing system (S9 system). The results indicated compounds 1b and 1d as the most active ones. The compounds have anti-Candida activity against both strains with MIC ranging from 50 to 100 μg ml

Objectives This study aimed to evaluate endophytic fungi isolated from Tocoyena bullata and Humiria balsamifera plant species for their antimycobacterial and anti-inflammatory activities, focusing on severe pulmonary tuberculosis cases which are often associated with exacerbated inflammation. Methods Mycobacterium suspensions were incubated with the samples for 5 days. RAW 264.7 macrophages stimulated with LPS were also incubated with them for 24 h to assess the inhibition of inflammatory mediator production and cytotoxicity. C57BL/6 mice were infected with Mtb M299 and treated for 15 days with lasiodiplodin (Lasio). Key findings Endophytic fungus Sordaria tamaensis, obtained from T. bullata, was the most promising. Its ethanolic extract impaired mycobacterial growth with MIC50 (µg/ml): 1.5 ± 0.6 (BCG), 66.8 ± 0.1 (H37Rv) and 80.0 ± 0.1 (M299). (R)-(+)-Lasio showed MIC50 92.2 ± 1.8 µg/ml (M299). In addition, Lasio was able to inhibit NO, IL-1β and TNF-α production and was not cytotoxic for macrophages. M. tuberculosis-infected C57BL/6 animals treated by Lasio reduced the number of acid-fast bacilli, lung pathology, leucocyte influx and proinflammatory cytokine production in the lungs. The class IIa fructose 1,6-bisphosphate aldolase was the predicted hypothetical target of Lasio. Conclusions (R)-(+)-Lasio stood out as a promising anti-TB compound, exhibiting anti-inflammatory and antimycobacterial effects, as well as low cytotoxicity.

The semisynthesis of 15 new thymol derivatives was achieved through Williamson synthesis and copper-catalyzed azide-alkyne cycloaddition (CuAAC) approaches. The reaction of CuAAC using the "Click Chemistry" strategy, in the presence of an alkynyl thymol derivative and commercial or prepared azides, provided nine thymol derivatives under microwave irradiation. This procedure reduces reaction time and cost. All molecular entities were elucidated by 1H and 13C NMR, IR, and HRMS data. These derivatives were evaluated in vitro for their fungicidal activity against Fusarium solani sp. Among the nine triazolic thymol derivatives obtained, seven of them were found to have moderated antifungal activity. In contrast, naphthoquinone/thymol hybrid ether 2b displayed activity comparable with that of the commercial fungicide thiabendazole. The structure-activity relationship for the most active compound 2b was discussed, and the mode of action was predicted by a possible binding to the fungic ergosterol and interference of osmotic balance of K+ into the extracellular medium.

Plant extracts from Dalbergia genus have demonstrated a wide range of biological activities including analgesic, antidiabetic, anti-inflammatory and antimicrobial. In this work, the chemical study of the extracts from the leaves and branches of Dalbergia miscolobium led to the identification of five isoflavonoids: prunetin, di- O -methyldaidzein, 8- O -methylretusin, duartin and sativan by means of nuclear magnetic resonance data. The inhibition activity of these isoflavonoids were screened against cathepsin V at concentration of 100 µM. Duartin and sativan showed remarkable activity against cathepsin V displaying inhibition values of 89% and 88%, respectively. In addition, docking simulations to predict the binding mode in this protein were performed and the results showed that the duartin is nicely bound to the cathepsin V and stabilized by two hydrogen bonds. The isoflavans duartin and sativan showed an important inhibition percentage of cathepsin V, which can be considered as targets into cathepsin V inhibitors investigation and further chemical study of Dalbergia species may afford novels isoflavonoids cathepsin inhibitors.

Background: Fusarium solani f. sp. piperis is a phytopathogen that causes one of the most destructive diseases in black pepper crops, resulting in significant economic and crop production losses. Consequently, the control of this fungal disease is a matter of current and relevant interest in agriculture. Objective: The objective was to synthesize eugenol derivatives with antifungal activity. Methods: In this study, using bimolecular nucleophilic substitution and click chemistry approaches, four new and three known eugenol derivatives were obtained. The eugenol derivatives were characterized and their antifungal and cytotoxic effects were evaluated. Results: Eugenol derivative 4 (2-(4-allyl-2-methoxyphenoxy)-3-chloronaphthalene-1,4-dione) was the most active against F. solani f. sp. piperis and showed acceptable cytotoxicity. Compound 4 was two-fold more effective than tebuconazole in an antifungal assay and presented similar cytotoxicity in macrophages. The in silico study of β-glucosidase suggests a potential interaction of 4 with amino acid residues by a cation-π interaction with residue Arg177 followed by a hydrogen bond with Glu596, indicating an important role in the interactions with 4, justifying the antifungal action of this compound. In addition, the cytotoxicity after metabolism was evaluated as a mimic assay with the S9 fraction in HepG2 cells. Compound 4 demonstrated maintenance of cytotoxicity, showing IC50 values of 11.18 ± 0.5 and 9.04 ± 0.2 μg mL-1 without and with the S9 fraction, respectively. In contrast, eugenol (257.9 ± 0.4 and 133.5 ± 0.8 μg mL-1), tebuconazole (34.94 ± 0.2 and 26.76 ± 0.17 μg mL-1) and especially carbendazim (251.0 ± 0.30 and 34.7 ± 0.10 μg mL-1) showed greater cytotoxicity after hepatic biotransformation. Conclusion: The results suggest that 4 is a potential candidate for use in the design of new and effective compounds that could control this pathogen.

