Phloroglucinol Derivatives Research Articles

Structurally diverse phenylpropanoyl phloroglucinol derivatives from Mallotus philippensis and their anti-bacterial activities

Fifteen undescribed phenylpropanoyl phloroglucinol derivatives featuring modified isoprenyl and/or geranyl units (1–15), in conjunction with thirteen known analogues (16–28), were obtained from the glandular hairs of the fruit of Mallotus philippensis. Meanwhile, fourteen pairs of new enantiomers [(±)-1–9, (±)-11–15] were further resolved by chiral purification. Their structures were determined by comprehensive spectroscopic analyses, single-crystal X-ray diffraction experiments and quantum chemical calculations. Bioactivity evaluation showed that compound 17 exhibited significant anti-bacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) with MIC of 6 μg/mL, while compounds 3, 4, 8 and 18 displayed moderate effects with MIC of 24, 12, 24, and 12 μg/mL, respectively. The KEGG enrichment analysis of 17 revealed that the phosphotransferase system (PTS) pathway was significantly enriched. In addition, compound 17 was found to affect the amino acids biosynthesis and amino acids/carbohydrate metabolism, and the qRT-PCR verified the accuracy of the transcriptome analysis.

Antifungal Activity of Phloroglucinol Derivatives against Botrytis cinerea and Monilinia fructicola.

Naturally derived compounds show promise as treatments for microbial infections. Polyphenols, abundantly found in various plants, fruits, and vegetables, are noted for their physiological benefits including antimicrobial effects. This study introduced a new set of acylated phloroglucinol derivatives, synthesized and tested for their antifungal activity in vitro against seven different pathogenic fungi. The standout compound, 3-methyl-1-(2,4,6-trihydroxyphenyl) butan-1-one (2b), exhibited remarkable fungicidal strength, with EC50 values of 1.39 μg/mL against Botrytis cinerea and 1.18 μg/mL against Monilinia fructicola, outperforming previously screened phenolic compounds. When tested in vivo, 2b demonstrated effective antifungal properties, with cure rates of 76.26% for brown rot and 83.35% for gray mold at a concentration of 200 μg/mL, rivaling the commercial fungicide Pyrimethanil in its efficacy against B. cinerea. Preliminary research suggests that 2b's antifungal mechanism may involve the disruption of spore germination, damage to the fungal cell membrane, and leakage of cellular contents. These results indicate that compound 2b has excellent fungicidal properties against B. cinerea and holds potential as a treatment for gray mold.

Acetylcholinesterase inhibitory phloroglucinols from tropic Rhodomyrtus tomentosa

Four previously undescribed phloroglucinols, including three pairs of enantiomers, (±)-rhodotomentodimer F, (±)-rhodotomentodimer G, and (±)-rhodotomentomonomer E, and one phloroglucinol-sesquiterpene meroterpenoid, rhodotomentodione E, together with one previously reported congener, (±)-rhodomyrtosone A, were obtained from the leaves of Rhodomyrtus tomentosa. The structures including absolute configurations of previously undescribed isolates were elucidated by extensive spectroscopic analysis (HRESIMS and NMR), ECD calculations, and single-crystal X-ray diffraction. (±)-Rhodotomentodimer F is a rare phloroglucinol derivative conjugated by a β-triketone moiety and an unprecedented resorcinol unit via the formation of a rare bis-furan ring system, whereas (±)-rhodotomentomonomer E shares a rearranged pentacyclic scaffold. Pharmacologically, (±)-rhodotomentomonomer E showed the strongest human acetylcholinesterase (hAChE) inhibitory effect with an IC50 value of 1.04 ± 0.05 μM. Molecular formula studies revealed that hydrogen bonds formed between hAChE residues Glu202, Ser203, Ala204, Gly121, Gly122, Tyr337, and His447 and (±)-rhodotomentomonomer E played crucial roles in its observed activity. These findings indicated that the leaves of Rhodomyrtus tomentosa can supply a rich source of hAChE inhibitors. These inhibitors might potentially be utilized in the therapeutic strategy for Alzheimer's disease, offering promising candidates for further research and development.

Phloroglucinol Derivatives Exert Anti-Inflammatory Effects and Attenuate Cognitive Impairment in LPS-Induced Mouse Model.

