Viscosity-Induced Emission of 5-(Diarylmethylene)imidazolone with Extended Conjugation via Attachment of N-Methylpyrrole at the 2-Position.

We have developed a series of 2-monoaryl-5-diarylmethylene analogs of the green fluorescent protein chromophore to study their viscosity-induced emission (VIE) properties. The analogs were synthesized by a condensation with methyl imidate and N-(diarylmethylene)glycinate. Among the analogs, the N-methylpyrrol-2-yl-substituted analog 1h induced the most remarkable VIE behavior in triglyceride and lipid bilayers probably due to the high π-electron-rich property of the pyrrole ring. The pyrrole substituent in imidazolone analogs can be expected to become a common template for introducing VIE behavior.

Synthesis, molecular docking study and biological evaluation of new pyrrole scaffolds as potential antitubercular agents for dual targeting of enoyl ACP reductase and dihydrofolate reductase.

In this study, new series of N'-(2-(substitutedphenoxy)acetyl)-4-(1H-pyrrol-1-yl)benzohydrazides (3a-j) 4-(2,5-dimethyl-1H-pyrrol-1-yl)-N'-(2-(substitutedphenoxy)acetyl)benzohydrazides (5a-j) were synthesized, characterized and assessed as inhibitors of enoyl ACP reductase and DHFR. Most of the compounds exhibited dual inhibition against the enzymes enoyl ACP reductase and DHFR. Several synthesized substances also demonstrated significant antibacterial and antitubercular properties. A molecular docking analysis was conducted in order to determine the potential mechanism of action of the synthesized compounds. The results indicated that there were binding interactions seen with the active sites of dihydrofolate reductase and enoyl ACP reductase. Additionally, important structural details were identified that play a critical role in sustaining the dual inhibitory activity. These findings were useful for the development of future dual inhibitors. Therefore, this study provided strong evidence that several synthesized molecules could exert their antitubercular properties at the cellular level through multi-target inhibition. By shedding light on the mechanisms through which these compounds exert their inhibitory effects, this research opens up promising avenues for the future development of dual inhibitors with enhanced antibacterial and antitubercular properties. The study's findings underscore the importance of multi-target approaches in drug design, providing a strong foundation for the design and optimization of novel compounds that can effectively target bacterial infections at the cellular level.

Synthesis, molecular modelling, and antibacterial evaluation of new sulfonamide-dyes based pyrrole compounds.

In this study, we synthesized new series of 5-oxo-2-phenyl-4-(arylsulfamoyl)sulphenyl) hydrazono)-4,5-dihydro-1H-pyrrole-3-carboxylate hybrids 4a-f with the goal of overcoming sulfonamide resistance and identifying novel therapeutic candidates by chemical changes. The chemical structures of the synthesized hybrids were established over the spectroscopic tools. The frontier molecular orbitals configuration and energetic possessions of the synthesized compounds were discovered utilizing DFT/B3LYP/6-311++ G** procedure. The 3D plots of both HOMO and LUMO showed comparable configuration of both HOMO and LUMO led to close values of their energies. Amongst the prepared analogues, the sulfonamide hybrids 4a-f, hybrid 4a presented potent inhibitory towards S. typhimurium with (IZD = 15 mm, MIC = 19.24 µg/mL) and significant inhibition with (IZD = 19 mm, MIC = 11.31 µg/mL) against E.coli in contrast to sulfonamide (Sulfamethoxazole) reference Whereas, hybrid 4d demonstrated potent inhibition with (IZD = 16 mm, MIC = 19.24 µg/mL) against S. typhimurium with enhanced inhibition against E. Coli, Additionally, the generated sulfonamide analogues'' molecular docking was estimated over (PDB: 3TZF and 6CLV) proteins. Analogue 4e had the highest documented binding score as soon as linked to the other analogues. The docking consequences were fitting and addressed with the antibacterial valuation.

Applications of Pyrrole and Pyridine-based Heterocycles in Cancer Diagnosis and Treatment.