Background: Effective cancer treatment is a major public health challenge. The limitations of current therapies and their adverse effects reduce the efficacy of treatment, leading to significant mortality rates worldwide. Moreover, natural product chemistry occupies a prominent role in the search for new treatment alternatives, by contributing a spectrum of chemical structures that may potentially yield new bioactive compounds. The compound [6]-gingerol (1) is the main active substance in ginger (Zingiber officinale) and several studies have shown it to produce beneficial effects, including antitumor activity. Objective: This work aims to obtain new gingerol derivatives with cytotoxic activity. Method: [6]-gingerol was isolated and its derivatives were produced using click chemistry, obtaining eight new compounds. All chemical structures were determined by means of IR, NMR and HRMS data, and cytotoxicity was evaluated in the HCT 116 (colon carcinoma) and MCF-7 (breast carcinoma) cell lines at concentrations of 5 µmol L-1 and 50 µmol L-1. Results: At 50 µmol L-1, more than 70% inhibition of cell growth was achieved with compounds 2e, 2g against HCT 116, and 2b, 2d, 2e, 2f and 2g against MCF-7. Conclusion: The obtained compounds showed only moderate cytotoxic activity. However, the products with substituents occupying the meta position in relation to the triazole ring showed increased cytotoxic properties. The brominated compound (2g) showed the strongest activity, inhibiting cell proliferation by 87%.

A cerveja e uma das bebidas alcoolicas mais antigas consumidas pela humanidade, tendo sido descoberta ha cerca de 7.000 anos. A bebida e composta por quatro ingredientes essenciais: agua, malte, lupulo e levedura. Quando consumida em quantidades moderadas, a cerveja pode trazer beneficios a saude semelhantes aos do vinho. Apesar da grande importância economica, cultural e cientifica que a cerveja possui, percebe-se a escassez de uma literatura em portugues voltada ao tema. Neste sentido, o presente trabalho tem como objetivo reunir informacoes presentes na literatura cientifica, apresentando os aspectos quimicos envolvidos na producao cervejeira, as tecnicas analiticas empregadas na caracterizacao da bebida, autenticacao e controle dos processos produtivos, assim como a atividade biologica que a cerveja possui. Dessa forma, na producao de cerveja sao observadas 5 etapas basicas, como a mostura, fervura, fermentacao, maturacao e envase, sendo avaliados na etapa final de producao o pH, acidez total, amargor, cor e teor alcoolico. Na identificacao dos compostos da cerveja, bem como na autenticacao e controle dos processos produtivos, as tecnicas analiticas utilizadas sao a espectroscopia na regiao do infravermelho (IV), ressonância magnetica nuclear de hidrogenio (RMN 1H), espectrometria de massas (MS) e cromatografia gasosa acoplada ao espectrometro de massas (CG-MS). Alem disso, estudos sobre as atividades biologicas de compostos presentes na cerveja revelam um potencial antioxidante, anti-inflamatorio, antimicrobiana, antitumoral, entre outros, ressaltando que o consumo moderado da bebida pode trazer beneficios na saude dos consumidores

Background: Amaryllidaceae plants are known to be a great source of alkaloids, which are considered an extensive group of compounds encompassing a wide range of biological activities. The remarkable cytotoxic activities observed in most of the Amaryllidaceae alkaloids derivatives have prompt the chemical and biological investigations in unexplored species from Brazil. Objective: To evaluate the cytotoxic and genotoxic properties of alkaloids of Griffinia gardneriana and Habranthus itaobinus bulbs and study the role of caspase-3 as a molecular apoptosis mediator. Methods: Methanolic crude extracts of Griffinia gardneriana and Habranthus itaobinus bulbs were submitted to acid-base extraction to obtain alkaloid-enriched fractions. The obtained fractions were fractionated using chromatographic techniques leading to isolation and identification of some alkaloids accomplished via HPLC and 1H-NMR, respectively. Molecular docking studies assessed the amount of free binding energy between the isolated alkaloids with the caspase-3 protein and also calculated the theoretical value of Ki. Studies have also been developed to evaluate in vitro cytotoxicity and genotoxicity in such alkaloids and apoptosis activation via the caspase pathway using both tumor and normal cell lines. Results: Seven alkaloids were isolated and identified. Among these, 11-hydroxyvittatine and 2-α-7- dimethoxyhomolycorine were not cytotoxic, whereas tazettine, trisphaeridine, and sanguinine only showed activity against the fibroblast lineage. Lycorine and pretazettine were 10 to 30 folds more cytotoxic than the other alkaloids, including cancerous lines, and were genotoxic and capable of promoting apoptosis via the caspase-3 pathway. This result supports data obtained in docking studies wherein these two compounds exhibited the highest free energy values. Conclusion: The cytotoxicity assay revealed that, among the seven alkaloids isolated, only lycorine and pretazettine were active against different cell lines, exhibiting concentration- and time-dependent cytotoxic actions alongside genotoxic action and the ability to induce apoptosis by caspase-3, a result consistent with those obtained in docking studies.

