Novel N1 or N9 modified α-carboline analogues as potential ligands in Alzheimer's disease therapy: Synthesis and neurobiological activity evaluation.

A series of new α-carboline analogues modified at N1 or N9 positions by alkyl, benzyl and phenyl were synthesized and characterized as potential ligands for AD therapy. These compounds exhibited multifunctional neurobiological activities including anti-neuroinflammatory, neuroprotective and cholinesterase inhibition. Among them, compound 5d with good drug-like properties and no cytotoxicity, showed potent inhibitory activity against NO production (IC50 = 1.45 µM), which could suppress the expression levels of iNOS and COX-2 in a dose-dependent manner. Further mechanism exploration indicated that compound 5d could regulate the NF-κB signaling pathway by decreasing the phosphorylation of IκB-α and p65. Notably, compound 5d could effectively decrease the LPS-induced aberrations in zebrafish. Compounds 3b, 4f, 5c, 5g, 5m and 6i exhibited potential neuroprotective activity (cell viability > 70 %) in the H2O2-induced PC-12 neuronal death model and rescued the SOD activity. In particular, compounds 3b, 4f, and 5g activated the Nrf2 signaling pathway, and improved the expressions of antioxidant proteins NQO-1 and HO-1, which alleviated the head cell apoptosis in zebrafish. Additionally, compound 6i exhibited potential inhibitory activity against BuChE with IC50 of 0.77 µM. Overall, this work provided some lead compounds based on α-carboline used for AD therapy.

Recent Developments of Gramine: Chemistry and Biological Activity.

The natural alkaloid gramine has attracted significant attention in both academic and industrial circles because of its potential and diverse biological activities, including antiviral, antibacterial, antifungal, anti-inflammatory and antitumor activities; application in therapy for Alzheimer's disease; serotonin-receptor-related activity; insecticidal activity; and application as an algicide. In this review, we focus on the research advances that have been made for gramine-based molecules since their discovery, providing key information on their extraction and separation, chemical synthesis and diverse biological activities. Data regarding their mechanisms of action are also presented. This comprehensive and critical review will serve as a guide for developing more drug candidates based on gramine skeletons.

Cellular and non-target metabolomics approaches to understand the antifungal activity of methylaervine against Fusarium solani.

Botanical fungicides are promising replacements for pure chemical synthetic pesticides in agriculture and organic food production. Methylaervine with good physicochemical properties exhibited effective activity against F. solani (EC50 = 10.56 µM) better than the positive control thiophanate-methyl (EC50 = 27.94 µM). The activity changes of malondialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD) showed that methylaervine could significantly induce lipid peroxidation and activate the antioxidant enzymes. According to the metabolomics analysis, fifty-one differential metabolites and two major antifungal-related pathways covering tricarboxylic acid (TCA) cycle and steroid biosynthesis were identified. Moreover, the disturbance for TCA cycle was validated by the activity changes of dehydrogenase (MDH) and succinate dehydrogenase (SDH) as well as docking simulation. Homology modeling and docking study revealed that hydrogen bonds and hydrophobic interactions played a vital role in methylaervine-protein stability. This study provided new insight into the antifungal activity of methylaervine, which is important for the development of novel botanical fungicides based on methylaervine.

Recent progress of antibacterial natural products: Future antibiotics candidates.

The discovery of novel antibacterial molecules plays a key role in solving the current antibiotic crisis issue. Natural products have long been an important source of drug discovery. Herein, we reviewed 256 natural products from 11 structural classes in the period of 2016-01/2020, which were selected by SciFinder with new compounds or new structures and MICs lower than 10 µg/mL or 10 µM as criterions. This review will provide some effective antibacterial lead compounds for medicinal chemists, which will promote the antibiotics research based on natural products to the next level.

Anti-inflammatory and α-Glucosidase Inhibitory Activities of Labdane and Norlabdane Diterpenoids from the Rhizomes of Amomum villosum.