BACKGROUND: The escalation of cancer worldwide is one of the major causes of economy burden and loss of human resources. According to the American Cancer Society, there will be 1,958,310 new cancer cases and 609,820 projected cancer deaths in 2023 in the United States. It is projected that by 2040, the burden of global cancer is expected to rise to 29.5 million per year, causing a death toll of 16.4 million. The hemostasis regulation by cellular protein synthesis and their targeted degradation is required for normal cell growth. The imbalance in hemostasis causes unbridled growth in cells and results in cancer. The DNA of cells needs to be targeted by chemotherapeutic agents for cancer treatment, but at the same time, their efficacy and toxicity also need to be considered for successful treatment. OBJECTIVE: The objective of this study is to review the published work on pyrrole and pyridine, which have been prominent in the diagnosis and possess anticancer activity, to obtain some novel lead molecules of improved cancer therapeutic. METHODS: A literature search was carried out using different search engines, like Sci-finder, Elsevier, ScienceDirect, RSC etc., for small molecules based on pyrrole and pyridine helpful in diagnosis and inducing apoptosis in cancer cells. The research findings on the application of these compounds from 2018-2023 were reviewed on a variety of cell lines, such as breast cancer, liver cancer, epithelial cancer, etc. Results: In this review, the published small molecules, pyrrole and pyridine and their derivatives, which have roles in the diagnosis and treatment of cancers, were discussed to provide some insight into the structural features responsible for diagnosis and treatment. The analogues with the chromeno-furo-pyridine skeleton showed the highest anticancer activity against breast cancer. The compound 5-amino-N-(1-(pyridin-4- yl)ethylidene)-1H-pyrazole-4-carbohydrazides was highly potent against HEPG2 cancer cell. Redaporfin is used for the treatment of cholangiocarcinoma, biliary tract cancer, cisplatin-resistant head and neck squamous cell carcinoma, and pigmentation melanoma, and it is in clinical trials for phase II. These structural features present a high potential for designing novel anticancer agents for diagnosis and drug development. CONCLUSION: Therefore, the N- and C-substituted pyrrole and pyridine-based novel privileged small Nheterocyclic scaffolds are potential molecules used in the diagnosis and treatment of cancer. This review discusses the reports on the synthesis of such molecules during 2018-2023. The review mainly discusses various diagnostic techniques for cancer, which employ pyrrole and pyridine heterocyclic scaffolds. Furthermore, the anticancer activity of N- and C-substituted pyrrole and pyridine-based scaffolds has been described, which works against different cancer cell lines, such as MCF-7, A549, A2780, HepG2, MDA-MB-231, K562, HT- 29, Caco-2 cells, Hela, Huh-7, WSU-DLCL2, HCT-116, HBL-100, H23, HCC827, SKOV3, etc. This review will help the researchers to obtain a critical insight into the structural aspects of pyrrole and pyridine-based scaffolds useful in cancer diagnosis as well as treatment and design pathways to develop novel drugs in the future.

Anchoring chitosan/phytic acid complexes on polypyrrole nanotubes as capacitive deionization electrodes for uranium capture from wastewater.

Capacitive deionization (CDI) technology holds great potential for rapid and efficient uranyl ion removal from wastewater. However, the related electrode materials still have much room for research. Herein, chitosan/phytic acid complexes were anchored on polypyrrole nanotubes (CS/PA-PPy) to fabricate the electrode for the electrosorption of uranyl ions (UO22+). In this system, polypyrrole nanotubes provided specific channels for ion and electron diffusion, and chitosan/phytic acid complexes offered selective sites for UO22+ binding. The results demonstrated that CS/PA-PPy via electrosorption showed faster kinetics and higher uranium uptake than those via physicochemical adsorption. The maximum adsorption capacity toward UO22+ via electrosorption (1.2 V) could reach 799.3 mg g-1, which was higher than most of the reported CDI electrodes. Electrochemical measurements and experimental characterizations showed that the electrosorption of UO22+ by CS/PA-PPy was a synergistic effect of capacitive process and physicochemical adsorption, in which the capacitive mechanism involved the formation of an electric double layer from hollow polypyrrole nanotubes, whereas the coordination of phosphate, amino and hydroxyl groups with UO22+ was attributed to physicochemical adsorption. With the rational design of material, along with its excellent uranium removal performance, this work exhibited a novel and potential composite electrode for uranium capture via CDI from wastewater.

