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Background: Through this study, the Chemical composition realized by UHPLC-DAD-ESI-MSn allowed the detection of different phenolic compounds groups from Pistacia atlantica Desf. leaves extracts. We studied the inhibition of main protease (CL3 Mpro) and RNA-dependent RNA polymerase (RdRp) of the SARS-CoV-2 by the identified molecules through molecular docking. Objective: The objective of this study is to identify compounds from Pistacia atlantica Desf. leaves extracts, which might have anti-viral effects. Methods: Chemical composition realized by UHPLC-DAD-ESI-MSn, the inhibition of main protease (CL3 Mpro) and RNA-dependent RNA polymerase (RdRp) of the SARS-CoV-2 is studied using molecular docking with Autodock Vina software. ADMET analysis was carried out. Results: The identified compounds are quinic acid, digallic acid, galloylquinic acid, gallic acid, trigallic acid, digalloylquinic acids, trigalloylquinic acids and methyl gallate; digallic and quinic acids are the best inhibitors. Digallic acid had binding affinity energy (BAE) of -8.2 kcal/mol, and Ki of 1µM for the CL3 Mpro, Ki of 0.62 mM for the RdRp. Quinic acid showed Ki of 4.6 mM, recorded for both enzymes. Through ADMET analysis, we have found that the two molecules are good drugs candidate. Conclusion: This is the first time that a group of identified compounds from Pistacia atlantica Desf. leaves is studied for their potential activity against the novel virus by inhibiting two key enzymes in its life cycle, and no further studies have been published in this context.

In the present study, two extracts from the aerial parts of the endemic species Satureja hispidula were analyzed for the first time by ultra-high-performance liquid chromatography coupled with a diode array detector and an electrospray mass spectrometer (UHPLC-DAD-ESI/MS) method in order to identify and quantify their phenolic compounds. These extracts’ antioxidant, α-glucosidase and α-amylase inhibitory activities were also evaluated. UHPLC-DAD-ESI/MS allowed the identification of 28 and 20 compounds in the ethanolic and aqueous extracts, respectively; among them, 5-O-caffeoylquinic acid was the most abundant in both extracts. The biological assay results indicate that the species S. hispidula, besides its high antioxidant power, is also potentially useful for inhibiting the α-glucosidase enzyme. In both antioxidant and α-glucosidase inhibitory assays, the aqueous extract exhibited the most promising results, significantly better than the standards used as positive controls.

Fucales are an order within the Phaeophyceae that include most of the common littoral seaweeds in temperate and subtropical coastal regions. Many species of this order have long been a part of human culture with applications as food, feedand remedies in folk medicine. Apart from their high nutritional value, these seaweeds are also a well-known reservoir of multiple bioactive compounds with great industrial interest. Among them, phlorotannins, a unique and diverse class of brown algae-exclusive phenolics, have gathered much attention during the last few years due to their numerous potential health benefits. However, due to their complex structural features, combined with the scarcity of standards, it poses a great challenge to the identification and characterization of these compounds, at least with the technology currently available. Nevertheless, much effort has been taken towards the elucidation of the structural features of phlorotannins, which have resulted in relevant insights into the chemistry of these compounds. In this context, this review addresses the major contributions and technological advances in the field of phlorotannins extraction and characterization, with a particular focus on Fucales., This work received financial support from PT national funds (FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior) through the projects UIDB/50006/2020 and UIDP/50006/2020. Thanks to PTDC/BAA-AGR/31015/2017, “Algaphlor—Brown algae phlorotannins: From bioavailability to the development of new functional foods”, co-financed by the Operational Programme for Competitiveness and Internationalization— POCI, within the European Regional Development Fund (FEDER), and the Science and Technology Foundation (FCT), through national funds. Silva S. thanks FCT for funding through program DL 57/2016–Norma transitória (Ref. SFRH/BPD/74299/2010).

Liver fructose 1,6-bisphosphatase (FBPase) is a recognized regulatory enzyme of the gluconeogenesis pathway, which has emerged as a valid target to control gluconeogenesis-mediated overproduction of glucose. As such, the management of diabetes with FBPase inhibitors represents a potential alternative for the currently used antidiabetic agents. In this study, the FBPase inhibition of a panel of 55 structurally related flavonoids was tested, through a microanalysis screening system. Then, a subset of seven active inhibitors and their close chemical relatives were further evaluated by molecular dynamics (MD) simulations using a linear interaction energy (LIE) approach. The results obtained showed that

The present study describes investigation of the effects of the bark resin extract of Garcinia nigrolineata (Clusiaceae) on the cognitive function and the induction of oxidative stress in both frontal cortex and hippocampus by unpredictable chronic mild stress (UCMS). By using behavioral mouse models, i.e., the Y-maze test, the Novel Object Recognition Test (NORT), and the Morris Water Maze Test (MWMT), it was found that the negative impact of repeated mild stress-induced learning and memory deficit through brain oxidative stress in the UCMS mice was reversed by treatment with the bark resin extract G. nigrolineata. Moreover, the prenylated xanthones viz. cowagarcinone C, cowaxanthone, α-mangostin, cowaxanthone B, cowanin, fuscaxanthone A, fuscaxanthone B, xanthochymusxanthones A, 7-O-methylgarcinone E, and cowagarcinone A, isolated from the bark resin of G. nigrolineata, were assayed for their inhibitory activities against β-amyloid (Aβ) aggregation and monoamine oxidase enzymes (MAOs).