A new tetranorditerpenoid (1), two new labdane diterpenoids (2, 3), and nine known analogues (4-12) were isolated from the rhizomes of Amomum villosum var. xanthioides. Compound 1 is an unprecedented rearranged tetranorlabdane diterpenoid, featuring a 6/6/5 fused tricarbocyclic skeleton with an α,ß-unsaturated cyclopentenone unit, while 2 is a structurally rare labdane diterpenoid carrying a five-membered cyclic anhydride moiety. Their structures and absolute configurations were established on the basis of spectroscopic data and the experimental and calculated ECD data. Compound 4 showed inhibitory activity against nitric oxide production, with an IC50 value of 2.4 µM, and also inhibited α-glucosidase activity (IC50 = 10.0 µM).

Benzonate derivatives of acetophenone as potent α-glucosidase inhibitors: synthesis, structure-activity relationship and mechanism.

In this article, 23 compounds (6 and 7a-7v) were prepared and evaluated for their in vitro α-glucosidase inhibitory activity. The compounds 7d, 7f, 7i, 7n, 7o, 7r, 7s, 7u, and 7v displayed the α-glucosidase inhibition activity with IC50 values ranging from 1.68 to 7.88 µM. Among all tested compounds, 7u was found to be the most efficient, being 32-fold more active than the standard drug acarbose, which significantly attenuated postprandial blood glucose in mice. In addition, the compound 7u also induced the fluorescence quenching and conformational changes of enzyme, by forming α-glucosidase-7u complex in a mixed inhibition type. The thermodynamic constants recognised the interaction between 7u and α-glucosidase and was an enthalpy-driven spontaneous exothermic reaction. The synchronous fluorescence and CD spectra also indicate that the compound 7u changed the enzyme conformation. The findings identify the binding interactions between new ligands and α-glucosidase and reveal the compound 7u as a potent α-glucosidase inhibitor.

Structure-antifungal relationships and preventive effects of 1-(2,4-dihydroxyphenyl)-2-methylpropan-1-one derivatives as potential inhibitors of class-II fructose-1,6-bisphosphate aldolase.

Emerging fungal phytodiseases are a food security threat and novel fungicides are in an urgent need. Herein, a series of isobutyrophenone derivatives were designed and synthesized. The derivatives exhibited excellent fungicidal activities against seven fungi. The structure-activity relationship (SAR) study indicated that the introduction of a bromo group at the position 3 or 5 of the phenyl ring, as well as esterification of the 4-hydroxy with a chloroacetyl group, could substantially increase the antifungal activity and spectrum of the compounds. Among all 23 compounds, 2-bromo-3-hydroxy-4-isobutyryl-6-methylphenyl 2-chloroacetate (12b) showed the highest fungicidal activity against all seven tested fungal pathogens with EC50 values ranging from 1.22 to 39.94 µg/mL and exhibited the most potent inhibition against class II fructose-1,6-bisphosphate aldolase with an IC50 of 3.63 µM. The lead compounds were proven to be safe to NIH3T3/293 T cells and silkworm larvae, and relatively stable under different harsh conditions. Detached fruit tests showed the practical potential of lead compounds for fruit (or plant) protection. Taken together, our results indicated that the isobutyrophenone derivatives could be further optimized and developed as advanced leads for new fungicides.

Design and synthesis of C10 modified and ring-truncated canthin-6-one analogues as effective membrane-active antibacterial agents.

A series of canthin-6-one analogues were designed and synthesized in order to study their antibacterial activity and structure-activity relationships. Compound 22 showed a broad spectrum of antibacterial activity and exhibited better bactericidal effect (8-fold superiority against Staphylococcus aureus and 2-fold superiority against Ralstonia solanacearum) than fosfomycin sodium and propineb with a minimum inhibitory concentration value of 2 µg/mL. Moreover, it showed low cytotoxicity, stimulation on germination rates and good "drug-like" properties. Membrane-active mechanism was further studied by fluorescent microscopy, scanning electron microscopy, cytoplasmic ß-galactosidase leakage assay and evaluation of the molecular docking. The results showed that 22 may exert its bactericidal effect by damaging bacterial cell membranes and influencing the membrane formation, both of which could lead to cell death. The in vivo antibacterial assay with a protective efficacy of 68% demonstrated the potential of C ring-truncated canthin-6-one 22 as a new bactericide.