The discovery of a novel pyrrolo[2,3-b]pyridine as a selective CDK8 inhibitor offers a new approach against psoriasis.

Currently, the drugs used in clinical to treat psoriasis mainly broadly suppress cellular immunity. However, these drugs can only provide temporary and partial symptom relief, they do not cure the condition and may lead to recurrence or even serious toxic side effects. In this study, we describe the discovery of a novel potent CDK8 inhibitor as a treatment for psoriasis. Through structure-based design, compound 46 was identified as the most promising candidate, exhibiting a strong inhibitory effect on CDK8 (IC50 value of 57 nM) along with favourable inhibition against NF-κB. Additionally, it demonstrated a positive effect in an in vitro psoriasis model induced by TNF-α. Furthermore, this compound enhanced the thermal stability of CDK8 and exerted evident effects on the biological function of CDK8, and it had favourable selectivity across the CDK family and tyrosine kinase. This compound showed no obvious inhibitory effect on CYP450 enzyme. Further studies confirmed that compound 46 exhibited therapeutic effect on IMQ-induced psoriasis, alleviated the inflammatory response in mice, and enhanced the expression of Foxp3 and IL-10 in the dorsal skin in vivo. This discovery provides a new strategy for developing selective CDK8 inhibitors with anti-inflammatory activity for the treatment of psoriasis.

Fungicidal Activity of New Pyrrolo[2,3-d]thiazoles and Their Potential Action on the Tryptophan Metabolic Pathway and Wax Biosynthesis.

The main challenge in the development of agrochemicals is the lack of new leads and/or targets. It is critical to discover new molecular targets and their corresponding ligands. YZK-C22, which contains a 1,2,3-thiadiazol-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole skeleton, is a fungicide lead compound with broad-spectrum fungicidal activity. Previous studies suggested that the [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole scaffold exhibited good antifungal activity. Inspired by this, a series of pyrrolo[2,3-d]thiazole derivatives were designed and synthesized through a bioisosteric strategy. Compounds C1, C9, and C20 were found to be more active against Rhizoctonia solani than the positive control YZK-C22. More than half of the target compounds provided favorable activity against Botrytis cinerea, where the EC50 values of compounds C4, C6, C8, C10, and C20 varied from 1.17 to 1.77 µg/mL. Surface plasmon resonance and molecular docking suggested that in vitro potent compounds C9 and C20 have a new mode of action instead of acting as pyruvate kinase inhibitors. Transcriptome analysis revealed that compound C20 can impact the tryptophan metabolic pathway, cutin, suberin, and wax biosynthesis of B. cinerea. Overall, pyrrolo[2,3-d]thiazole is discovered as a new fungicidal lead structure with a potential new mode of action for further exploration.

Denigrins H-L: Sulfated Derivatives of Denigrins D and E from a New Zealand Dictyodendrilla c.f. dendyi Marine Sponge.

Five new sulfated arylpyrrole and arylpyrrolone alkaloids, denigrins H-L (1-5), along with two known compounds, dictyodendrin B and denigrin G, were isolated from an extract of a New Zealand Dictyodendrilla c.f. dendyi marine sponge. Denigrins H-L represent the first examples of sulfated denigrins, with denigrins H and I (1-2), as derivatives of denigrin D, containing a pyrrolone core, and denigrins J-L (3-5), as derivatives of denigrin E (6), containing a pyrrole core. Their structures were elucidated by interpretation of 1D and 2D NMR spectroscopic data, ESI, and HR-ESI-MS spectrometric data, as well as comparison with literature data. Compounds 1-5, along with six known compounds previously isolated from the same extract, showed minimal cytotoxicity against the HeLa cervical cancer cell line.

Akt Inhibitor Advancements: From Capivasertib Approval to Covalent-Allosteric Promises.