An undescribed hybrid phenalenone dimer, talaropinophilone (3), an unreported azaphilone, 7-epi-pinazaphilone B (4), an unreported phthalide dimer, talaropinophilide (6), and an undescribed 9R,15S-dihydroxy-ergosta-4,6,8 (14)-tetraen-3-one (7) were isolated together with the previously reported bacillisporins A (1) and B (2), an azaphilone derivative, Sch 1385568 (5), 1-deoxyrubralactone (8), acetylquestinol (9), piniterpenoid D (10) and 3,5-dihydroxy-4-methylphthalaldehydic acid (11) from the ethyl acetate extract of the culture of a marine sponge-derived fungus, Talaromyces pinophilus KUFA 1767. The structures of the undescribed compounds were elucidated by 1D and 2D NMR as well as high-resolution mass spectral analyses. The absolute configuration of C-9′ of 1 and 2 was revised to be 9′S using the coupling constant value between C-8′ and C-9′ and was confirmed by ROESY correlations in the case of 2. The absolute configurations of the stereogenic carbons in 7 and 8 were established by X-ray crystallographic analysis. Compounds 1,2, 4–8, 10 and 11 were tested for antibacterial activity against four reference strains, viz. two Gram-positive (Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212) and two Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853), as well as three multidrug-resistant strains, viz. an extended-spectrum β-lactamase (ESBL)-producing E. coli, a methicillin-resistant S. aureus (MRSA) and a vancomycin-resistant E. faecalis (VRE). However, only 1 and 2 exhibited significant antibacterial activity against both S. aureus ATCC 29213 and MRSA. Moreover, 1 and 2 also significantly inhibited biofilm formation in S. aureus ATCC 29213 at both MIC and 2xMIC concentrations.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00589. Malaria, leishmaniasis, and sleeping sickness are potentially fatal diseases that represent a real health risk for more than 3,5 billion people. New antiparasitic compounds are urgent leading to a constant search for novel scaffolds. Herein, pyrazino[2,1-b]quinazoline-3,6-diones containing indole alkaloids were explored for their antiparasitic potential against Plasmodium falciparum, Trypanosoma brucei, and Leishmania infantum. The synthetic libraries furnished promising hit compounds that are species specific (7, 12) or with broad antiparasitic activity (8). Structure-activity relationships were more evident for Plasmodium with anti-isomers (1S,4R) possessing excellent antimalarial activity, while the presence of a substituent on the anthranilic acid moiety had a negative effect on the activity. Hit compounds against malaria did not inhibit β-hematin, and in silico studies predicted these molecules as possible inhibitors for prolyl-tRNA synthetase both from Plasmodium and Leishmania. These results disclosed a potential new chemotype for further optimization toward novel and affordable antiparasitic drugs. publishersversion published

Reversing protein aggregation within cells may be an important tool to fight protein-misfolding disorders such as Alzheimer’s, Parkinson’s, and cardiovascular diseases. Here we report the design and synthesis of a family of steroid−quinoline hybrid compounds based on the framework combination approach. This set of hybrid compounds effectively inhibited Aβ1−42 self-aggregation in vitro by delaying the exponential growth phase and/or reducing the quantity of fibrils in the steady state. Their disaggregation efficacy was further demonstrated against preaggregated Aβ1−42 peptides in cellular assays upon their endocytosis by neuroblastoma cells, as they reverted both the number and the average area of fibrils back to basal levels. The antiaggregation effect of these hybrids was further tested and demonstrated in a cellular model of general protein aggregation expressing a protein aggregation fluorescent sensor. Together, our results show that the new cholesterol−quinoline hybrids possess wide and marked disaggregation capacities and are therefore promising templates for the development of new drugs to deal with conformational disorders. Thanks are due to the University of Aveiro, FCT/MEC, Centro 2020 and Portugal2020, the COMPETE Program, and the European Union (FEDER Program) via the financial support to the research units LAQV-REQUIMTE (UIDB/50006/2020), IBiMED (UID/BIM/04501/2019) and CICECO- Aveiro Institute of Materials (UID/CTM/50011/2019), financed by national funds through the FCT/MCTES, to the Portuguese NMR Network, to the ThiMES Project (POCI-01- 0145-FEDER-016630), and to the PAGE Project “Protein Aggregation Across the Lifespan” (CENTRO-01-0145- FEDER-000003), including postdoctoral grants to H.M.T.A. (BPD/UI98/4861/2017) and R.N.d.S. (BPD/UI98/6327/2018). M.P. was supported by Ph.D. Grant SFRH/BD/135655/2018. A.R.S. and S.G. were supported by national funds (OE) through FCT, I.P., in the scope of the framework contract foreseen in numbers 4, 5, and 6 of Article 23 of the Decree-Law 57/2016 of August 29, changed by Law 57/2017 of July 19. Microphotographs were acquired in the LiM facility of iBiMED/UA, a member of the Portuguese Platform of BioImaging (PPBI) (POCI-01-0145-FEDER-022122). info:eu-repo/semantics/publishedVersion

Microwave irradiation has become a popular heating technique in organic synthesis, mainly due to its short reaction times, solventless reactions, and, sometimes, higher yields. Additionally, microwave irradiation lowers energy consumption and, consequently, is ideal for optimization processes. Moreover, there is evidence that microwave irradiation can improve the regioselectivity and stereoselectivity aspects of vital importance in synthesizing bioactive compounds. These crucial features of microwave irradiation contribute to its inclusion in green chemistry procedures. Since 2003, the use of microwave-assisted organic synthesis has become common in our laboratory, making our group one of the first Portuguese research groups to implement this heating source in organic synthesis. Our achievements in the transformation of heterocyclic compounds, such as (E/Z)-3-styryl-4H-chromen-4-ones, (E)-3-(2-hydroxyphenyl)-4-styryl-1H-pyrazole, (E)-2-(4-arylbut-1-en-3-yn-1-yl)-4H-chromen-4-ones, or (E)-2-[2-(5-aryl-2-methyl-2H-1,2,3-triazol-4-yl)vinyl]-4H-chromen-4-ones, will be discussed in this review, highlighting the benefits of microwave irradiation use in organic synthesis.

N-heterocycles, both saturated and unsaturated, are ubiquitous biologically active molecules that are extremely appealing scaffolds in drug discovery programs. Although classical synthetic methods have been developed to access many relevant N-heterocyclic scaffolds, representing well-established and reliable routes, some do not meet the needs of sustainability. In this context, several advances have been made towards the sustainable synthesis of N-heterocycles. This review focuses on the most recent examples from the last five years of catalytic synthesis of several heterocyclic compounds of medicinal relevance. Thus, the synthesis of isoindoloquinazolines, quinazolines and azaindoles, among others, are covered. The synthetic methods selected include the use of homogeneous and heterogeneous catalysts and the use of alternative and sustainable methods such as, for example, metal-catalyzed acceptorless coupling and one-pot reactions. The green aspects of the individual synthetic approaches are highlighted, and the scope of each methodology is described.