Natural products as sources of new fungicides (V): Design and synthesis of acetophenone derivatives against phytopathogenic fungi in vitro and in vivo.

A series of acetophenone derivatives (10a-10i, 11, 12a-12g, 13a-13g, 14a-14d and 15a-15l) were designed, synthesized and evaluated for antifungal activities in vitro and in vivo. The antifungal activities of 53 compounds were tested against several plant pathogens, and their structure-activity relationship was summarized. Compounds 10a-10f displayed better antifungal effects than two reference fungicides. Interestingly, the most potent compound 10d exhibited antifungal properties against Cytospora sp., Botrytis cinerea, Magnaporthe grisea, with IC50 values of 6.0-22.6 µg/mL, especially Cytospora sp. (IC50 = 6.0 µg/mL). In the in vivo antifungal assays, 10d displayed the significant protective efficacy of 55.3% to Botrytis cinerea and 73.1% to Cytospora sp. The findings indicated that 10d may act as a potential pesticide lead compound that merits further investigation.

Natural products as sources of new fungicides (IV): Synthesis and biological evaluation of isobutyrophenone analogs as potential inhibitors of class-II fructose-1,6-bisphosphate aldolase.

Several recently identified antifungal compounds share the backbone structure of acetophenones. The aim of the present study was to develop new isobutyrophenone analogs as new antifungal agents. A series of new 2,4-dihydroxy-5-methyl isobutyrophenone derivatives were prepared and characterized by 1H, 13C NMR and MS spectroscopic data. These products were evaluated for in vitro antifungal activities against seven plant fungal pathogens by the mycelial growth inhibitory rate assay. Compounds 3, 4a, 5a, 5b, 5e, 5f and 5g showed a broad-spectrum high antifungal activity. On the other hand, for the first time, these compounds were also assayed as potential inhibitors against Class II fructose-1,6-bisphosphate aldolase (Fba) from the rice blast fungus, Magnaporthe grisea. Compounds 5e and 5g were found to exhibit the inhibition constants (Ki) for 15.12 and 14.27 µM, respectively, as the strongest competitive inhibitors against Fba activity. The possible binding-modes of compounds 5e and 5g were further analyzed by molecular docking algorithms. The results strongly suggested that compound 5g could be a promising lead for the discovery of new fungicides via targeting Class II Fba.

Natural products as sources of new fungicides (III): Antifungal activity of 2,4-dihydroxy-5-methylacetophenone derivatives.

A series of new 2,4-dihydroxy-5-methylacetophenone 2 derivatives were synthesized, and characterized by (1)H, (13)C NMR and ESI-MS. Their antifungal activities were evaluated in vitro against five important plant fungal pathogens including Cytospora sp., Glomerella cingulate, Pyricularia oryzaecar, Botrytis cinerea and Alternaria solani by the mycelial growth inhibitory rate assay. Compounds 2b-d, 2g and 2h displayed a broad-spectrum activity. The logP value of these active compounds is ranging from 1.71 to 2.54. Especially, isopropyl ketone 2g (logP 2.27) was found to be the most active to the tested organisms with IC50 values of 17.28-32.32 µg/mL. The results suggest that compound 2g might be a promising candidate in the development of new agrochemical antifungal agents. Preliminary structure-activity relationship (SAR) studies of the acetophenone derivatives are also discussed.

Synthesis, in vitro antibacterial activities of a series of 3-N-substituted canthin-6-ones.

An improved synthetic route of canthin-6-one was accomplished. To further enhance the antibacterial potency and improve water solubility, a series of 3-N-alkylated and 3-N-benzylated canthin-6-ones were designed and synthesized, and their in vitro antibacterial activities were evaluated. A clear structure-activity relationship with peak minimal inhibitory concentration (MIC) values of 0.98 (µg·mL(-)(1)) was investigated. Particularly, compounds 6i-r and 6t were found to be the most potent compounds with minimal inhibitory concentration (MIC) values lower than 1.95 (µg·mL(-)(1)) against Staphylococcus aureus.