Akt kinase is vital in cell growth, survival, metabolism, and migration. Dysregulation of Akt signaling is implicated in cancer and metabolic disorders. In the context of cancer, overactive Akt promotes cell survival and proliferation. This has spurred extensive research into developing Akt inhibitors as potential therapeutic agents to disrupt aberrant Akt signaling. Akt inhibitors are classified into three main types: ATP-competitive, allosteric, and covalent-allosteric inhibitors (CAAIs). ATP-competitive inhibitors compete with ATP for binding to Akt, allosteric inhibitors interact with the Pleckstrin homology (PH) domain, and covalent-allosteric inhibitors form covalent bonds, making them more potent and selective. Notably, capivasertib (AZD5363), a potent ATP-competitive Akt inhibitor, received FDA approval in November 2023 for use in combination with the estrogen receptor degrader fulvestrant to treat breast cancer. Challenges remain, including improving selectivity, identifying biomarkers to tailor treatments, and enhancing therapeutic efficacy while minimizing adverse effects. Particularly covalent-allosteric inhibitors hold promise for future more effective and personalized treatments.

Tofacitinib and peficitinib inhibitors of Janus kinase for autoimmune disease treatment: a quantum biochemistry approach.

Autoimmune inflammatory diseases, such as rheumatoid arthritis (RA) and ulcerative colitis, are associated with an uncontrolled production of cytokines leading to the pronounced inflammatory response of these disorders. Their therapy is currently focused on the inhibition of cytokine receptors, such as the Janus kinase (JAK) protein family. Tofacitinib and peficitinib are JAK inhibitors that have been recently approved to treat rheumatoid arthritis. In this study, an in-depth analysis was carried out through quantum biochemistry to understand the interactions involved in the complexes formed by JAK1 and tofacitinib or peficitinib. Computational analyses provided new insights into the binding mechanisms between tofacitinib or peficitinib and JAK1. The essential amino acid residues that support the complex are also identified and reported. Additionally, we report new interactions, such as van der Waals; hydrogen bonds; and alkyl, pi-alkyl, and pi-sulfur forces, that stabilize the complexes. The computational results revealed that peficitinib presents a similar affinity to JAK1 compared to tofacitinib based on their interaction energies.

Dynamic simulation and experimental studies of molecularly imprinted label-free sensor for determination of milk quality marker.

Bovine serum albumin (BSA) has emerged as a biomarker for mammary gland health and cow quality, being recognized as a significant allergenic protein. In this study, a novel flexible molecular imprinted electrochemical sensor by surface electropolymerization using pyrrole (Py) as functional monomer, which can be better applied to the detection of milk quality marker BSA. Based on computational results, with regard to all polypyrrole (PPy) conformations and amino-acid positions within the protein, the BSA molecule remained firmly embedded into PPy polymers with no biological changes. The molecular imprinted electrochemical sensor displayed a broad linear detection range from 1.0 × 10-4 to 50 ng·mL-1 (R2 = 0.995) with a low detection limit (LOD) of 4.5 × 10-2 pg·mL-1. Additionally, the sensor was highly selective, reproducible, stable and recoverable, suggesting that it might be utilized for the evaluation of milk quality.

Enhancing Glioblastoma Immunotherapy with Integrated Chimeric Antigen Receptor T Cells through the Re-Education of Tumor-Associated Microglia and Macrophages.