Neuroinflammation is an inflammatory immune response that arises in the central nervous system. It is one of the primary causes of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Phloroglucinol (PG) is a natural product contained in extracts of plant, algae and microbe and has been reported to have antioxidant and anti-inflammatory properties. In this study, we synthesized PG derivatives to enhance antioxidant and anti-inflammatory activity. Among PG derivatives, 6 a suppressed pro-oxidative and inflammatory molecule nitric oxide (NO) production more effectively than PG. Moreover, 6 a dose-dependently reduced the expression of proinflammatory cytokines such as IL-6, IL-1β, TNF-α, and NO producing enzyme iNOS in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Additionally, we confirmed that 6 a alleviated cognitive impairment and glial activation in mouse model of LPS-induced neuroinflammation. These findings suggest that novel PG derivative, 6 a, is a potential treatment for neurodegenerative diseases.

Synthesis of Thiadiazoles Based on Phloroglucinol Derivatives and Their Glycosylation

Synthesis of Thiadiazoles Based on Phloroglucinol Derivatives and Their Glycosylation

HPLC-based cytotoxicity profiling and LC-ESIQTOF-MS/MS analysis of Helichrysum leucocephalum

IntroductionHelichrysum leucocephalum Boiss. (Asteraceae) is an endemic plant to Iran. No reports have studied the cytotoxicity of the plant. The current study aimed to evaluate the cytotoxicity of H. leucocephalum collected from Fars province (Iran) against MCF-7 and HDF cell lines using HPLC-based activity profiling and to annotate the active constituents by LC-ESIQTOF-MS/MS. MethodsH. leucocephalum was collected from three locations in Fars province. The dried flowers and leaves were separately extracted by percolation using methanol. The crude extracts were fractionated by liquid-liquid partitioning with dichloromethane (DCM) and aqueous methanol. The cytotoxicity of the fractions was evaluated against MCF-7 and HDF cells by Alamarblue assay. HPLC-based activity profiling was used to track the active constituents. LC-MS dereplication strategy was used for the annotation of the compounds in the active time window. LC-MS data were preprocessed by MZmine 3.3.0 and submitted to multivariate analysis to compare the differences and similarities in the metabolites of the samples. ResultsThe DCM fractions showed a dose-dependent cytotoxicity against the cancerous cells (IC50s, 9.8–105.1 μg/ml). In general, the metabolites of the flowers and their cytotoxicity were higher than the leaves. LCESIMS/MS analyses revealed that prenylated and geranylated α,β-unsaturated spiroketal phloroglucinols were among the active constituents. ConclusionIt can be concluded that H. leucocephalum is a rich source of phloroglucinol derivatives with cytotoxic activities. Further phytochemical analysis is needed to characterize the bioactive components.

TLC-Bioautography-Guided Isolation and Assessment of Antibacterial Compounds from Manuka (Leptospermum scoparium) Leaf and Branch Extracts.

A rapid procedure for the targeted isolation of antibacterial compounds from Manuka (Leptospermum scoparium) leaf and branch extracts was described in this paper. Antibacterial compounds from three different Manuka samples collected from New Zealand and China were compared. The active compounds were targeted by TLC-bioautography against S. aureus and were identified by HR-ESI-MS, and -MS/MS analysis in conjunction with Compound Discoverer 3.3. The major antibacterial component, grandiflorone, was identified, along with 20 β-triketones, flavonoids, and phloroglucinol derivatives. To verify the software identification, grandiflorone underwent purification via column chromatography, and its structure was elucidated through NMR analysis, ultimately confirming its identity as grandiflorone. This study successfully demonstrated that the leaves and branches remaining after Manuka essential oil distillation serve as excellent source for extracting grandiflorone. Additionally, we proposed an improved TLC-bioautography protocol for evaluating the antibacterial efficacy on solid surfaces, which is suitable for both S. aureus and E. coli. The minimum effective dose (MED) of grandiflorone was observed to be 0.29-0.59 μg/cm2 against S. aureus and 2.34-4.68 μg/cm2 against E. coli, respectively. Furthermore, the synthetic plant growth retardant, paclobutrazol, was isolated from the samples obtained in China. It is hypothesized that this compound may disrupt the synthesis pathway of triketones, consequently diminishing the antibacterial efficacy of Chinese Manuka extract in comparison to that of New Zealand.

