Novel aurone-derived piperazine sulfonamides: Development and mechanisms of action as immunostimulants against plant bacterial diseases.

Bacterial diseases pose a significant threat to the sustainable production of crops. Given the unsatisfactory performance and poor eco-compatibility of conventional bactericides, here we present a series of newly structured bactericides that are inspiringly designed by aurone found in plants of the Asteraceae family. These aurone-derived compounds contain piperazine sulfonamide motifs and have shown promising in vitro performance against Xanthomonas oryzae pv. oryzae, Xanthomonas oryzae pv. oryzicola and Xanthomonas axonopodis pv. citri, in particular, compound II23 achieved minimum half-maximal effective concentrations of 1.06, 0.89, and 1.78 µg/mL, respectively. In vivo experiments conducted in a greenhouse environment further revealed that II23 offers substantial protective and curative effects ranging between 68.93 and 70.29% for rice bacterial leaf streak and 53.17-64.43% for citrus bacterial canker, which stands in activity compared with lead compound aurone and commercial thiodiazole copper. Additional physiological and biochemical analyses, coupled with transcriptomics, have verified that II23 enhances defense enzyme activities and chlorophyll levels in rice. Significantly, it also stimulates the accumulation of abscisic acid (ABA) and upregulates the expression of key genes OsPYL/RCAR5, OsBIPP2C1, and OsABF1, thereby activating the ABA signaling pathway in rice plants under biological stress from bacterial infections.

Synthesis, molecular docking evaluation for LOX and COX-2 inhibition and determination of in-vivo analgesic potentials of aurone derivatives.

In the current study, seven (7) aurone derivatives (ADs) were synthesized and employed to in-vitro LOX and COX-2 assays, in-vivo models of acetic acid-induced mice writhing, formalin-induced mice paw licking and tail immersion test to evaluate their analgesic potential at the doses of 10 mg and 20 mg/kg body weight. Molecular docking was performed to know the active binding site at both LOX and COX-2 as compared to standard drugs. Among the ADs, 2-(3,4-dimethoxybenzylidene)benzofuran-3(2H)-one (WE-4)possessed optimal LOX and COX-2 inhibitory strength (IC50=0.30 µM and 0.22 µM) as compared to standard (ZileutonIC50 = 0.08 µM, CelecoxibIC50 = 0.05 µM). Similarly in various pain models compound WE-4 showed significantly (p < 0.05) highest percent analgesic potency as compared to control at a dose of 20 mg/kg i.e. 77.60 % analgesic effect in acetic acid model, 49.97 % (in Phase-1) and 70.93 % (inPhase-2) analgesic effect in formalin pain model and 74.71 % analgesic response in tail immersion model. By the administration of Naloxone, the tail flicking latencies were reversed (antagonized) in all treatments. The WE-4 (at 10 mg/kg and 20 mg/kg) was antagonized after 90 min from 11.23 ± 0.93 and 13.41 ± 1.21 to 5.30 ± 0.48 and 4.80 ± 0.61 respectively as compared to standard Tramadol (from 17.74 ± 1.33 to 3.70 ± 0.48), showing the opiodergic receptor involvement. The molecular docking study of ADs revealed that WE-4 had a higher affinity for LOX and COX-2 with docking scores of -4.324 and -5.843 respectively. As a whole, among the tested ADs, compound WE-4 demonstrated excellent analgesic effects that may have been caused by inhibiting the LOX and COX-2 pathways.

Design and Synthesis of Novel Amino and Acetamidoaurones with Antimicrobial Activities.

The development of new and effective antimicrobial compounds is urgent due to the emergence of resistant bacteria. Natural plant flavonoids are known to be effective molecules, but their activity and selectivity have to be increased. Based on previous aurone potency, we designed new aurone derivatives bearing acetamido and amino groups at the position 5 of the A ring and managing various monosubstitutions at the B ring. A series of 31 new aurone derivatives were first evaluated for their antimicrobial activity with five derivatives being the most active (compounds 10, 12, 15, 16, and 20). The evaluation of their cytotoxicity on human cells and of their therapeutic index (TI) showed that compounds 10 and 20 had the highest TI. Finally, screening against a large panel of pathogens confirmed that compounds 10 and 20 possess large spectrum antimicrobial activity, including on bioweapon BSL3 strains, with MIC values as low as 0.78 µM. These results demonstrate that 5-acetamidoaurones are far more active and safer compared with 5-aminoaurones, and that benzyloxy and isopropyl substitutions at the B ring are the most promising strategy in the exploration of new antimicrobial aurones.