Glioblastoma (GBM) is an aggressive brain cancer that is highly resistant to treatment including chimeric antigen receptor (CAR)-T cells. Tumor-associated microglia and macrophages (TAMs) are major contributors to the immunosuppressive GBM microenvironment, which promotes tumor progression and treatment resistance. Hence, the modulation of TAMs is a promising strategy for improving the immunotherapeutic efficacy of CAR-T cells against GBM. Molecularly targeting drug pexidartinib (PLX) has been reported to re-educate TAMs toward the antitumorigenic M1-like phenotype. Here, we developed a cell-drug integrated technology to reversibly conjugate PLX-containing liposomes (PLX-Lip) to CAR-T cells and establish tumor-responsive integrated CAR-T cells (PLX-Lip/AZO-T cells) as a combination therapy for GBM. We used a mouse model of GBM to show that PLX-Lip was stably maintained on the surface of PLX-Lip/AZO-T cells in circulation and these cells could transmigrate across the blood-brain barrier and deposit PLX-Lip at the tumor site. The uptake of PLX-Lip by TAMs effectively re-educated them into the M1-like phenotype, which in turn boosted the antitumor function of CAR-T cells. GBM tumor growth was completely eradicated in 60% of the mice after receiving PLX-Lip/AZO-T cells and extended their overall survival time beyond 50 days; in comparison, the median survival time of mice in other treatment groups did not exceed 35 days. Overall, we demonstrated the successful fusion of CAR-T cells and small-molecule drugs with the cell-drug integrated technology. These integrated CAR-T cells provided a superior combination strategy for GBM treatment and presented a reference for the construction of integrated cell-based drugs.

Insight into soft chemometric computational learning for modelling oily-wastewater separation efficiency and permeate flux of polypyrrole-decorated ceramic-polymeric membranes.

Reliable modeling of oily wastewater emphasizes the paramount importance of sustainable and health-conscious wastewater management practices, which directly aligns with the Sustainable Development Goals (SDG) while also meeting the guidelines of the World Health Organization (WHO). This research explores the efficiency of utilizing polypyrrole-coated ceramic-polymeric membranes to model oily wastewater separation efficiency (SE) and permeate flux (PF) based on established experimental procedures. In this area, computational simulation still needs to be explored. The study developed predictive regression models, including robust linear regression (RLR), stepwise linear regression (SWR) and linear regression (LR) for the ceramic-polymeric porous membrane, aiming to interpret its complex performance across diverse conditions and, thus, develop its utility in oily wastewater treatment applications. Subsequently, a novel, simple average ensemble paradigm was explored to reduce errors and improve prediction skills. Prior to the development of the model, stability and reliability analysis of the data was conducted based on Philip Perron tests with the Bartlett kernel estimation method. The accuracy of the SE exhibited a high consistency, averaging 99.92% with minimal variability (standard deviation of 0.026%), potentially simplifying its prediction compared to PF. The modes were validated and evaluated using metrics like MAE, RMSE, Speed, and MSE, in addition to 2D graphical and cumulative distribution function graphs. The LR model emerged as the best with the lowest RMSE =0.21951, indicating superior prediction accuracy, followed closely by RLR with an RMSE = 0.22359. SWLR, while having the highest RMSE = 0.34573, marked its dominance in prediction speed with 110 observations per second. Notably, the RLR model justified a reduction in error by approximately 35.29% compared to SWLR. Moreover, the training efficiency of the LR model exceeded, demanding a mere 2.9252 s, marking a reduction of about 32.54% compared to SWLR. The improved simple ensemble learning proved merit over the three models regarding error accuracy. This study emphasizes the essential role of soft-computing learning in optimizing the design and performance of ceramic-polymeric membranes.

A liquid metal/polypyrrole electrospun TPU composite conductive network for highly sensitive strain sensing in human motion monitoring.

Developing soft wearable sensors with high sensitivity, low cost, and a wide monitoring range is crucial for monitoring human health. Despite advances in strain sensor technology, achieving high sensitivity and a wide operating range in a single device remains a major challenge in its design and preparation. Herein, a liquid metal (LM) is innovatively ultrasonically anchored to the gaps and surfaces of thermoplastic polyurethane (TPU) electrospun fibers, and then a conductive pathway is constructed through polypyrrole (PPy) self-polymerization to prepare a composite film. The strain sensor developed by ultrasonic anchoring and original polymerization technology shows a high strain coefficient (GF = 4.36 at 12.5% strain) and a low detection limit (less than 1% strain). Importantly, this sensor can monitor joint motion and subtle skin deformations in real time. In addition, the integration of strain sensors and N95 masks enables real-time monitoring of human respiration.

Potentiometric sensing of ibuprofen over ferric oxide doped chitosan grafted polypyrrole-based electrode.