Antimicrobial activity and mechanism of anti-MRSA of phloroglucinol derivatives.

In previous studies, authors have completed the total synthesis of several phloroglucinol natural products and synthesized a series of their derivatives, which were tested with good biological activities. To discover anti-MRSA lead compound and study their mechanism of action. Phloroglucinol derivatives were tested to investigate their activities against several gram-positive strains including Methicillin-resistant Staphylococcus aureus (MRSA). The mechanism study was conducted by determining extracellular potassium ion concentration, intracellular NADPH oxidase content, SOD activity, ROS amount in MRSA and MRSA survival rate under A5 treatment. The in vitro cytotoxicity test of A5 was conducted. The activity of monocyclic compounds was stronger than that of bicyclic compounds, and compound A5 showed the best MIC value of 0.98μg/mL and MBC value of 1.95μg/mL, which were 4-8 times lower than that of vancomycin. The mechanism study of A5 showed that it achieved anti-MRSA effect through membrane damage, which is proved by increased concentration of extracellular potassium ion after A5 treatment. Another possible mechanism is the over ROS production induced cell death, which is suggested by observed alternation of several reactive oxygen species (ROS) related indicators including NADPH concentration, superoxide dismutase (SOD) activity, ROS content and bacterial survival rate after A5 treatment. The cytotoxicity results in vitro showed that A5 was basically non-toxic to cells. Acylphloroglucinol derivative A5 showed good anti-MRSA activity, possibly via membrane damage and ROS-mediated oxidative stress mechanism. It deserves further exploration to be a potential lead for the development of new anti-MRSA agent.

Comparative extraction and antioxidant potential of bioactive compounds from Fucus vesiculosus: Kinetic modeling and UPLC-Q-TOF-MS phenolic profiling

This study explores efficient bioactive compounds extraction from Fucus vesiculosus (FV) seaweed using Ultrasound-assisted extraction (UAE) and Solid Liquid Extraction (SLE). Varied ultrasound intensities (UI) (58.8, 103.1 and 164.5 kW m−2 for U1, U2 and U3, respectively) were employed, and Peleg's model simulated extraction kinetics, revealing UAE's remarkable 10-min equilibrium contrasted with SLE's 3 h, showcasing UAE's time efficiency. UAE, particularly at U3, yielded significantly higher Total Phenolic Content (TPC) and Uronic Acid Content (UAC) compared to SLE, reaching maximum concentrations of 2.26 ± 0.01 g PGE 100 g−1 DFV and 7.87 ± 0.11 g GAE 100 g−1, respectively. Increased UI enhanced DPPH and ABTS antioxidant activities, while low UI resulted in higher FRAP values. After 20 min of extraction, U3 demonstrated superior DPPH scavenging activity (5.75 ± 0.23 μM TE g−1 DFV), surpassing that of SLE after 20 h of extraction (4.76 ± 0.11 μM TE g−1 DFV). Additionally, U3 displayed elevated ABTS values (8.92 ± 0.33 μM TE g−1 DFV) compared to 6.46 ± 0.41 μM TE g−1 DFV for SLE, with no significant difference observed in FRAP values. These results highlight U3's enhanced antioxidant potential in comparison to SLE. The chromatographic analysis identified six main compounds through UPLC-Q-TOF-MS and HPLC. Higher concentrations of phloroglucinol, gallic acid, catechin, protocatechuic acid, and chlorogenic acid were observed in U3. However, SLE exhibited a higher ferulic acid content. Future research aims to explore phloroglucinol derivatives and FC, contributing to FV' potential applications.

Anti-Herpes Simplex Virus Type 1 Activity Evaluation of Natural Derived Phloroglucinol Derivatives and Their Molecular Mechanisms Study.