Pyrazole-based and N,N-diethylcarbamate functionalized some novel aurone analogs: Design, synthesis, cytotoxic evaluation, docking and SAR studies, against AGS cancer cell line.

The present study involves the design, synthesis, and biological evaluation of a series of thirty-three, pyrazole-based and N,N-diethylcarbamate functionalized, novel aurone analogs, against AGS cancer cell line. These novel aurone analogs are obtained from the reaction of pyrazole-based 6-hydroxyaurones with diethyl carbamoyl chloride using mild basic reagent. The cytotoxic activities of these compounds were evaluated against a human gastric adenocarcinoma cell line (AGS) and disclosed some potential outcomes as several analogs were found to have cytotoxicity better than the reference drugs Oxaliplatin and Leucovorin. The structure-activity relationship (SAR) study further unveiled the critical role of replacing the hydroxyl group in ring A with a carbamoyl group for cytotoxic activity. Among these aurone analogs, 8e and 8f, with IC50 values of 6.5 ± 0.024 µM and 6.6 ± 0.035 µM, respectively, are identified as the most active compounds. Molecular docking studies were conducted against HER2, a human epidermal growth factor involved in gastric and ovarian cancer, to investigate the binding interactions between the compounds and the protein HER2, where7e and 8e exhibited maximum interactions.

Hybrid pharmacophore design and synthesis of donepezil-inspired aurone derivative salts as multifunctional acetylcholinesterase inhibitors.

Flavonoids, a ubiquitous group of plant polyphenols, are well-known for their beneficial effects on human health. Their phenylchromane skeletons have structural similarities to donepezil [the US FDA-approved drug used to treat Alzheimer's disease (AD)]. The objective of this study was to design and synthesize valuable agents derived from flavonoids for relieving the symptoms of AD. A variety of flavonoid derivative salts incorporating benzylpyridinium units were synthesized and several of them remarkedly inhibited acetylcholinesterase (AChE) activity in vitro. Additionally, aurone derivative salts protected against cell death resulting from t-BHP exposure in rat pheochromocytoma PC12 cells and slightly promoted neurite outgrowth. Furthermore, they potently suppressed the aggregation of amyloid-ß (Aß1-42). Our findings highlight the effectiveness of donepezil-inspired aurone derivative salts as multipotent candidates for AD.

Design, synthesis, biological evaluation and molecular docking of alkoxyaurones as potent pancreatic lipase inhibitors.

Aurones are a minor subgroup of flavonoids. Unlike other subgroups such as chalcones, flavones, and isoflavones, aurones have not been extensively explored as pancreatic lipase inhibitors. In this work, we studied the pancreatic lipase inhibitory potency of synthetic aurone derivatives. Thirty-six compounds belonging to four series (4,6-dihydroxyaurone, 6-hydroxyaurone, 4,6-dialkoxyaurone, and 6-alkoxyaurone) were designed and synthesized. Their in vitro inhibitory activities were determined by spectrophotometric assay in comparison with quercetin and orlistat. Alkoxyaurone derivatives with long-chain (6-10 carbons) alkoxy substituents showed greater potency. Of them, 4,6-dialkoxyaurone 8 displayed the highest activity against pancreatic lipase (IC50 of 1.945 ± 0.520 µM) relative to quercetin (IC50 of 86.98 ± 3.859 µM) and orlistat (IC50 of 0.0334 ± 0.0015 µM). Fluorescence quenching measurement confirmed the affinity of alkoxyaurone derivatives to pancreatic lipase. Kinetic study showed that 8 inhibited lipase through a competitive mechanism (Ki of 1.288 ± 0.282 µM). Molecular docking results clarified the role of long-chain substituents on ring A in interacting with the hydrophobic pockets and pushing the inhibitor molecule closer to the catalytic triad. The findings in this study may contribute to the development of better pancreatic lipase inhibitors with aurone structure.