The present work demonstrates the correlation between structure, properties, and self-sensing protocols of in situ prepared ferric oxide doped grafted copolymer composite, comprised of ferric oxide, chitosan, and polypyrrole (α-Fe2O3-en-CHIT-g-PPy) for residual ibuprofen present in natural and artificial samples. The chemical structure, morphology, functionality, and physio-mechanical properties of the composite were determined by Fourier transform infrared spectrometer (FT-IR), Raman spectra, X-ray diffraction (XRD), Scanning electron microscope (SEM), X-ray photoelectron spectroscopy (XPS), Two probe method, and standard ASTM techniques to explore sensing nature. The results confirm the evolution of axially aligned structure against 110 planes of α-Fe2O3 and chemically functionalized expanded polymer matrix during in-situ chemical polymerization of pyrrole, with better porosity, interactivity, and improved electrical conductivity i.e. 7.32 × 10-3 S cm-1. Further, a thin film of prepared composite coated on an ITO glass plate was explored for potentiometric sensing of ibuprofen (IBU) present in artificial and natural samples without the use of any additional energy sources. The observed sensing parameters are the sensing ranging 0.5 µM to 100.0 µM, sensitivity 2.5081 mV µM-1 cm-2, response time 50 s, recovery time 10 s, and stability for 60 days. The sensing mechanism of the IBU sensor and effective charge transfer in the electrode was also discussed based on changes in IR spectra of the electrode recorded before and after sensing due to surface oxidation of IBU due to the presence of iron and doping effect of iron oxide in the composite.

Discovery of a new class of potent pyrrolo[3,4-c]quinoline-1,3-diones based inhibitors of human dihydroorotate dehydrogenase: Synthesis, pharmacological and toxicological evaluation.

Twenty N-substituted pyrrolo[3,4-c]quinoline-1,3-diones 3a-t were synthesized by a cyclization reaction of Pfitzinger's quinoline ester precursor with the selected aromatic, heteroaromatic and aliphatic amines. The structures of all derivatives were confirmed by IR, 1H NMR, 13C NMR and HRMS spectra, while their purity was determined using HPLC techniques. Almost all compounds were identified as a new class ofpotent inhibitors against hDHODH among which 3a and 3t were the most active ones with the same IC50 values of 0.11 µM, about seven times better than reference drug leflunomide. These two derivatives also exhibited very low cytotoxic effects toward healthy HaCaT cells and the optimal lipophilic properties with logP value of 1.12 and 2.07 respectively, obtained experimentally at physiological pH. We further evaluated the comparative differences in toxicological impact of the three most active compounds 3a, 3n and 3t and reference drug leflunomide. The rats were divided into five groups and were treated intraperitoneally, control group (group I) with a single dose of leflunomide (20 mg/kg) group II and the other three groups, III, IV and V were treated with 3a, 3n and 3t (20 mg/kg bw) separately. The investigation was performed in liver, kidney and blood by examining serum biochemical parameters and parameters of oxidative stress.

LC-MS/MS method for quick detection of vonoprazan fumarate in human plasma: Development, validation and its application to a bioequivalence study.

A liquid chromatography-tandem mass spectrometry method with vonoprazan fumarate-d4 as a stable isotope-labeled internal standard was developed and validated aiming at quantification of vonoprazan fumarate in human plasma for a bioequivalence study. Chromatographic separation was achieved by acetonitrile one-step protein precipitation using a gradient elution of 0.1% formic acid aqueous solution and acetonitrile with a run time of 3.65 min. Detection was carried out on a tandem mass spectrometer in multiple reaction monitoring mode via a positive electrospray ionization interface. The multiple reaction monitoring mode of precursor-product ion transitions for vonoprazan fumarate and vonoprazan fumarate-d4 were m/z 346.0 → 315.1 and 350.0 → 316.0, respectively. The linear range was 0.150-60.000 ng/ml. This method was fully validated with acceptable results in terms of selectivity, carryover, lower limit of quantification, calibration curve, accuracy, precision, dilution effect, matrix effect, stability, recovery and incurred sample reanalysis. A successful application of this method was realized in the bioequivalence study of vonoprazan fumarate tablet (20 mg) among healthy Chinese volunteers.