Efficient Synthesis and Antibacterial Evaluation of (±)-Yanglingmycin and Its Analogues.

An efficient synthetic route was developed for the large-scale preparation of (±)-Yanglingmycin and its analogues. Three series of derivatives of (±)-Yanglingmycin were synthesized and the structures of all compounds were elucidated by analyses of NMR and ESI-MS spectra data. Moreover, their antibacterial activities against seven species of bacteria were systematically evaluated by the micro-broth dilution method, most of which displayed considerable activity. It was worth noting that compounds 5b, 5c, 5d, 6g, and 7 were found to be the most promising leading candidates, with peak MIC values of 0.98 µg·mL(-1) for Bacillus subtilis, which is superior to positive controls (MIC = 3.91 µg·mL(-1)). The above results might lay the firm foundation for the design and synthesis of novel antibacterial drugs based on (±)-Yanglingmycin.

Synthesis and antibacterial activities of Yanglingmycin analogues.

The synthesis of Yanglingmycin and its enantiomer, along with eighteen Yanglingmycin analogues is reported. The structures were confirmed mainly by analyses of NMR spectral data. Antibacterial activity assays showed that Yanglingmycin and some of its analogues exhibited significant antibacterial activities against two important agricultural pathogenic bacteria, Ralstonia solanacearum and Pseudomonas syringae pv. actinidiae, with minimum inhibitory concentration (MIC) values ranging from 3.91 to 15.62 µg/mL. The antibacterial activities exhibited by Yanglingmycin and its analogues are promising, suggesting potential in the development of compounds for novel bactericides.

Synthesis and Antibacterial Activities of Yanglingmycin Analogues.

The synthesis of Yanglingmycin and its enantiomer, along with eighteen Yanglingmycin analogues is reported. The structures were confirmed mainly by analyses of NMR spectral data. Antibacterial activity assays showed that Yanglingmycin and some of its analogues exhibited significant antibacterial activities against two important agricultural pathogenic bacteria, Ralstonia solanacearum and Pseudomonas syringae pv. actinidiae, with MIC values ranging from 3.91 to 15.62 µg/mL. The antibacterial activities exhibited by Yanglingmycin and its analogues are promising, suggesting potential in the development of compounds for novel bactericides.

Synthesis of 3-formyl-eudistomin U with anti-proliferation, anti-migration and apoptosis-promoting activities on melanoma cells.

The discovery of new lead skeleton against melanoma are urgently needed due to its highly malignant and mortality. Herein, a new molecular entity (EU-5) derived from eudistomin U was synthesized with total yield of 46%, which displayed potent activity against malignant melanoma A375 cells (IC50 = 4.4 µM), no hemolytic toxicity and good physicochemical properties in silico. Colony formation and cell cycle arrest assays revealed that EU-5 suppressed cell proliferation by causing cell cycle arrest at G0/G1 phase. Wound healing and transwell assays suggested that EU-5 could effectively inhibit migration of A375 cells in a dose-dependent manner. Calcein-AM/PI staining, Annexin V-FITC/PI apoptosis detection, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), transcriptomics, quantitative real­time polymerase chain reaction (qRT­PCR), spectrometric titration and molecular docking assays indicated that EU-5 could activate p53 signaling pathway and trigger mitochondria-mediated cell apoptosis. Taken together, this study provided a promising lead structure for the design of a new generation of anti-melanoma drugs.