Recently, we reported the development of new chiral stationary phases (CSPs) for liquid chromatography (LC) based on chiral derivatives of xanthones (CDXs). Based on the most promising CDX selectors, 12 new CSPs were successfully prepared starting from suitable functionalized small molecules including xanthone and benzophenone derivatives. The chiral selectors comprising one, two, three, or four chiral moieties were covalently bonded to a chromatographic support and further packed into LC stainless-steel columns (150 × 2.1 mm I.D.). The enantioselective performance of the new CSPs was evaluated by LC using different classes of chiral compounds. Specificity for enantioseparation of some CDXs was observed in the evaluation of the new CSPs. Besides, assessment of chiral recognition mechanisms was performed by computational studies using molecular docking approach, which are in accordance with the chromatographic parameters. X-Ray analysis was used to establish a chiral selector 3D structure.

An unreported isocoumarin, (3S,4R)-4-hydroxy-6-methoxymellein (2), an undescribed propylpyridinium anthraquinone (4), and an unreported C-glucosyl resorcinol derivative, acetyl carnemycin E (5c), were isolated, together with eight previously reported metabolites including p-hydroxybenzaldehyde (1), 1,3-dimethoxy-8-hydroxy-6-methylanthraquinone (3a), 1,3-dimethoxy-2,8-dihydroxy-6-methylanthraquinone (3b), emodin (3c), 5[(3E,5E)-nona-3,5-dien-1-yl]benzene (5a), carnemycin E (5b), tajixanthone hydrate (6a) and 15-acetyl tajixanthone hydrate (6b), from the ethyl acetate extract of the culture of a marine sponge-derived fungus, Aspergillus stellatus KUFA 2017. The structures of the undescribed compounds were elucidated by 1D and 2D NMR and high resolution mass spectral analyses. In the case of 2, the absolute configurations of the stereogenic carbons were determined by comparison of their calculated and experimental electronic circular dichroism (ECD) spectra. The absolute configurations of the stereogenic carbons in 6a and 6b were also determined, for the first time, by X-ray crystallographic analysis. Compounds 2, 3a, 3b, 4, 5a, 5b, 5c, 6a, and 6b were assayed for antibacterial activity against four reference strains, viz. two Gram-positive (Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212) and two Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853), as well as three multidrug-resistant strains. However, only 5a exhibited significant antibacterial activity against both reference and multidrug-resistant strains. Compound 5a also showed antibiofilm activity against both reference strains of Gram-positive bacteria.

Warionia saharae Benth. &amp, Coss. (Asteraceae) is an endemic species of North Africa naturally grown in the southwest of the Algerian Sahara. In the present study, this species’ hydromethanolic leaf extract was investigated for its phenolic profile characterized by ultra-high-performance liquid chromatography coupled with a diode array detector and an electrospray mass spectrometer (UHPLC-DAD-ESI/MS). Additionally, the chemical composition of W. saharae was analyzed by gas chromatography–mass spectrometry, and its antioxidant potential was assessed through five in vitro tests: DPPH● scavenging activity, ABTS●+ scavenging assay, galvinoxyl scavenging activity, ferric reducing power (FRP), and cupric reducing antioxidant capacity. The UHPLC-DAD-ESI/MS analysis allowed the detection and quantification of 22 compounds, with taxifolin as the dominant compound. The GC–MS analysis allowed the identification of 37 compounds, and the antioxidant activity data indicate that W. saharae extract has a very high capacity to capture radicals due to its richness in compounds with antioxidant capacity. The extract also showed potent α-glucosidase inhibition as well as a good anti-inflammatory activity. However, weak anti-α-amylase and anticholinesterase activities were recorded. Moreover, an in silico docking study was performed to highlight possible interactions between three significant compounds identified in W. saharae extract and α-glucosidase enzyme.

Introduction Peptidomics is an emerging field of omics sciences using advanced isolation, analysis, and computational techniques that enable qualitative and quantitative analyses of various peptides in biological samples. Peptides can act as useful biomarkers and as therapeutic molecules for diseases. Areas covered The use of therapeutic peptides can be predicted quickly and efficiently using data-driven computational methods, particularly artificial intelligence (AI) approach. Various AI approaches are useful for peptide-based drug discovery, such as support vector machine, random forest, extremely randomized trees, and other more recently developed deep learning methods. AI methods are relatively new to the development of peptide-based therapies, but these techniques already become essential tools in protein science by dissecting novel therapeutic peptides and their functions (Figure 1).[Figure: see text]. Expert opinion Researchers have shown that AI models can facilitate the development of peptidomics and selective peptide therapies in the field of peptide science. Biopeptide prediction is important for the discovery and development of successful peptide-based drugs. Due to their ability to predict therapeutic roles based on sequence details, many AI-dependent prediction tools have been developed (Figure 1).

In recent decades, fungi-derived naturally occurring quinazolines have emerged as potential drug candidates. Nevertheless, most studies are conducted for bioactivity assays, and little is known about their absorption, distribution, metabolism, and elimination (ADME) properties. To perform metabolic studies, the synthesis of the naturally occurring quinazolinone, fiscalin B (1), and its chloro derivative, 4-((1H-indol-3-yl)methyl)-8,10-dichloro-1-isobutyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione (2), disclosed as an antibacterial agent, was performed in a gram scale using a microwave-assisted polycondensation reaction with 22% and 17% yields, respectively. The structure of the non-natural (+)-fiscalin B was established, for the first time, by X-ray crystallography as (1R,4S)-1, and the absolute configuration of the naturally occurring fiscalin B (-)-1 was confirmed by comparison of its calculated and experimental electronic circular dichroism (ECD) spectra as (1S,4R)-1. in vitro metabolic studies were monitored for this class of natural products for the first time by ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS). The metabolic characteristics of 1 and 2 in human liver microsomes indicated hydration and hydroxylation mass changes introduced to the parent drugs.