Aurones and derivatives as promising New Delhi metallo-ß-lactamase (NDM-1) inhibitors.

Bacterial resistance is undoubtedly one of the main public health concerns especially with the emergence of metallo-ß-lactamases (MBLs) able to hydrolytically inactivate ß-lactam antibiotics. Currently, there are no inhibitors of MBLs in clinical use to rescue antibiotic action and the New Delhi metallo-ß-lactamase-1 (NDM-1) is still considered as one of the most relevant targets for inhibitor development. Following a fragment-based strategy to find new NDM-1 inhibitors, we identified aurone as a promising scaffold. A series of 60 derivatives were then evaluated and two of them were identified as promising inhibitors with Ki values as low as 1.7 and 2.5 µM. Moreover, these two most active compounds were able to potentiate meropenem in in vitro antimicrobial susceptibility assays. The molecular modelling provided insights about their likely interactions with the active site of NDM-1, thus enabling further improvement in the structure of this new inhibitor family.

Repurposing Synthetic Congeners of a Natural Product Aurone Unveils a Lead Antitumor Agent Inhibiting Folded P-Loop Conformation of MET Receptor Tyrosine Kinase.

A library of 24 congeners of the natural product sulfuretin were evaluated against nine panels representing nine cancer diseases. While sulfuretin elicited very weak activities at 10 µM concentration, congener 1t was identified as a potential compound triggering growth inhibition of diverse cell lines. Mechanistic studies in HCT116 colon cancer cells revealed that congener 1t dose-dependently increased levels of cleaved-caspases 8 and 9 and cleaved-PARP, while it concentration-dependently decreased levels of CDK4, CDK6, Cdc25A, and Cyclin D and E resulting in induction of cell cycle arrest and apoptosis in colon cancer HCT116 cells. Mechanistic study also presented MET receptor tyrosine kinase as the molecular target mediating the anticancer activity of compound 1t in HCT116 cells. In silico study predicted folded p-loop conformation as the form of MET receptor tyrosine kinase responsible for binding of compound 1t. Together, the current study presents compound 1t as an interesting anticancer lead for further development.

Evaluation of the Antibacterial Effect of Aurone-Derived Triazoles on Staphylococcus aureus.

Infections caused by antibiotic-resistant bacteria continue to pose a significant public health threat despite their overall decreasing numbers in the last two decades. One group of compounds fundamental to the search for new agents is low-cost natural products. In this study, we explored a group of newly synthesized novel aurone-derived triazole compounds to identify those with pharmaceutical potential as inhibitors of antibiotic-resistant Staphylococcus aureus. Using the broth microdilution method, antibacterial activities against methicillin-resistant S. aureus ATCC 43300 (MRSA) and methicillin-sensitive S. aureus ATCC 29213 (MSSA) were identified for four aurone-derived triazole compounds, AT106, AT116, AT125, and AT137, using the half-maximal inhibitory concentrations for the bacteria (IC50) and mammalian cell lines (CC50). Compounds AT125 and AT137 were identified to have pharmaceutical potential as the IC50 values against MRSA were 5.412 µM and 3.870 µM, whereas the CC50 values measured on HepG2 cells were 50.57 µM and 39.81 µM, respectively, resulting in selectivity indexes (SI) > 10. Compounds AT106 and AT116 were also selected for further study. IC50 values for these compounds were 5.439 µM and 3.178 µM, and the CC50 values were 60.33 µM and 50.87 µM, respectively; however, SI values > 10 were for MSSA only. Furthermore, none of the selected compounds showed significant hemolytic activity for human erythrocytes. We also tested the four compounds against S. aureus biofilms. Although AT116 and AT125 successfully disrupted MSSA biofilms, there was no measurable potency against MRSA biofilms. Checkerboard antibiotic assays to identify inhibitory mechanisms for these compounds indicated activity against bacterial cell membranes and cell walls, supporting the pharmaceutical potential for aurone-derived triazoles against antibiotic-resistant bacteria. Examining structure-activity relationships between the four compounds in this study and other aurone-derived triazoles in our library suggest that substitution with a halogen on either the salicyl ring or triazole aryl group along with triazoles having nitrile groups improves anti-Staphylococcal activity with the location of the functionality being very important.