The semisynthesis of 15 new thymol derivatives was achieved through Williamson synthesis and copper-catalyzed azide-alkyne cycloaddition (CuAAC) approaches. The reaction of CuAAC using the "

The present work focused on the chemical study of the main alkaloid component in Brazilian indigenous Amaryllidaceae species Hippeastrum puniceum (Lam.) Kuntze. The strategy applied was based on a distinct partitioning process and chromatographic-purification steps using the crude methanolic extract as the starting material. In this way, the glycosylated derivative narciclasine-4-O-β-D-xylopyranoside was isolated from the ethyl acetate fraction of H. puniceum. Structural elucidation of the compound was performed through NMR (Nuclear Magnetic Resonance) analysis including mono- and bi-dimensional experiments. The absolute configuration was determined herein for the first time by means of X-Ray Crystallography. The compound was also evaluated as cytotoxic agent against colon (HCT 116) and breast (MCF-7) tumor cells, showing no significant activity at the tested concentrations of 10 and 50 μM.

Acetylcholinesterase (AChE) inhibitors remain the class of drugs used for the treatment of Alzheimer disease (AD). For the aim of discovering new sources of potent AChE inhibitors, a combined AChE-inhibitory activity together with alkaloid profiles by GC-MS, combined with multivariate statistical analysis for biomarkers determination and in silico studies were attempted. Strategy was applied on leaves, roots and bulbs of six aquatic and terrestrial Amaryllidaceae species. Thirty alkaloids were identified and the AChE inhibitory activities of the extracts were tested by in-vitro Ellman method. Principal bioactive markers were discovered by correlating AChE inhibitory activity with chemical fingerprints via PLS and OPLS modeling which revealed that galanthamine, lycoramine, caranine, tazettine and N-demethylgalanthamine were the most bio-significant markers. Furthermore, the molecular docking was performed to illustrate binding orientations of the top scoring alkaloids in the active site of human acetylcholinesterase. Suggested strategy revealed that, beside galanthamine, caranine, N-demethylgalanthamine, and lycoramine are promising AChE inhibitors.

Natural products are often used by the population to treat and/or prevent several disorders. Tucumã is an Amazonian fruit widely consumed by local population and no

Capsaicinoids are widely known for their pharmacological properties and are responsible for flavoring peppers through their pungent aroma. In turn, this pungency can be determined by quantifying the capsaicinoids present in peppers by means of chromatographic and spectroscopic techniques, or sensory analysis such as the Scoville scale. The present research presents a rapid and simple method for capsaicinoid quantification in commercial peppers by way of the relationship between analytes and an internal standard area resulting from 1H NMR analysis without the use of a deuterated solvent solution. Samples were diluted in a mixture of water and methanol, and then compared to a solution of maleic acid in deuterated water. For validation of the method, figures of merit such as selectivity, linearity, detection, and quantification limits, accuracy, precision, and robustness were obtained for capsaicin and dihydrocapsaicin. The presented method exhibits great linearity, with a correlation coefficient (R) of 0.9967, good accuracy for samples with concentration greater than 3 mg mL−1, with an error rate close to 3%, good robustness with minimal variation observed even one month after sample stored, good precision (

The use of conductive polymers (CPs) as a substrate in ambient paper spray ionization was achieved under high DC voltage. Some pharmaceuticals, drugs of abuse, adulterants, metabolites, and impurities showed a signal that was higher in absolute intensity compared to that of uncoated papers. Surface characterization of the coated paper confirmed that the modified features on the paper surface were responsible for high electrical fields, signal stability, and reusability. The linearity and performance of CP-coated papers were demonstrated for a range of forensically relevant analytes, proving that CP-coated papers are an easy and cheap alternative for use in both qualitative and quantitative analyses.