Previously unreported anthraquinone, acetylpenipurdin A (4), biphenyl ether, neospinosic acid (6), dibenzodioxepinone, and spinolactone (7) were isolated, together with (R)-6-hydroxymellein (1), penipurdin A (2), acetylquestinol (3), tenellic acid C (5), and vermixocin A (8) from the culture of a marine sponge-associated fungus Neosartorya spinosa KUFA1047. The structures of the previously unreported compounds were established based on an extensive analysis of 1D and 2D NMR spectra as well as HRMS data. The absolute configurations of the stereogenic centers of 5 and 7 were established unambiguously by comparing their calculated and experimental electronic circular dichroism (ECD) spectra. Compounds 2 and 5–8 were tested for their in vitro acetylcholinesterase and tyrosinase inhibitory activities as well as their antibacterial activity against Gram-positive and Gram-negative reference, and multidrug-resistant strains isolated from the environment. The tested compounds were also evaluated for their capacity to inhibit biofilm formation in the reference strains.

The development of novel anticancer agents is essential to finding new ways to treat this disease, one of the deadliest diseases. Some marine organisms have proved to be important producers of chemically active compounds with valuable bioactive properties, including anticancer. Thus, the ocean has proved to be a huge source of bioactive compounds, making the discovery and study of these compounds a growing area. In the last few years, several compounds of marine origin, which include algae, corals, and sea urchins, have been isolated, studied, and demonstrated to possess anticancer properties. These compounds, mainly from securamines and sterols families, have been tested for cytotoxic/antiproliferative activity in different cell lines. Bioactive compounds isolated from marine organisms in the past 5 years that have shown anticancer activity, emphasizing the ones that showed the highest cytotoxic activity, such as securamines H and I, cholest-3β,5α,6β-triol, (E)-24-methylcholest-22-ene-3β,5α,6β-triol, 24-methylenecholesta-3β,5α,6β-triol, and 24-methylcholesta-3β,5α,6β-triol, will be discussed in this review. These studies reveal the possibility of new compounds of marine origin being used as new therapeutic agents or as a source of inspiration to develop new therapeutic agents.

Recent studies indicate that plant polyphenols could be pointed as potential prebiotic candidates since they may interact with the gut microbiota, stimulating its growth and the production of metabolites. However, little is known about the fate of brown seaweeds’ phlorotannins during their passage throughout the gastrointestinal tract. This work aimed to evaluate the stability and bioaccessibility of Fucus vesiculosus phlorotannins after being submitted to a simulated digestive process, as well as their possible modulatory effects on gut microbiota and short-chain fatty acids production following a fermentation procedure using fecal inoculates to mimic the conditions of the large intestine. The stability of phlorotannins throughout the gastrointestinal tract was reduced, with a bioaccessibility index between 2 and 14%. Moreover, slight alterations in the growth of certain commensal bacteria were noticed, with Enterococcus spp. being the most enhanced group. Likewise, F. vesiculosus phlorotannins displayed striking capacity to enhance the levels of propionate and butyrate, which are two important short-chain fatty acids known for their role in intestinal homeostasis. In summary, this work provides valuable information regarding the behavior of F. vesiculosus phlorotannins along the gastrointestinal tract, presenting clear evidence that these compounds can positively contribute to the maintenance of a healthy gastrointestinal condition.

A family of iminoboronates was prepared through a one-pot multicomponent reaction, starting from boronic acid, anthranilic acid, and different salicylaldehydes. Their synthesis was straightforward and the complexes were obtained in good to excellent yields. Their photophysical properties were assessed in a diluted solution, and the complexes proved to be faintly luminescent. These chelates demonstrated remarkable Aggregation-Induced Emission Enhancement, which was rationalized using crystal structures.

Microwave-assisted extraction (MAE) was carried out to maximize the extraction of phlorotannins from Fucus vesiculosus using a hydroethanolic mixture as a solvent, as an alternative to the conventional method with a hydroacetonic mixture. Optimal MAE conditions were set as ethanol concentration of 57% (v/v), temperature of 75 &deg, C, and time of 5 min, which allowed a similar recovery of phlorotannins from the macroalgae compared to the conventional extraction. While the phlorotannins richness of the conventional extract was slightly superior to that of MAE (11.1 &plusmn, 1.3 vs. 9.8 &plusmn, 1.8 mg PGE/g DWextract), both extracts presented identical phlorotannins constituents, which included, among others, tetrafucol, pentafucol, hexafucol, and heptafucol structures. In addition, MAE showed a moderate capacity to scavenge ABTS&bull, + (IC50 of 96.0 &plusmn, 3.4 &micro, g/mL) and to inhibit the activity of xanthine oxidase (IC50 of 23.1 &plusmn, g/mL) and a superior ability to control the activity of the key metabolic enzyme &alpha, glucosidase compared to the pharmaceutical drug acarbose.

Several epidemiological studies indicate that neutrophils, under hyperglycemic conditions, are involved in the perpetuation of the inflammatory status, a characteristic of diabetes mellitus, leading to the production of prodigious quantities of reactive species and the release of neutrophil extracellular traps (NETs). Accordingly, our aim was to study the ability of a panel of 25 structurally related chalcones to modulate human neutrophil oxidative burst and the production of NETs under physiological and high glucose conditions. In general, all chalcones presented similar effects under physiological and high glucose conditions. 2',4-Dihydroxy-3-methoxychalcone (3), here studied for the first time, was the most active (IC50 ≤ 5 μM) on the inhibition of neutrophil oxidative burst, showing the importance of the presence of hydroxy substituents at the C-2' and C-4 positions of the A and B rings, respectively, and a 3-methoxy substituent at B ring of the chalcone scaffold. In the present experimental conditions, NETs release only occurred under high glucose levels. The pentahydroxylated chalcone 1 was the only one that was able to modulate the NETs release. This study provided important considerations about the chalcones' scaffold and their modulatory effect on human neutrophil activities at physiological and high glucose conditions, evidencing their potential use as complementary antidiabetic agents.

Chromenes and quinolines are recognized as important scaffolds in medicinal chemistry. Herein, the efficient use of chromene- and quinoline-3-carbaldehydes to synthesize other valuable heterocycles is described. These carbaldehydes are obtained in excellent yields through the Vilsmeyer-Haack reaction of flavanones and azaflavanones. Protocols towards the synthesis of new heterocycles, such as 3H-chromeno[3&ndash, c]quinolines, (Z/E)-2-aryl-4-chloro-3-styryl-2H-chromenes, and (E)-2-aryl-4-chloro-3-styrylquinoline-1(2H)-carbaldehydes were established. Altogether, we demonstrate the value of chromene- and quinoline-3-carbaldehydes as building blocks.