HSV-1 is a common infection that can cause cold sores. In this study, the anti-HSV-1 virus activity of three series compounds A1-A9, B1-B12, C1-C22 was screened by MTT assay, qRT-PCR assay, Western blot assay and viruses' plaque assays. The results of MTT assay disclosed that phloroglucinol derivatives C2 and C3 effectively inhibited the death of HSV-1 infected vero cells with the CC50 values of C2 and C3 were 72.64 μmol/L and 32.62 μmol/L in HaCaT cells, 137.6 μmol/L and 48.55 μmol/L in Hela cells. The IC50 values of C3 in vero cells and Hela cells were 19.26 μmol/L and 22.98 μmol/L, respectively. In the qRT-PCR experiments, it showed that C2 and C3 effectively reduced the synthesis of HSV-1 early viral gene VP16 and late viral gene gD. The Western blot results showed that both C2 and C3 inhibited the expression of HSV-1 gD protein in a concentration-dependent manner. Lastly, viruses' plaque assay results showed that C2 and C3 inhibited the production of HSV-1 progeny virus in Hela cells and HaCaT cells in a concentration-dependent manner. Taken together, these results suggest that C2 and C3 are promising candidate that warrants further attention in the development of anti-HSV-1 drugs.

Cellular neurobiology of hyperforin.

Hyperforin is a phloroglucinol derivative isolated from the medicinal plant Hypericum perforatum (St John's wort, SJW). This lipophilic biomolecule displays antibacterial, pro-apoptotic, antiproliferative, and anti-inflammatory activities. In addition, in vitro and in vivo data showed that hyperforin is a promising molecule with potential applications in neurology and psychiatry. For instance, hyperforin possesses antidepressant properties, impairs the uptake of neurotransmitters, and stimulates the brain derived neurotrophic factor (BDNF)/TrkB neurotrophic signaling pathway, the adult hippocampal neurogenesis, and the brain homeostasis of zinc. In fact, hyperforin is a multi-target biomolecule with a complex neuropharmacological profile. However, one prominent pharmacological feature of hyperforin is its ability to influence the homeostasis of cations such as Ca2+ , Na+ , Zn2+ , and H+ . So far, the pathophysiological relevance of these actions is currently unknown. The main objective of the present work is to provide an overview of the cellular neurobiology of hyperforin, with a special focus on its effects on neuronal membranes and the movement of cations.

Dereplication of natural cytotoxic products from Helichrysum oligocephalum using ultra‐performance liquid chromatography–quadrupole time of flight‐mass spectrometry

AbstractIn an ongoing project on the Iranian Helichrysum Mill. species (Asteraceae), the phytochemical profiles of the extracts obtained from the flower and leaves of Helichrysum oligocephalum were investigated utilizing ultra‐performance liquid chromatography–mass spectrometry (MS) coupled with quadrupole time of flight. In addition, the cytotoxic activity of the extracts was evaluated against different cancerous cell lines by AlamarBlue assay. The apoptotic effects of the fractions were measured by propidium iodide staining and flow cytometry. HPLC‐based activity profiling was used to track the cytotoxic constituents. The MS and MSn data were analyzed by MZmine3. Clustering and visualization of the MS data were established by an online platform FreeClust. Concentration‐dependent cytotoxicity was observed for dichloromethane fractions. The active constituents were annotated as pyrone and phloroglucinol derivatives by comparing their MS and MSn profiles to an in‐house library, available databases, Dictionary of Natural Products, and literature. Additionally, plausible MS fragmentation pathways were suggested for the compounds; this can help in the dereplication process of similar compounds from the genus. In conclusion, this plant is rich in valuable phloroglucinol and pyrone compounds and can be used as a source of active phytochemicals. However, further phytochemical and pharmacological studies are necessary.