Some morpholine tethered novel aurones: Design, synthesis, biological, kinetic and molecular docking studies.

Enzymes are the biological macromolecules that have emerged as an important drug target as their upregulation/imbalance leads to various pathological conditions, such as inflammation, parasitic infection, Alzheimer's, cancer, and many others. Here, we designed and synthesized some morpholine tethered novel aurones and evaluated them as potential inhibitors for CTSB, α-amylase, lipase and activator for trypsin. All the newly synthesized compounds were fully characterized by various spectroscopic techniques (1H NMR, 13C NMR, HRMS) and the Z-configuration to them was assigned based on single crystal XRD data and 1H NMR chemical shift values. Further, the hybrids were evaluated for their intracellular (cathepsin B) and extracellular (trypsin, lipase, amylase) enzyme inhibition potencies. The in-vitro inhibition screening against cathepsin B revealed that most of the synthesized compounds are good competitive inhibitors (% inhibition = 22.91-75.04), with 6q (% inhibition = 75.04) and 6r (% inhibition = 71.13) as the eminent inhibitors of the series. At the same time, they exhibited weak to moderate inhibition towards amylase (% inhibition = 7.22-22.48) and lipase (% inhibition = 16.29-54.83). A significant trypsin activation (% activation = 107.42-196.47) was observed even at the micromolar concentration of the compounds. Furthermore, the drug-modeling studies showed a good correlation between the in-vitro experimental results and the calculated binding affinity of the screened compounds with all the tested enzymes. These findings are expected to provide a new lead in drug development for different pathological disorders wherever these enzymes are involved.

An update of aurones: food resource, health benefit, biosynthesis and application.

Aurones are a subclass of active flavonoids characterized with a scaffold of 2-benzylidene-3(2H)-benzofuranone. This type of chemicals are widely distributed in fruit, vegetable and flower, and contribute to human health. In this review, we summarize the natural aurones isolated from dietary plants. Their positive effects on immunomodulation, antioxidation, cancer prevention as well as maintaining the health status of cardiovascular, nervous system and liver organs are highlighted. The biosynthesis strategies of plant-derived aurones are elaborated to provide solutions for their limited natural abundance. The potential application of natural aurones in food coloration are also discussed. This paper combines the up-to-date information and gives a full image of dietary aurones.

Halogen substituted aurones as potential apoptotic agents: synthesis, anticancer evaluation, molecular docking, ADMET and DFT study.

A series of halogen-substituted aurone derivatives (2a-k) were synthesized and evaluated for an anti-proliferative study against NCI 60 cancer cell line panel and showed that most of the compounds predominantly exhibited promising activity against MCF-7. Compound 2e exhibited promising anticancer activity against the MCF-7 cancer cell line with 84.98% percentage growth inhibition in a single dose assay of 10 µM with an IC50 value of 8.157 ± 0.713 µM. In apoptotic assay, the effect of compound 2e on the cell cycle progression indicated that exposure of MCF-7 cells to compound 2e induced a significant disruption in the cell cycle profile including a time-dependent decrease in the cell population at G0/G1 and G2/M phase and arrests the cell cycle at the S phase. In silico, molecular docking ADME and toxicity studies of all compounds were also carried out. The docking study revealed that all the aurone derivatives displayed good docking scores ranging from -7.066 to -8.573. The results of Molecular Electrostatic Potential Mapping (MESP) and Density Functional Theory (DFT) studies of the most active compound 2e and least active compound 2k also favoured the experimental results.

Nature as a source and inspiration for human monoamine oxidase B (hMAO-B) inhibition: A review of the recent advances in chemical modification of natural compounds.