Discovery of new quaternized norharmane dimers as potential anti-MRSA agents.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA)-caused infections greatly threaten public health. The discovery of natural-product-based anti-MRSA agents for treating infectious diseases has become one of the current research focuses. OBJECTIVES: This study aims to identify promising anti-MRSA agents with a clear mechanism based on natural norharmane modified by quaternization or dimerization. METHODS: A total of 32 norharmane analogues were prepared and characterized. Their antibacterial activities and resistance development propensity were tested by the broth double-dilution method. Cell counting kit-8 and hemolysis experiments were used to assess their biosafety. The plasma stability, bactericidal mode, and biofilm disruption effects were examined by colony counting and crystal violet staining assays. Fluorescence microscopy, metabolomic analysis, docking simulation and spectra titration revealed its anti-MRSA mechanisms. The mouse skin infection model was used to investigate the in vivo efficacy. RESULTS: Compound 5a was selected as a potential anti-MRSA agent, which exhibited potent anti-MRSA activity in vitro and in vivo, low cytotoxicity and hemolysis under an effective dose. Moreover, compound 5a showed good stability in 50% plasma, a low tendency of resistance development and capabilities to disrupt bacterial biofilms. The mechanism studies revealed that compound 5a could inhibit the biosynthesis of bacteria cell walls, damage the membrane, disturb energy metabolism and amino acid metabolism pathways, and interfere with protein synthesis and nucleic acid function. CONCLUSIONS: These results suggested that compound 5a is a promising candidate for combating MRSA infections, providing valuable information for further exploiting a new generation of therapeutic antibiotics.

Natural and synthetic ß-carboline as a privileged antifungal scaffolds.

The discovery of antifungal agents with novel structure, broad-spectrum, low toxicity, and high efficiency has been the focus of medicinal chemists. Over the past decades, ß-carboline scaffold has attracted extensive attention in the scientific community due to its potent and diverse biological activities with nine successfully marketed ß-carboline-based drugs. In this review, we summarized the current states and advances in the antifungal activity of natural and synthetic ß-carbolines. Additionally, the structure-activity relationships and their antifungal mechanisms targeting biofilm, cell wall, cell membrane, and fungal intracellular targets were also systematically discussed. In summary, ß-carbolines have the great potential to develop new efficient scaffolds to combat fungal infections.

Methylaervine as Potential Lead Compound Against Cervical Carcinoma: Pharmacologic Mechanism Prediction based on Network Pharmacology.

BACKGROUND: The discovery of therapeutic anticancer agents based on natural products is one of the current research focuses. Network pharmacology will broaden our understanding of drug actions by bioinformatics analysis. OBJECTIVE: To explore the potential and provide scientific evidence for methylaervine as a lead compound against cervical carcinoma. METHODS: Methylaervine was synthesized, and its activity against four cancer cell lines was evaluated by MTT assay. Pharmacokinetic properties were obtained by in silico approaches, and the pharmacologic mechanism was predicted by network pharmacology. Then we validated and investigated our predictions of candidate targets using a molecular docking study. RESULTS: Methylaervine was synthesized with a total yield of 54.9%, which displayed activity against HeLa (IC50 = 14.8 µM) with good predicted pharmacokinetic properties, thus it was considered a potential lead compound. The network pharmacology study indicated that methylaervine could act against cervical carcinoma by regulating the function of multiple pivotal targets, such as CTNNB1, PTPRJ, RPA1, and TJP1, mainly covering cell growth, cell motility, and cell proliferation. Moreover, docking analysis showed that hydrogen bonds and hydrophobic interactions were the main forms of interactions. CONCLUSION: This work would provide new insight into the design of anti-cervical carcinoma drugs based on methylaervine.

Antibacterial quaternary ammonium agents: Chemical diversity and biological mechanism.

Bacterial infections have seriously threatened public health especially with the increasing resistance and the cliff-like decline of the number of newly approved antibacterial agents. Quaternary ammonium compounds (QACs) possess potent medicinal properties with 95 successfully marketed drugs, which also have a long history as antibacterial agents. In this review, we summarize the chemical diversity of antibacterial QACs, divided into chain-like and aromatic ring, reported over the past decade (2012 to mid-2022). Additionally, the structure-activity relationships, mainly covering hydrophobicity, charges and skeleton features, are discussed. In the cases where sufficient information is available, antibacterial mechanisms including biofilm, cell membrane, and intracellular targets are presented. It is hoped that this review will provide sufficient information for medicinal chemists to discover the new generation of antibacterial agents based on QACs.