Aims: This study evaluates the ability of chalcones to scavenge hypochlorous acid (HOCl) and modulate oxidative burst. Background: The chemistry of chalcones has long been a matter of interest to the scientific community due to the phenolic groups often present and to the various replaceable hydrogens that allow the formation of a broad number of derivatives. Due to this chemical diversity, several biological activities have been attributed to chalcones, namely anti-diabetic, anti-inflammatory and antioxidant. Objective: Evaluate the ability of a panel of 34 structurally related chalcones to scavenge HOCl and/or suppress its production through the inhibition of human neutrophils’ oxidative burst, followed by the establishment of the respective structure-activity relationships. Methods: The ability of chalcones to scavenge HOCl was evaluated by fluorimetric detection of the inhibition of dihydrorhodamine 123 oxidation. The ability of chalcones to inhibit neutrophils’ oxidative burst was evaluated by chemiluminometric detection of the inhibition of luminol oxidation. Results: It was observed that the ability to scavenge HOCl depends on the position and number of hydroxy groups on both aromatic rings. Chalcone 5b was the most active with an IC50 value of 1.0 ± 0.1 μM. The ability to inhibit neutrophils’ oxidative burst depends on the presence of a 2’-hydroxy group on A-ring and on other substituents groups, e.g. methoxy, hydroxy, nitro and/or chlorine atom( s) at C-2, C-3 and/or C-4 on B-ring, as in chalcones 2d, 2f, 2j, 2i, 4b, 2n and 1d, which were the most actives with IC50 values ranging from 0.61 ± 0.02 μM to 1.7 ± 0.2 μM. Conclusion: The studied chalcones showed high activity at a low micromolar range, indicating their potential as antioxidant agents and to be used as a molecular structural scaffold for the design of new anti-inflammatory compounds.

In order to meet the increasing demand for environmentally benign chemical processes, we developed a Suzuki&ndash, Miyaura reaction protocol based on the combination of ohmic heating (&Omega, H) and supported ionic liquid phase catalysis (SILPC) in aqueous media. This methodology was applied to the synthesis of a series of flavonoid derivatives, including isoflavones, styrylisoflavones, and diarylalkenylisoflavones.

A series of novel 10-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-3-methyl-1H,10H-pyrano[4,3-b]chromen-1-ones were synthesized by a pseudo-three-component reaction of 4-hydroxy-6-methyl-2-oxo-2H-pyran-2-one (TAL) with 2-hydroxyarylaldehydes using different acids as catalysts and solvents. The approach relies on a regioselective cascade reaction involving two molar equiv of the TAL iteratively acting as active methylene in a Knoevenagel condensation and in a Michael addition. The antioxidant activity of the synthesized compounds were determined using the DPPH scavenging assay, being the results dependent on the nature and number of chromone substituents. The compound bearing an ortho-dihydroxy (catechol) moiety showed excellent activity at lower concentrations, while derivatives bearing alkoxy groups as substituents present pro-oxidant activity.

Alzheimer's disease (AD) is a chronic neurodegenerative disease and represents the major cause of dementia worldwide. Currently, there are no available treatments capable to deliver disease-modifying effects, and the available drugs can only alleviate the symptoms. The exact pathology of AD is not yet fully understood and several hallmarks such as the presence of amyloid-β (Aβ) senile plaques, neurofibrillary tangles (NFTs) as well as the loss of cholinergic function have been associated to AD. Distinct pharmacological targets have been validated to address AD, with acetylcholinesterase (AChE) and β-secretase-1 (BACE-1) being two of the most explored ones. A great deal of research has been devoted to the development of new AChE and BACE-1 effective inhibitors, tackled separately or in combination of both. The multi-factorial nature of AD conducted to the development of multi-target directed ligands (MTDLs), defined as single molecules capable to modulate more than one biological target, as an alternative approach to the old paradigm one-target one-drug. In this context, this review describes a collection of natural and synthetic compounds with dual-inhibitory properties towards both AChE and BACE-1 in the MTDLs context. Furthermore, this review also provides a critical comprehensive analysis of structure-activity relationships (SAR) of the synthetic compounds.

In recent years, more attention has been paid to natural sources of antioxidants. Flavonoids are natural substances synthesized in several parts of plants that exhibit a high antioxidant capacity. They are a large family, presenting several classes based on their basic structure. Flavonoids have the ability to control the accumulation of reactive oxygen species (ROS) via scavenger ROS when they are formed. Therefore, these antioxidant compounds have an important role in plant stress tolerance and a high relevance in human health, mainly due to their anti-inflammatory and antimicrobial properties. In addition, flavonoids have several applications in the food industry as preservatives, pigments, and antioxidants, as well as in other industries such as cosmetics and pharmaceuticals. However, flavonoids application for industrial purposes implies extraction processes with high purity and quality. Several methodologies have been developed aimed at increasing flavonoid extraction yield and being environmentally friendly. This review presents the most abundant natural flavonoids, their structure and chemical characteristics, extraction methods, and biological activity.

Different families of new amino compounds were efficiently synthesized, through optimized sequential processes, involving rhodium catalyzed hydroformylation as the key step. The selection of appropriate hydroformylation catalytic systems and reaction conditions allowed obtaining aldehydes derived from several n-alkyl olefins, cholest-4-ene and 3-vinyl-1H-indole, which were subsequently transformed, in one-pot, in to α-amino acids via hydroformylation/Strecker reaction, and in to tertiary amines via hydroaminomethylation, with excellent yields.

Ethnopharmacological surveys on Portuguese flora reveal that Genista tridentata L. is a shrub used in traditional medicine for the treatment of various inflammation-related health problems, although scientific support of its benefits is still necessary. In order to establish the anti-inflammatory potential of G. tridentata and support its traditional use, ethanolic extracts of three sections of the plant (root, stem, and leaves) were subjected to in vitro evaluation of anti-inflammatory activity using lipopolysaccharide (LPS)-stimulates macrophages as an inflammation model. Simultaneously, we also aimed to establish the extracts&rsquo, flavonoids profile. The ethanolic extracts, obtained by Soxhlet extraction, profile of the three sections confirmed their richness in flavonoids, being three prenylated flavonoids isolated and characterized in the root, including a new natural compound, the 3-methoxymundulin. The extracts from the three plant sections showed strong antioxidant activity at the cellular level and significantly inhibit the LPS-triggered NO production by downregulating Nos2 gene transcription and consequently iNOS expression. Additionally, root and stem extracts also decreased the LPS-induced transcription of the pro-inflammatory genes Il1b, Il6, and Ptgs2. Thus, the results support the anti-inflammatory properties attributed to G. tridentate preparations. Relevantly, the roots of the shrub, plant part not used, is an unexplored source of compounds with pharmacological and nutraceutical value.