INTRODUCTION: Over the past 5 years, we have witnessed intense research activity about the biological potential of natural products (NPs) as human monoamine oxidase B (hMAO-B) inhibitors. Despite the promising inhibitory activity, natural compounds often suffer from pharmacokinetic lissues, such as poor aqueous solubility, extensive metabolism, and low bioavailability. AREAS COVERED: This review provides an overview of the current landscape NPs as selective hMAO-B inhibitors and highlights their use as a starting scaffold to design (semi)synthetic derivatives to overcome the therapeutic (pharmacodynamic and pharmacokinetic) limitations of NPs and to obtain more robust structure-activity relationships (SARs) for each scaffold. EXPERT OPINION: All the natural scaffolds herein presented displayed a broad chemical diversity. The knowledge of their biological activity as inhibitors of hMAO-B enzyme allows the positive correlations associated with the consumption of specific food or the possible herb-drug interactions and suggests to the Medicinal Chemists how to address chemical functionalization to obtain more potent and selective compounds.

Synthesis, Nematicidal Evaluation, and the Structure-Activity Relationship Study of Aurone Derivatives.

Plant-parasitic nematodes (PPNs) are one of the major threats to modern agriculture. Chemical nematicides are still required for the management of PPNs. Based on our previous work, the structure of aurone analogues was obtained using a hybrid 3D similarity calculation method (SHAFTS, SHApe-FeaTure Similarity). Thirty-seven compounds were synthesized. The nematicidal activity of target compounds against Meloidogyne incognita (root-knot nematode, M. incognita) was evaluated, and the structure-activity relationship of synthesized compounds was analyzed. The results showed that compound 6 and some of its derivatives exhibited impressive nematicidal activity. Among these compounds, compound 32 bearing 6-F showed the best in vitro and in vivo nematicidal activity. Its lethal concentration 50% after exposure to 72 h (LC50/72 h) value was 1.75 mg/L, and the inhibition rate reached 97.93% in the sand at 40 mg/L. At the same time, compound 32 also exhibited excellent inhibition on egg hatching and moderate inhibition on the motility of Caenorhabditis elegans (C. elegans).

Semi-Synthesis of Different Pyranoflavonoid Backbones and the Neurogenic Potential.

Flavonoids and chalcones are known for their manifold biological activities, of which many affect the central nervous system. Pyranochalcones were recently shown to have a great neurogenic potential, which is partly due to a specific structural motif-the pyran ring. Accordingly, we questioned if other flavonoid backbones with a pyran ring as structural moiety would also show neurogenic potential. Different semi-synthetic approaches starting with the prenylated chalcone xanthohumol, isolated from hops, led to pyranoflavanoids with different backbones. We identified the chalcone backbone as the most active backbone with pyran ring using a reporter gene assay based on the promoter activity of doublecortin, an early neuronal marker. Pyranochalcones therefore appear to be promising compounds for further development as a treatment strategy for neurodegenerative diseases.

Prenylated Flavonoids with Selective Toxicity against Human Cancers.

The antiproliferative activity of xanthohumol (1), a major prenylated chalcone naturally occurring in hops, and its aurone type derivative (Z)-6,4'-dihydroxy-4-methoxy-7-prenylaurone (2) were investigated. Both flavonoids, as well as cisplatin as a reference anticancer drug, were tested in vivo against ten human cancer cell lines (breast cancer (MCF-7, SK-BR-3, T47D), colon cancer (HT-29, LoVo, LoVo/Dx), prostate cancer (PC-3, Du145), lung cancer (A549) and leukemia (MV-4-11) and two normal cell lines (human lung microvascular endothelial (HLMEC)) and murine embryonic fibroblasts (BALB/3T3). Chalcone 1 and aurone 2 demonstrated potent to moderate anticancer activity against nine tested cancer cell lines (including drug-resistant ones). The antiproliferative activity of all the tested compounds against cancer and the normal cell lines was compared to determine their selectivity of action. Prenylated flavonoids, especially the semisynthetic derivative of xanthohumol (1), aurone 2, were found as selective antiproliferative agents in most of the used cancer cell lines, whereas the reference drug, cisplatin, acted non-selectively. Our findings suggest that the tested flavonoids can be considered strong potential candidates for further studies in the search for effective anticancer drugs.