Hippeastrum psittacinum, Amaryllidaceae, is used in traditional medicine as a purgative, aphrodisiac, and anticough remedy. The ethanol extract (EE) and alkaloid-rich fractions (ARF) from H. psittacinum bulbs were evaluated for their acetylcholinesterase (AChE) inhibition. The EE cytotoxic and anti-inflammatory effects in RAW 264.7 cells, and the neuroprotective and genotoxic activities in SH-SY5Y cells, were also estimated. Fifteen alkaloids were identified in the EE by gas chromatography–mass spectrometry. ARFs were less active for AChE inhibition than EE. The viability of both cell lines was higher than 70% with EE concentrations below 25 μg/mL. The EE decreased nitrite release in RAW cells stimulated with lipopolysaccharide, showing values of 83, 67, and 53% at 6.25, 12.5, and 25 μg/mL, respectively. Furthermore, the EE partially protected SH-SY5Y cells from hydrogen peroxide-mediated deleterious effects by approximately 50% at the same concentrations. The micronucleus assays showed that the extract caused chromosomal missegregation at concentrations above 12.5 μg/mL. The in silico analyses showed that some alkaloids presented properties of permeation of the blood-brain barrier and the intestine. Our findings present new evidence of the potential of H. psittacinum potential as an AChE inhibitor, as well as an anti-inflammatory and neuroprotective agent.

Ecstasy is a synthetic drug whose main ingredient is 3,4-methylenedioxy-N-methylamphetamine (MDMA), as well as other sympathomimetic amines, including amphetamine (AP) and methamphetamine (MA). This drug is widespread and increasingly popular among young people worldwide and has become a very serious public health problem. The users become more sociable and communicative but also experience psychological disorders, such as changes in visual perception and euphoria. Ecstasy components have been determined in formulations and biological materials through various instrumental techniques, including (but not limited to) spectrophotometry, high-performance liquid chromatography (HPLC) with ultraviolet detection and/or tandem mass spectrometry, gas chromatography (GC) and capillary electrophoresis (CE). Usually, these methodologies involve elaborate sample preparation, with solid-phase extraction (SPE) and liquid–liquid extraction (LLE) being the most commonly employed. This overview includes the most relevant analytical methodologies (sample preparation and instrumental techniques) used to determine the ecstasy components in complex matrices.

Marijuana, a drug derived from the Cannabis sativa L. plant, is the world's most consumed illicit drug. In this paper, a total of 156 marijuana samples seized in the state of Espirito Santo (ES), Brazil were studied and analysed by proton nuclear magnetic resonance (1H NMR) spectroscopy to identify the major cannabinoids present. A crude extract of all samples was purified using high performance liquid chromatography so that these compounds could serve as reference substances. Nine fractions were obtained and analysed by 1H NMR and gas chromatography-mass spectrometry (GC-MS), with five presented cannabinoids. ∆9-THC (Δ9-trans-tetrahydrocannabinol), ∆9-THCA (∆9-tetrahydrocannabinolic acid), ∆8-THC (∆8-tetrahydrocannabinol), 11-hydroxycannabinol, CBV (cannabivarin), and CBN (cannabinol) were found, and their chemical structures were confirmed by GC-MS. The latter compound was obtained with high purity (≈100%), while the others were obtained as less complex mixtures with purity higher than 75% (except for Δ8-THC). Principal component analysis (PCA) was used on the 1H NMR spectra of the 156 samples, and it was found that the samples were grouped according to the months, differentiating into two groups (from July 2014 to January 2015 and from February 2015 to July 2015), where non-grouping was observed from four macro-regions of the ES state (North, Central, Metropolitan, and South). The chemical profile of the seized samples was correlated to the 1H NMR spectrum of an isolated CBN sub-fraction, in which the group formed by samples seized in the year 2015 presented lower CBN content in the chemical composition. From the PCA score plot, two groups of samples were confirmed using the partial least squares discriminant analysis and orthogonal projections to latent structures classification methods.

Lycorine is an Amaryllidaceae alkaloid that presents anti-Trichomonas vaginalis activity. T. vaginalis causes trichomoniasis, the most common non-viral sexually transmitted infection. The modulation of T. vaginalis purinergic signaling through the ectonucleotidases, nucleoside triphosphate diphosphohydrolase (NTPDase), and ecto-5'-nucleotidase represents new targets for combating the parasite. With this knowledge, the aim of this study was to investigate whether NTPDase and ecto-5'-nucleotidase inhibition by lycorine could lead to extracellular ATP accumulation. Moreover, the lycorine effect on the reactive oxygen species (ROS) production by neutrophils and parasites was evaluated as well as the alkaloid toxicity. The metabolism of purines was assessed by HPLC. ROS production was measured by flow cytometry. Cytotoxicity against epithelial vaginal cells and fibroblasts was tested, as well as the hemolytic effect of lycorine and its in vivo toxicity in Galleria mellonella larvae. Our findings showed that lycorine caused ATP accumulation due to NTPDase inhibition. The alkaloid did not affect the ROS production by T. vaginalis; however, it increased ROS levels in neutrophils incubated with lycorine-treated trophozoites. Lycorine was cytotoxic against vaginal epithelial cells and fibroblasts; conversely, it was not hemolytic neither exhibited toxicity against the in vivo model of G. mellonella larvae. Overall, besides having anti-T. vaginalis activity, lycorine modulates ectonucleotidases and stimulates neutrophils to secrete ROS. This mechanism of action exerted by the alkaloid could enhance the susceptibility of T. vaginalis to host immune cell, contributing to protozoan clearance.