Reagentless Glucose Biosensor Based on Combination of Platinum Nanostructures and Polypyrrole Layer.

Two types of low-cost reagentless electrochemical glucose biosensors based on graphite rod (GR) electrodes were developed. The electrodes modified with electrochemically synthesized platinum nanostructures (PtNS), 1,10-phenanthroline-5,6-dione (PD), glucose oxidase (GOx) without and with a polypyrrole (Ppy) layer-(i) GR/PtNS/PD/GOx and (ii) GR/PtNS/PD/GOx/Ppy, respectively, were prepared and tested. Glucose biosensors based on GR/PtNS/PD/GOx and GR/PtNS/PD/GOx/Ppy electrodes were characterized by the sensitivity of 10.1 and 5.31 µA/(mM cm2), linear range (LR) up to 16.5 and 39.0 mM, limit of detection (LOD) of 0.198 and 0.561 mM, good reproducibility, and storage stability. The developed glucose biosensors based on GR/PtNS/PD/GOx/Ppy electrodes showed exceptional resistance to interfering compounds and proved to be highly efficient for the determination of glucose levels in blood serum.

A biomimetic approach to lycogarubin C, lynamicin D and related analogues.

An efficient and biomimetic synthetic approach to 3,4-diindolylpyrrole-2,5-dicarboxylate derivatives, including lycogarubin C, lynamicin D and related analogues, was discovered. The crucial transformation included the one-pot formation of two C-N bonds and one C-C bond to construct characteristic pyrrole rings.

N-Cinnamoylpyrrole-derived alkaloids from the genus Piper as promising agents for ischemic stroke by targeting eEF1A1.

BACKGROUND: Ischemic stroke (IS) is a serious cerebrovascular disease characterized by significantly elevated mortality and disability rates, and the treatments available for this disease are limited. Neuroinflammation and oxidative stress are deemed the major causes of cerebral ischemic injury. N-Cinnamoylpyrrole alkaloids form a small group of natural products from the genus Piper and have not been extensively analyzed pharmacologically. Thus, identifying the effect and mechanism of N-cinnamoylpyrrole-derived alkaloids on IS is worthwhile. PURPOSE: The present research aimed to explore the antineuroinflammatory and antioxidative stress effects of N-cinnamoylpyrrole-derived alkaloids isolated from the genus Piper and to explain the effects and mechanism on IS. METHODS: N-cinnamoylpyrrole-derived alkaloids were isolated from Piper boehmeriaefolium var. tonkinense and Piper sarmentosum and identified by various chromatographic methods. Lipopolysaccharide (LPS)-induced BV-2 microglia and a mouse model intracerebroventricularly injected with LPS were used to evaluate the antineuroinflammatory and antioxidative stress effects. Oxygen‒glucose deprivation/reperfusion (OGD/R) and transient middle cerebral artery occlusion (tMCAO) models were used to evaluate the effect of PB-1 on IS. To elucidate the fundamental mechanism, the functional target of PB-1 was identified by affinity-based protein profiling (ABPP) strategy and verified by cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and circular dichroism (CD) analyses. The effect of PB-1 on the NF-κB and NRF2 signaling pathways was subsequently evaluated via western blotting and immunofluorescence staining. RESULTS: The results showed that N-cinnamoylpyrrole-derived alkaloids significantly affected neuroinflammation and oxidative stress. The representative compound, PB-1 not only inhibited neuroinflammation and oxidative stress induced by LPS or OGD/R insult, but also alleviated cerebral ischemic injury induced by tMCAO. Further molecular mechanism research found that PB-1 promoted antineuroinflammatory and antioxidative stress activities via the NF-κB and NRF2 signaling pathways by targeting eEF1A1. CONCLUSION: Our research initially unveiled that the therapeutic impact of PB-1 on cerebral ischemic injury might rely on its ability to target eEF1A1, leading to antineuroinflammatory and antioxidative stress effects. The novel discovery highlights eEF1A1 as a potential target for IS treatment and shows that PB-1, as a lead compound that targets eEF1A1, may be a promising therapeutic agent for IS.