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.

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).

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.

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.

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.

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.