Alzheimer's disease (AD) is a multifactorial health problem widespread over the world. Regarding the historical importance of the alkaloids in the central nervous system pharmacology they remain as promising drug candidates against AD. Seven alkaloids from Amaryllidaceae and Fabaceae were evaluated

The phytochemical study of Hippeastrum goianum led to the identification of 13 compounds by means of gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR). Compounds 7-demethoxy-9-O-methylhostasine (1) and 7-deoxi-trans-dihydronarciclasine (2) had their absolute configurations determined by vibrational circular dichroism (VCD). This is the first time that compound 1 is described in the Amaryllidaceae family. The cytotoxicity of all isolated compounds was tested against colorectal carcinoma (HCT 116), breast carcinoma (MCF-7), and non-tumor human retinal pigment epithelium (RPE) cell lines. The half-maximum inhibitory concentration (IC50) of compound 2 against each cell line was equivalent to the positive control (doxorubicin), indicating a considerable cytotoxic activity. Keywords: narciclasine; galasine; cytotoxic activity; absolute configuration; vibrational circular dichroism

The semi-synthesis of 11 isatin derivatives was achieved through bimolecular nucleophilic substitution and click chemistry. Seven new compounds were obtained. All chemical structures were determined by infrared spectroscopy (IR), nuclear magnetic resonance spectrometry (NMR) and high-resolution mass spectrometry (HRMS) data. These derivatives were evaluated for their anti-GSK-3 activity and all isatin derivatives (N-alkyl and 1,2,3-triazolic) exhibited strong inhibitory activity, with 2b and 4h exhibiting remarkable potency. In addition, docking studies were performed with 2b and 2e models to unravel the molecular mechanism underlying the polar interactions on the GSK-3 ATP-binding site., This study was funded by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES), Finance Code 001, by the National Council of Scientific and Technological Development (CNPq) and Foundation of Support to Research and Innovation of Espírito Santo (FAPES PPE-Agro No. 76418880/16). We also would like to acknowledge INCTBioNat (CNPq 465637/2014-0) for additional support and NCQP-UFES, as well as the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2019 unit and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020, Programa Operacional Regional do Norte. L. R. R. also acknowledges her sabbatical leave fellowship (SFRH/BSAB/142991/2018) funded by FCT. D. F. is recipient of a doctoral fellowship (call NORTE-69-2015-15) funded by the European Social Fund under the scope of Norte2020, Programa Operacional Regional do Norte., info:eu-repo/semantics/publishedVersion

Alzheimer’s disease (AD) is a multifactorial health problem widespread over the world. Regarding the historical importance of the alkaloids in the central nervous system pharmacology they remain as promising drug candidates against AD. Seven alkaloids from Amaryllidaceae and Fabaceae were evaluated in vivo, in vitro and in silico targets related to the AD pathophysiology. Erythraline and erysodine showed the greatest potential compared to Memantine, a drug currently used in AD therapy, by delaying the Aβ1-42-induced paralysis in the transgenic strain CL2006 Caenorhabditis elegans, an alternative model to assess the impairment of beta-amyloid peptide deposition. The in vitro inhibition of the acetylcholinesterase was observed for the first time for Erythrina alkaloids; however Lycorine was the most active. Docking simulation contributed to comprehend this potential by showing a hydrophobic interaction between acetylcholinesterase and Lycorine in the amino acid residue TRP 84 as well as hydrogen bonds with TRY 121 and ASP 72.

Background: Glycogen synthase kinase-3 (GSK-3) is involved in the phosphorylation and inactivation of glycogen synthase. GSK-3 inhibitors have been associated with a variety of diseases, including Alzheimer´s disease (AD), diabetes type II, neurologic disorders, and cancer. The inhibition of GSK-3β isoforms is likely to represent an effective strategy against AD. Objective: The present work aimed to design and synthesize coumarin derivatives to explore their potential as GSK-3β kinase inhibitors. Method: The through different synthetic methods were used to prepare coumarin derivatives. The GSK-3β activity was measured through the ADP-Glo™ Kinase Assay, which quantifies the kinasedependent enzymatic production of ADP from ATP, using a coupled-luminescence-based reaction. A docking study was performed by using the crystallographic structure of the staurosporine/GSK-3β complex [Protein Data Bank (PDB) code: 1Q3D]. Results: The eleven coumarin derivatives were obtained and evaluated as potential GSK-3β inhibitors. Additionally, in silico studies were performed. The results revealed that the compounds 5c, 5d, and 6b inhibited GSK-3β enzymatic activity by 38.97–49.62% at 1 mM. The other coumarin derivatives were tested at 1 mM, 1 µM, and 1 nM concentrations and were shown to be inhibitor candidates, with significant IC50 (1.224–6.875 µM) values, except for compound 7c (IC50 = 10.809 µM). Docking simulations showed polar interactions between compound 5b and Lys85 and Ser203, clarifying the mechanism of the most potent activity. Conclusion: The coumarin derivatives 3a and 5b, developed in this study, showed remarkable activity as GSK-3β inhibitors.