Conference Report XVI International Symposium on Marine Natural Products | XI European Conference on Marine Natural Products, 1-5 September 2019, Peniche, Portugal. Asparagopsis armata is considered a biological invader and this red alga is in the last few years one of the worst nightmares for Azores coast biodiversity. So efforts to find an economically valuable application are welcome. In this context biological evaluations of its extracts, such as anti-aging, antioxidant and anticholinesterasic activities, were recently presented [1,2]. Naturally, the knowledge of this species chemical composition is utmost importance not only to find some valuable utilization but also to discovery its mechanisms of defence that can explain its invasive behaviour. In our effort to contribute to this problem solution we establish the GC-MS and UHPLC-MS profiles of both the non-polar and polar extracts. The main compounds in the lipophilic extract were palmitic acid and 1-monopalmitin and brominated compounds dominate both extracts. The detailed results will be presented and discussed in the presentation. info:eu-repo/semantics/publishedVersion

Leishmaniasis is one of the most neglected diseases of modern times that mainly affects people from developing countries, with approximately 350 million people considered at risk of developing leishmaniasis. Therefore, the development of novel antileishmanial treatments is becoming the focus of numerous research groups, with the support of the World Health Organization, which hopes to eradicate this disease in the near future. This review focuses on the interest of chromones for the development of future treatments against leishmaniasis. In addition to plant-based chromone derivatives, structure-activity relationship studies that aim to identify the optimal structural features of the chromones’ antileishmanial activity are also described and discussed. The numerous examples of chromones depicted in this paper, allied with the SAR studies presented herein, suggest that the chromone scaffold is a privileged core for the design and development of novel antileishmanial agents. However, some concerns have been raised concerning the considerable variability observed in the results throughout the scientific bibliography. These inconsistencies may explain the absence of pharmacodynamic and pharmacokinetic studies as well as clinical trials.

Currently drug resistance is rising to dangerously high levels worldwide and threatening our ability to treat even common infectious diseases. Secondary metabolites, especially alkaloids containing an indole group and structurally related to fumiquinazolines, are of crucial importance in the area of drug discovery, having representatives such as fiscalin B that was reported as substance P antagonist and neofiscalin A, a potent antibacterial agent active in both reference and multidrug-resistant isolates. [1] Herein, the synthesis of quinazolinone alkaloid derivatives containing an indole moiety is reported, using two different methodologies – a highly efficient three-component one-pot microwave-assisted and a multi-step Mazurkiewicz-Ganesan approach. With this approach, 38 derivatives were obtained in low to moderate yields and were further tested for their antitumor [2,3], neuroprotection [2], antibacterial, and antifungal activities. While 16 compounds exhibited weak to moderate tumor cell growth inhibitory activity, other four compounds showed potential for in vitro neuroprotection in Parkinson disease. It was also observed for some derivatives a good antibacterial activity against clinical Staphylococcus aureus resistant to methicillin (MRSA). Structure-activity relationship was established and four hit compounds containing the quinazolinone scaffold emerged as potential drug candidates. Acknowledgements: We thank the UID/Multi/04423/2019 through national funds provided by FCT-Foundation for Science and Technology and European Regional Development Fund (ERDF), in the framework of the program PT2020. This research was developed under Project No. POCI-01-0145-FEDER-028736, co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF, and by FCT through national funds, and Solida Long thanks Erasmus-Lotus+ program (LOTUS+, LP15DF0205). References: [1] Resende, D. I. S. P.; Boonpothong, P.; Sousa, E.; Kijjoa, A.; Pinto, M. M. M., Chemistry of the fumiquinazolines and structurally related alkaloids. Natural Product Reports 2019, 36, 7-34. [2] Long, S.; Resende, D. I. S. P.; Kijjoa, A.; Silva, A. M. S.; Fernandes, R.; Xavier, C. P. R.; Vasconcelos, M. H.; Sousa, E.; Pinto, M. M. M., Synthesis of New Proteomimetic Quinazolinone Alkaloids and Evaluation of Their Neuroprotective and Antitumor Effects. Molecules 2019, 24 (3), 534. [3] Long, S.; Resende, D.; Kijjoa, A.; Silva, A.; Pina, A.; Fernandez-Marcelo, T.; Vasconcelos, M.; Sousa, E.; Pinto, M., Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products. Mar. Drugs 2018, 16 (8), 261.

Halophytic grasses have been recently targeted as possible sources of nutraceutical and medicinal compounds. Nonetheless, few studies have been conducted on the phytochemistry and biological activities of metabolites produced by these plants. Among these, Spartina maritima (Curtis) Fernald, Spartina patens (Aiton.) Muhl., and Puccinellia maritima (Hudson) Parl. are three halophytic grasses whose chemical composition and bioactivities are unknown. The present work broadens the knowledge on the polyphenolic and chlorophyll composition of these species identifying for the first time hydroxycinnamic acids and their derivatives, flavones, flavonols, lignans, as well as chlorophylls and xantophylls. The extracts were particularly rich in caffeic and ferulic acids as well as in trihydroxymethoxyflavone, apigenin and tricin derivatives. Interestingly, several of the identified compounds are relevant from a medicinal and nutraceutical point of view putting in evidence the potential of these species. Thus, the antioxidant, anti-acetylcholinesterase, antibacterial, and antifungal activities of the polyphenolic extracts were assessed as well as the photophysical properties of the chlorophyll-rich extracts. The results, herein presented for the first time, reinforce the nutritional and the medicinal potential of these halophytic grasses.