Discovery of blood-brain barrier permeant amine-functionalized aurones as inhibitors of activated microglia.

Sulfuretin, a naturally occurring aurone is reported to inhibit macrophage and microglia activation. A series of aurones incorporating basic amines and lipophilic functionalities at ring A and/or ring B were synthesized to improve upon present sulfuretin activity towards targeting brain microglia while overcoming the blood-brain barrier (BBB). Evaluation of the ability of the aurones to inhibit lipopolysaccharide (LPS)-stimulated nitric oxide (NO) secretion by murine BV-2 microglia has identified several inhibitors showing significant NO reduction at 1 to 10 µM. Potent inhibitors were represented by aurones with bulky, planar moieties at ring A (3f) or at ring B (1e and 1f) and having a pendant piperidine at ring B (1a, 2a, 2b, and 3f). The active aurones inhibited the BV-2 microglia polarizing towards the M1 state as indicated by attenuation of IL-1ß and TNF-α secretions in LPS-activated microglia but did not induce the microglia towards the M2 state. The aurones 2a, 2b, and 1f showed high passive BBB permeability in the parallel artificial membrane permeability assay (PAMPA) owing to their optimal lipophilicities. 2a, being non-cell toxic, BBB permeant and potent, represents a new lead for the development of aurones as inhibitors of activated microglia.

A Polyphenol Oxidase Catalyzes Aurone Synthesis in Marchantia polymorpha.

Aurones constitute one of the major classes of flavonoids, with a characteristic furanone structure that acts as the C-ring of flavonoids. Members of various enzyme families are involved in aurone biosynthesis in different higher plants, suggesting that during evolution plants acquired the ability to biosynthesize aurones independently and convergently. Bryophytes also produce aurones, but the biosynthetic pathways and enzymes involved have not been determined. The present study describes the identification and characterization of a polyphenol oxidase (PPO) that acts as an aureusidin synthase (MpAS1) in the model liverwort, Marchantia polymorpha. Crude enzyme assays using an M. polymorpha line overexpressing MpMYB14 with high accumulation of aureusidin showed that aureusidin was biosynthesized from naringenin chalcone and converted to riccionidin A. This activity was inhibited by N-phenylthiourea, an inhibitor specific to enzymes of the PPO family. Of the six PPOs highly induced in the line overexpressing MpMyb14, one, MpAS1, was found to biosynthesize aureusidin from naringenin chalcone when expressed in Saccharomyces cerevisiae. MpAS1 also recognized eriodictyol chalcone, isoliquiritigenin and butein, showing the highest activity for eriodictyol chalcone. Members of the PPO family in M. polymorpha evolved independently from PPOs in higher plants, indicating that aureusidin synthases evolved in parallel in land plants.

Synthesis and Activity of Aurone and Indanone Derivatives.

INTRODUCTION: Based on bioactive group splicing, classical bioisosterism, and the rule of alkene insertion, forty-eight aurone, and indanone derivatives were designed and synthesized. They were evaluated for inhibitory activity against C. albicans, E. coli, and S. aureus. Among them, thirty compounds exhibited moderate to excellent antibacterial activity. METHODS: The maximum circle of inhibition was 18 mm (compounds B15, B16, and E7), and the minimum values of MIC and MBC were respectively 15.625 µM (compounds A5 and D2) and 62.5 µM (compounds A6, A8, and E7). RESULTS: The SAR showed that aurone and indanone derivatives could strongly inhibit the growth of Gram-positive bacteria. The introduction of electron-withdrawing groups or hydroxyl is beneficial to the activity. It was exciting that the 3-phenylallylbenzofuranone and 3-allylindanone skeletons with antimicrobial activity were first reported in this study. Compounds A5 and E7 were selected for molecular docking studies with targets MetRS (PBD: 7WPI) and PBP (PDB: 6C3K) to determine the binding interactions at the active site. CONCLUSION: On this basis, the physicochemical and pharmacological properties of the compounds were predicted and analyzed. The influence of these properties on antimicrobial activity and their implications for subsequent work were discussed. The ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) predictions showed that most of the compounds had good pharmacokinetic profiles and high safety profiles.