Skin cancer has evolved as the most common malignant disease, accounting for 4.5% of all new cancer cases. Melanoma, the most aggressive skin cancer type, develops in melanocytes and has high mortality rates due to its biological features and frequent failures of therapeutic alternatives. On the other hand, non-melanoma skin cancers (NMSC), the most common malignant tumors in humans, are developed in keratinocytes of the basal or spinous layer, and increased exposure to ultraviolet (UV) light remains the most important modifiable risk factor. To date, treatment alternatives for melanoma are limited to surgery, in cases of early diagnosis, and a few pharmacological options in inoperable tumors. These limitations for skin cancer management evidence the need to develop therapeutic options for prevention and treatment. The antiproliferative effects of Amaryllidaceae alkaloids have been tested for different types of cancer. However, their activity on skin models is not well-established. Pure alkaloids and alkaloidal fractions characterized by GC-MS of several Amaryllidaceae species from Crinum, Zephyranthes, Hippeastrum, and Eucharis genera were assayed by their effects on skin cancer. Photoprotective effects of the alkaloids and fractions were determined through cell viability assay, and the quantification of intracellular reactive oxygen species (ROS) and inflammation biomarker IL-6 in UVB-stimulated keratinocytes (HaCaT). Cytotoxicity were assessed in human metastatic melanoma cells (CRL-3229) to evaluate therapeutic potential, and chemometric techniques were used to analyze data. Most substances enhanced HaCaT proliferation at 5.0 µg/mL. E. caucana and Z. carinata bulbs alkaloidal fractions significantly reduced intracellular ROS and IL-6 production in UVB-stimulated HaCaT, respectively. Tazettine and lycoramine showed photoprotective effects. Additionally, E. caucana bulbs alkaloidal fraction was selectively cytotoxic in melanoma cells at 20.0 µg/mL. Collectively, these results demonstrate that Amaryllidaceae alkaloids could represent a new option in skin cancer management, acting as photoprotective agents in healthy UVB-exposed keratinocytes and therapeutic agents in melanoma.

The subfamily Amaryllidoideae within of the Amaryllidaceae family has an exclusive group of compounds called Amaryllidaceae alkaloids. Galanthamine, the most known Amaryllidaceae alkaloid, is approved by the FDA as an inhibitor of the enzyme acetylcholinesterase (AChE) for the palliative treatment of Alzheimer Disease (AD). However, butyrylcholinesterase (BChE) contributes critically to cholinergic dysfunction associated with AD. Thus, the development of novel therapeutics may involve the inhibition of both cholinesterase enzymes. Zephyranthes carinata, a species of the Amaryllidaceae family, has been reported to have inhibitory activity against cholinesterases. In order to determine the enzymatic inhibition potential, the major alkaloids of bulbs and leaves of Z. carinata were evaluated in both AChE and BChE. A purification and characterization process was made using different chromatographic and spectrometric techniques, and the inhibitory activity was evaluated with the Ellman method. Alkaloidal extracts of bulbs and leaves exhibited an inhibitory activity with IC50 values of 5.8 ± 0.2 and 8.7 ± 0.3 μg/mL, respectively, against AChE. Further, bulb extract showed IC50 values of 77.9 ± 3.4 μg/mL against BChE. Amaryllidaceae alkaloids hamayne, pseudolycorine, galanthine, criasbetaine, tazettine, lycoramine, hippeastidine, galanthamine, trisphaeridine, 3-epimacronine, haemanthamine, lycorine, and vittatine were purified and evaluated for their AChE and BChE inhibitory activities. Lycoramine (galanthamine type) presented the lowest IC50 value in AChE (17 ± 0.7 μg/mL), and trisphaeridine (narciclasine type) showed the lowest IC50 value in BChE (33.1 ± 3.6 μg/mL). Combined major alkaloids (>10%) were analyzed to observe synergistic behavior. The mixture alkaloids lycoramine and galanthine presented IC50 values of 14.55 ± 1.0 μg/mL against AChE, and the lycoramine, trisphaeridine, and vittatine mix presented IC50 values of 38.42 ± 3.4 μg/mL in BChE. These results showed prominent inhibitory activity against AChE and BChE enzymes, indicating their potential as agents for treating AD through a combined strategy.

Acetylcholinesterase (AChE) inhibitors remain the class of drugs used for the treatment of Alzheimer disease (AD). For the aim of discovering new sources of potent AChE inhibitors, a combined AChE-inhibitory activity together with alkaloid profiles by GC-MS, combined with multivariate statistical analysis for biomarkers determination and