Brown macroalgae, particularly those from Fucus genus, are a rich and balanced source of bioactive nutrients and phytochemicals, such as dietary fibres (fucoidans, laminarins, and/or alginates), phlorotannins, and fucoxanthin, and some minerals, such as iodine, which have been demonstrated to possess numerous health-promoting properties. In fact, aqueous extracts of Fucus vesiculosus have been used as food supplements due to its rich content in bioactive compounds, though no study has been published on the optimization of this operation. Therefore, this study aimed to evaluate the impact of different extraction temperatures (25 &deg, C, 50 &deg, C, 75 &deg, C, 100 &deg, C, and 120 &deg, C) and times (5 min, 1 h, 2 h, and 4 h) on the recovery of those bioactive compounds. The temperature was observed to positively influence the extraction of crude mass and of fucose polysaccharides only at 75 &deg, C and above, and of iodine extraction at 50 &deg, C and above. At these temperatures, time also showed to increase yields. Yields of crude extract, fucose, and iodine were successfully mathematically modelled with a power law, and its maximum yields were obtained at the highest temperature studied (120 &deg, C) and longest extraction time (4 h). Iodine yield at these conditions provided extracts with relevant content to contribute to the recommended daily ingestion. Phlorotannins were significantly recovered at 120 &deg, C though evidence of degradation was observed during time.

The inhibition of carbohydrate-hydrolyzing enzymes, α-amylase and α-glucosidase, is one of the major therapeutic strategies for the treatment of type 2 diabetes mellitus. Chalcones have been recognized for their multiple biological activities, including antidiabetic properties, through unclear mechanisms. In the present work, a panel of chalcones bearing hydroxy, methoxy, methyl, nitro, chloro, fluoro and bromo substituents were evaluated against α-amylase and α-glucosidase activities, most of them for the first time. The results showed that the substitution patterns and the type of substituents of chalcones influence their inhibitory activity. The presence of hydroxy groups at C-2’- and C-4’ of the A ring and at C-3 and C-4 of the B ring favors the intended effect. Chalcones holding nitro groups and chloro substituents, together with a hydroxy group in the chalcone scaffold, showed strong inhibition of the α-glucosidase activity. The present study provides related scaffolds that may serve as the basis for the design and synthesis of new structures in order to obtain the ideal antidiabetic chalcone. This work received financial support from the European Union (FEDER funds POCI/01/0145/FEDER/007265) and National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement PT2020 UID/QUI/50006/2013, and “Programa Operacional Competitividade e Internacionalização” (COMPETE) (POCI-01-0145-FEDER-029241). Thanks are due to University of Aveiro, Instituto Politécnico de Bragança, FCT/ MEC for the financial support to the QOPNA (FCT UID/QUI/ 00062/2013) and CIMO (UID/AGR/00690/2013) research Units through national funds and where applicable co-financed by the FEDER, within the PT2020 Partnership Agreement, and also to the Portuguese NMR Network. Sónia Rocha acknowledges FCT the financial support for the PhD grant (PD/BD/ 145169/2019), in the ambit of “QREN – POPH – Tipologia 4.1 – Formação Avançada”, co-sponsored by Fundo Social Europeu (FSE) and by national funds of Ministério da Ciência, Tecnologia e Ensino Superior (MCTES). info:eu-repo/semantics/publishedVersion

The impact of air-drying at 25 &deg, C, brining at 25%, and dry-salting (at 28% and 40%) on the quality and nutritional parameters of Ulva rigida were evaluated over six months of storage. Overall, the main changes occurred in physical aspects during storage time, with U. rigida intensifying its yellow/browning tones, which were more evident in salt-treated samples. The force necessary to fracture the seaweed also increased under all the preservative conditions in the first month. Conversely, the nutritional parameters of U. rigida remained stable during the 180 days of storage. All processed samples showed a high content of insoluble and soluble fibers, overall accounting for 55%&ndash, 57% dw, and of proteins (17.5%&ndash, 19.2% dw), together with significant amounts of Fe (86&ndash, 92 mg/kg dw). The total fatty acids pool only accounted for 3.9%&ndash, 4.3% dw, but it was rich in unsaturated fatty acids (44%&ndash, 49% total fatty acids), namely palmitoleic (C16:1), oleic (C18:1), linoleic (C18:2), linolenic (C18:3), and stearidonic (18:4) acids, with an overall omega 6/omega 3 ratio below 0.6, a fact that highlights their potential health-promoting properties.

Seaweeds, which have been widely used for human consumption, are considered a potential source of biological compounds, where enzyme-assisted extraction can be an efficient method to obtain multifunctional extracts. Chemical characterization of Sargassum muticum and Osmundea pinnatifida extracts obtained by Alcalase and Viscozyme assisted extraction, respectively, showed an increment of macro/micro elements in comparison to the corresponding dry seaweeds, while the ratio of Na/K decreased in both extracts. Galactose, mannose, xylose, fucose, and glucuronic acid were the main monosaccharides (3.2&ndash, 27.3 mg/glyophilized extract) present in variable molar ratios, whereas low free amino acids content and diversity (1.4&ndash, 2.7 g/100gprotein) characterized both extracts. FTIR-ATR and 1H NMR spectra confirmed the presence of important polysaccharide structures in the extracts, namely fucoidans from S. muticum or agarans as sulfated polysaccharides from O. pinnatifida. No cytotoxicity against normal mammalian cells was observed from 0 to 4 mglyophilized extract/mL for both extracts. The comprehensive characterization of the composition and safety of these two extracts fulfils an important step towards their authorized application for nutritional and/or nutraceutical purposes.

Phlorotannins are phloroglucinol-based phenolic compounds, occurring particularly in brown macroalgae, that have been recognized for their promising bioactive properties. In this study, the extraction of phlorotannins from Fucus vesiculosus was evaluated with particular emphasis on the influential parameters, including the solvent concentration, solvent-solid ratio, extraction temperature and extraction time, using a single-factor design followed by a Box-Behnken design. The maximum total phlorotannin content, determined using the 2,4-dimethoxybenzaldehyde (DMBA) method, corresponded to 2.92 &plusmn, 0.05 mg of phloroglucinol equivalents/g dry seaweed (mg PGE/g DS), and was achieved for extracts carried out with acetone 67% (v/v), a solvent-solid ratio of 70 mL/g and temperature at 25 &deg, C. This crude extract, together with a semi-purified phlorotannin fraction, were further evaluated for their anti-enzymatic capacity against &alpha, glucosidase, &alpha, amylase and pancreatic lipase, both showing promising inhibitory effects, particularly against &alpha, glucosidase for which a greater inhibitory effect was observed compared to the pharmaceutical drug acarbose (IC50 = 4.5 &plusmn, 0.8 and 0.82 &plusmn, 0.3 &mu, g/mL, respectively, against 206.6 &plusmn, 25.1 &mu, g/mL). Additionally, the ultra-high-pressure liquid chromatography coupled to mass spectrometry (UHPLC-MS) analysis carried out on the ethyl acetate fraction revealed the presence of fucols, fucophlorethols, fuhalols and several other phlorotannin derivatives. Moreover, possible new phlorotannin compounds, including fucofurodiphlorethol, fucofurotriphlorethol and fucofuropentaphlorethol, have been tentatively identified in this extract. Overall, this study provides evidence that F. vesiculosus phlorotannin-rich extracts hold potential for the management of the activity of &alpha, amylase and pancreatic lipase, which are well known to be linked to metabolic disorders such as diabetes and obesity.