A combined phytochemical, crystallographic and biological study of Worsleya procera roots was performed. Fifteen alkaloids were identified by gas chromatography mass spectrometry (GC-MS) and seven of them were isolated. The structures of the alkaloids were elucidated by spectroscopic methods, and a detailed crystallographic study of tazettine was carried out. The isolated alkaloids and the obtained extracts were tested in vitro against Plasmodium falciparum (3D7 and K1 strains) and human hepatocarcinoma cells (HepG2) to assess their antiplasmodial and cytotoxic effects, respectively. One of the isolated alkaloid derivatives, lycorine, exhibited antiplasmodial activity against both sensitive (3D7) and resistant (K1) parasite strains in the low micromolar range (half-maximal sample inhibitory concentration (IC50) values of 2.5 and 3.1 µM, respectively) and displayed a low cytotoxicity profile, with a selectivity index greater than 100. Our findings indicate that lycorine is a hit for antimalarial drug discovery. Keywords: isoquinolinic alkaloids; Amaryllidaceae; Plasmodium falciparum; lycorine; tazettine

In this work, we report the synthesis of a mesoporous molecularly imprinted polymer on the surface of silica nanoparticles (core@mMIP) to be applied as adsorbent in microextraction by packed sorbent (MEPS) for selective determination of pesticides in apple juice. The core@mMIP was properly characterized, showing good adhesion of the polymer to the silica core. The best extraction conditions were: 200 µL of ultrapure water as washing solvent, 150 µL of acetonitrile as eluent, 100 µL of sample at pH 2.5, five draw-eject cycles and 8 mg of adsorbent. Thereby, recoveries of 96.12 ± 1.05%, 76.88 ± 6.18% and 76.18 ± 5.57% were obtained for pyriproxyfen (PPX), deltamethrin (DTM) and etofenprox (ETF), respectively. After validation, the method presented linearity in the range of 0.02–10 µg mL−1 (r > 0.99), limit of detection of 0.005 µg mL−1, satisfactory selectivity, and proper precision and accuracy. The method was successfully applied real samples of processed and fresh apple juice.

A new magnetic molecularly imprinted polymer (MMIP) was firstly synthesized using terephthalic acid as a functional monomer to extract atenolol (ATL) from human plasma by magnetic solid phase extraction (MSPE). ATL enantiomers separation was performed by capillary electrophoresis using carboxymethyl-β-cyclodextrin (CM-β-CD: 5.5 mg) as chiral selector in background electrolyte with 125 mmol L−1 triethylamine pH 6.0 using a capillary with 75 µm of internal diameter. After MSPE optimization, the best conditions were: 500 µL of ultrapure water as washing solvent, 1000 µL of methanol as eluting solvent, 25 mg of MMIP, and 250 µL of sample (human plasma at pH 12.5). Recoveries/relative standard deviation percentage were 75.8 ± 6.3% and 76.1 ± 5.7% for (-)-(S)-ATL and (+)-(R)-ATL, respectively. The method was linear over the concentration range from 5.0 to 1500.0 ng mL−1, with coefficients of correlation larger than 0.99 for both enantiomers. The method was successfully applied in plasma samples from volunteers under continuous use of ATL racemate. Finally, MMIP imprinting test confirmed that the material was selective for ATL, with low recoveries for other drugs.

Helicobacter pylori colonizes half of the World population and has been associated with gastric diseases including gastric cancer. In this scenario, Plectranthus barbatus is a wide-used medicinal plant in Brazil in the treatment of gastric injuries, however, no scientific report describe it against H. pylori. The aim of this study was to evaluate the ethyl acetate fraction (EAF) chemical profile from P. barbatus and its anti-H. pylori, immunomodulatory, antioxidant and cytotoxic activities. The substances identified by (-)-ESI-FT-ICR MS were plectrin, hydrolyzed abieatane, barbatusin, 3β-hydroxy-3-deoxibarbatusin, cyclobutatusin, luteolin, rosmarinic acid and coleoside B. The anti-H. pylori results presented a minimum inhibitory concentration (MIC) of 256 μg/mL and minimum bactericidal concentration (MBC) of 1024 μg/mL. Scanning electron microscopy evidenced H. pylori morphological changes in its surface induced by EAF. Molecular docking studies were conducted to investigate the binding mode of the proposed compounds at H. pylori Penicillin-Binding Protein active site. Antioxidant activities presented IC50 ranging from 26.64 ± 0.62–69.96 ± 1.25 μg/mL and the immunomodulatory activity was significant to IL-6 and NO with 28 % and 35 % of inhibition at 25 μg/mL. EAF showed significant cytotoxic activity with CI50 of 33.89 ± 0.32 μg/mL on gastric adenocarcinoma cells. These results indicate the potential of P. barbatus as candidate for H. pylori eradication and H. pylori induced related gastric disease prevention.

In the present work, hydrophobic nanoprecipitates (HNPs) of inclusion complexes formed between β-cyclodextrin (βCD) and the avermectins (AVMs) named eprinomectin (EPRI) and ivermectin (IVER) were synthesized and characterized, and their larvicidal activity against Aedes aegypti and human safety against fibroblasts were evaluated. Initially, thermogravimetric analysis/differential thermal analysis data revealed that inclusion increased the thermal stability of AVMs in the presence of βCD. Nuclear magnetic resonance experiments and density functional theory calculations pointed out the inclusion of the benzofuran ring of the two AVMs in the βCD cavity. Isothermal titration calorimetry experiments allowed identification of different binding constants for EPRI/βCD ( Kb = 1060) and βCD/IVER ( Kb = 1700) systems, despite the structural similarity. Dynamic light scattering titrations of AVMs' dimethyl sulfoxide solution in βCD aqueous solution demonstrated that the formed HNPs have lower sizes in the presence of βCD. Finally, the inclusion of EPRI in βCD increased its larval toxicity and reduced its human cytotoxicity, while for IVER/βCD no beneficial effect was observed upon inclusion. These results were rationalized in terms of structural differences between the two molecules. Finally, the EPRI/βCD complex has great potential as an insecticide against A. aegypti larvae with high human safety.

A new phytochemical study of the indigenous Brazilian species Hippeastrum papilio is reported herein. Three novel Amaryllidaceae alkaloids were isolated, including hippapiline (1), papiline (2), and 3-O-demethyl-3-O-(3-hydroxybutanoyl)haemanthamine (3). Their structures were determined by physical and spectroscopic methods. In addition, the known alkaloids, haemanthamine (4), galanthamine (5), narwedine (6), 11β-hydroxygalanthamine (7), apogalanthamine (8), and 9-O-demethyllycosinine B (9) were identified. The unusual cis-B/C-ring fusion for the new homolycorine representative hippapiline was ratified by NMR and CD spectroscopy. Fil: Guo, Ying. University of Barcelona. Faculty of Pharmacy. Department of Natural Products, Plant Biology and Soil Science; España Fil: Andrade, Jean P. de. University of Barcelona. Faculty of Pharmacy. Department of Natural Products, Plant Biology and Soil Science; España. Universidade Federal do Espírito Santo; Brasil Fil: Pigni, Natalia Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Ciencia y Tecnología de Alimentos Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Ciencia y Tecnología de Alimentos Córdoba; Argentina. University of Barcelona. Faculty of Pharmacy. Department of Natural Products, Plant Biology and Soil Science; España Fil: Torras-Claveria, Laura. University of Barcelona. Faculty of Pharmacy. Department of Natural Products, Plant Biology and Soil Science; España. Universidade Federal do Espírito Santo; Brasil Fil: Tallini, Luciana R.. University of Barcelona. Faculty of Pharmacy. Department of Natural Products, Plant Biology and Soil Science; España Fil: Souza Borges, Warley de. Universidade Federal do Espírito Santo; Brasil Fil: Viladomat, Francesc. University of Barcelona. Faculty of Pharmacy. Department of Natural Products, Plant Biology and Soil Science; España Fil: Nair, Jerald J.. University of Barcelona. Faculty of Pharmacy. Department of Natural Products, Plant Biology and Soil Science; España Fil: Zuanazzi, José A. S.. Universidade Federal do Rio Grande do Sul; Brasil Fil: Bastida, Jaume. University of Barcelona. Faculty of Pharmacy. Department of Natural Products, Plant Biology and Soil Science; España

Natural products play an important role in the development of new drugs. In this context, the Amaryllidaceae alkaloids have attracted considerable attention in view of their unique structural features and various biological activities. In this study, twenty-three alkaloids were identified from; Crinum amabile; by GC-MS and two new structures (augustine; N; -oxide and buphanisine; N; -oxide) were structurally elucidated by NMR. Anti-parasitic and cholinesterase (AChE and BuChE) inhibitory activities of six alkaloids isolated from this species, including the two new compounds, are described herein. None of the alkaloids isolated from; C. amabile; gave better results than the reference drugs, so it was possible to conclude that the; N; -oxide group does not increase their therapeutic potential.

In this work, four secondary metabolites were isolated from leaves of Pachystroma longifolium (Euphorbiaceae): loliolide, gallic acid, methyl protocatechuate and ethyl gallate. Their structures were established by physical and spectroscopic methods. The extracts of P. longifolium and the purified compounds were tested as cathepsins inhibitors and the extracts were active.

The chemistry of natural products in Brazil has experienced a rapid development during the 21st century, with a diversification of lines of research, methodological approaches, exploration of diverse natural sources for the isolation of secondary metabolites and establishment of several multidisciplinary initiatives. These topics are critically discussed, evidencing achievements and new challenges to be faced for the future of Brazilian natural products chemistry.

In this work, the development of a new restricted access material combined to molecularly imprinted polymer for selective magnetic solid-phase extraction (MSPE) of estrogens was studied. The main parameters that affecting the extraction efficiency during sample preparation were systematically optimized, including agitation time, amount of adsorbent material, volume of sample and eluent and pH of the sample. The average recoveries with their respective relative standard deviation (RSD%) for ethinylestradiol (EE2) and estradiol (E2) were 98.75 ± 4.02% and 95.73 ± 0.24%, respectively. The method was linear over the concentration range from 80 to 1100 ng mL−1 for each hormone, with correlation coefficient of 0.9971 and 0.9954, to EE2 and E2, respectively. The new method was successfully applied in urine samples from voluntaries on hormonal contraceptive use.