The hemi-synthesis of chiral imine, benzimidazole and benzodiazepine structures is reported by the condensation of (S)-(&minus, )-perillaldehyde, the major phytochemical of Ammodaucus leucotrichus subsp. leucotrichus essential oil, with different amine derivatives of 2,3-diaminomaleonitrile, o-phenylenediamine and 3-[(2-aminoaryl)amino]dimedone. The reaction proceeds in situ at ambient temperature without prior isolation of the natural (S)-(&minus, )-perillaldehyde. Final products precipitate in the ethanolic reaction medium. 2D NMR and single-crystal X-ray diffraction studies were used to unequivocally characterize the structures in solution and in the solid state, respectively. Chiral HPLC analysis confirms the formation of unique enantiomers and diastereomeric mixtures.

Pyrazoles and their reduced form, pyrazolines, are considered privileged scaffolds in medicinal chemistry, owing to their remarkable biological activities, physicochemical properties and occurrence in many low-molecular-weight compounds present in several marketed drugs (e [...]

Alzheimer's disease (AD) is one of the most common types of dementia, especially in elderly, with an increasing number of people suffering from this disease worldwide. There are no available disease-modifying therapies and only four drugs are approved for the relief of symptoms. Currently, the therapeutic approach used for AD treatment is based on single target drugs, which are not capable to stop its progression. To address this issue, multi-target compounds, combining two or more pharmacophores in a single molecular entity, have gained increasing interest to deal with the multiple factors related to AD. The exact cause of AD is not yet completely disclosed, and several hallmarks have been associated to this neurodegenerative disease. Even though, the accumulation of both amyloid-β plaques (Aβ) and neurofibrillary tangles (NFTs) are fully accepted as the main AD hallmarks, being object of lots of research for early-stage diagnosis and pharmacological therapy. In this context, this review summarizes the state-of-the-art in the field of dual-target inhibitors of both Aβ and tau aggregation simultaneously, including the design and synthetic strategy of the dual-target compounds, as well as a brief structure-activity relationships (SAR) analysis.

α-Glucosidase inhibitors are described as the most effective in reducing post-prandial hyperglycaemia (PPHG) from all available anti-diabetic drugs used in the management of type 2 diabetes mellitus. As flavonoids are promising modulators of this enzyme’s activity, a panel of 44 flavonoids, organised in five groups, was screened for their inhibitory activity of α-glucosidase, based on in vitro structure–activity relationship studies. Inhibitory kinetic analysis and molecular docking calculations were also applied for selected compounds. A flavonoid with two catechol groups in A- and B-rings, together with a 3-OH group at C-ring, was the most active, presenting an IC50 much lower than the one found for the most widely prescribed α-glucosidase inhibitor, acarbose. The present work suggests that several of the studied flavonoids have the potential to be used as alternatives for the regulation of PPHG.

The quest for safer anti-inflammatory drugs is still the focus of several medicinal chemistry programs. Chromones (4H-chromen-4-ones) are a group of naturally occurring compounds ubiquitous in plants, and the chromone core has proven to be a privileged scaffold in medicinal chemistry. Herein we provide an overview of the relevance of chromones as anti-inflammatory agents, specifically as inhibitors of cyclooxygenase (COX), 5-lipoxygenase (5-LOX), interleukin-5 (IL-5), and nitric oxide (. NO) production. Numerous structure-activity relationships and mechanisms of action are discussed. This review is therefore intended to provide a foundation for the design and synthesis of novel chromone-based compound libraries for further development into safer and more efficient anti-inflammatory agents.

3,4-Dihydropyrimidinones were synthesized by a multicomponent condensation of an aldehyde, a β-keto ester, and urea, in acetonitrile and ethanol using Keggin and Dawson type polyoxometalates as catalysts. Keggin heteropolyacid, H 4 SiMO 12 O 40 , is more efficient compared to Keggin and Dawson salts and to the Biginelli classical reaction conditions. It leads to good yields and short reaction times. Theoretical calculations let us to confirm the reaction mechanism.

The pyrazole nucleus and its reduced forms, pyrazolines and pyrazolidine, are privileged scaffolds in medicinal chemistry due to their remarkable biological activities. A huge number of pyrazole derivatives have been studied and reported over time. This review article gives an overview of pyrazole derivatives that contain a styryl (2-arylvinyl) group linked in different positions of the pyrazole backbone. Although there are studies on the synthesis of styrylpyrazoles dating back to the 1970s and even earlier, this type of compound has rarely been studied. This timely review intends to summarize the properties, biological activity, methods of synthesis and transformation of styrylpyrazoles; thus, highlighting the interest and huge potential for application of this kind of compound.

Aminopyridines are key building blocks for the synthesis of bioactive N-heterocyclic compounds such as azaindoles and imidazopyridines. However, the functionalization of aminopyridines is challenging, due to their electronic properties and coordination with metals. Herein we describe a reactivity study of aminopyridines under palladium-catalyzed reaction conditions. Several aminopyridines underwent a one-pot Pd-catalyzed C–N cross coupling reaction/C–H functionalization sequence affording azaindoles. The role of additives, ligands, and bases was investigated. This work consists of a platform for future studies on aminopyridines involving metal-catalyzed reactions and represents the first report on the direct conversion of non-halogenated aminopyridines into azaindoles via Pd-catalyzed C–H functionalization reactions.