Two New Phloroglucinol Derivatives from Syzygium fluviatile

Two New Phloroglucinol Derivatives from Syzygium fluviatile

Structure-dependent activity of plant natural products against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the major causes for nosocomial infections and has been classified as "high priority pathogen" by the World Health Organization. Its ability to develop resistances has been a challenge for the last decades and is still a threat to health care systems, as strains with resistances to the so-called drugs of last resort have been discovered. Therefore, new antibiotics are urgently needed. Natural products are an important source for the development of new drugs, thereby mostly serving as lead compounds for further modification. In this review, the data on plant natural products with reported anti-MRSA activity until the end of 2022 is discussed, highlighting the most effective drugs with respect to their inhibitory concentrations as well as with regard to eventual synergistic effects with existing antibiotics. In the latter sense, the class of alkaloids must be mentioned, exhibiting additive or synergistic effects by inhibiting bacterial efflux pumps. With regard to the antibiotic activity, phloroglucinol derivatives certainly belong to the most promising compounds, revealing several candidates with remarkable effects, e.g., lupulone, ivesinol, rhodomyrtone, aspidinol, or hyperforin. Also, the class of terpenoids yielded noteworthy compounds, such as the sesquiterpene lactones parthenolide and lactopicrin as well as acetophenone sesquiterpenes and sphaerodiene type diterpenoids, respectively. In addition, pronounced effects were observed for the macrolide neurymenolide A and three flavonol dicoumaroylrhamnosides.

Discovery of unusual phloroglucinol–triterpenoid adducts from Leptospermum scoparium and Xanthostemon chrysanthus by building blocks-based molecular networking

The first phloroglucinol-triterpenoid hybrids, myrtphlotritins A–E (1–5), were rapidly recognized and isolated from two species of Myrtaceae by employing the building blocks-based molecular network (BBMN) strategy. Compounds 1–5 featured new carbon skeletons in which phloroglucinol derivatives were coupled with lupane- and dammarane-type triterpenoids through different linkage patterns. Their structures and absolute configurations were elucidated by comprehensive analysis of spectroscopic data and quantum chemical calculations. Biosynthetic pathways for compounds 1–5 were proposed on the basis of the coexisting precursors. Guided by the biogenetic pathways, the biomimetic synthesis of compound 1 was also achieved. Additionally, compounds 2, 3, and 5 exhibited potent antiviral activities against herpes simplex virus type-1 (HSV-1) infection, and compounds 2 and 5 displayed significant anti-inflammatory activities on RAW264.7 cells.

Phloroglucinol derivatives, coumarins and an alkaloid from the roots of Evodia lepta Merr.

Two previously undescribed phloroglucinol derivatives [(±) evolephloroglucinols A and B], five unusual coumarins [evolecoumarins A and B and (±) evolecoumarins C–E], and one novel enantiomeric quinoline-type alkaloid [(±) evolealkaloid A], along with 20 known compounds, were isolated from the EtOH extract of the roots of Evodia lepta Merr. Their structures were elucidated by extensive spectroscopic analyses. The absolute configurations of the undescribed compounds were determined by X-ray diffraction or computational calculations. Their anti-neuroinflammatory effects were assayed. Among the identified compounds, compound 5a effectively reduced nitric oxide (NO) production with an EC50 value of 22.08 ± 0.46 μM. Hence, it could indeed inhibit the lipopolysaccharide (LPS)-induced Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome.

Baeckea frutescens L.: A Review on Phytochemistry, Biosynthesis, Synthesis, and Pharmacology

Background In traditional medicine of Southeast Asian countries, Baeckea frutescens L. (family Myrtaceae) has a long history of use. Numerous research projects have shown that this plant contains metabolites with remarkable medicinal value. No review document, to date, has given an insight into the role of B frutescens constituents in pharmacological development. Objective The current review briefly offers crucial information on the phytochemistry, biosynthesis, synthesis, and pharmacology of B frutescens. Methods B frutescens is the most meaningful keyword to search for literature data. It was used either on its own or in combination with other keywords. References have been gathered from various resources such as Google Scholar, SciFinder, and PubMed. More than 50 electronic references were collected from the 1960s. Results Approximately 130 metabolites have been isolated and structurally determined from this medicinal plant. They included phloroglucinols, phloroglucinol-based meroterpenoids, sesquiterpenoids, triterpenoids, flavonoids, chromones, 5-membered ring compounds, and others. B frutescens fresh tissues were thought to be a rich resource of essential oils. Tasmanone is a precursor in the biosynthesis of various B frutescens compounds, while phloroglucinol derivatives can be seen as initial compounds in the synthetic procedures of various B frutescens molecules. B frutescens plant extracts and compounds isolated from them possess a variety of pharmacological properties, such as cytotoxic, antimicrobial, anti-inflammatory, antioxidant, antirheumatoid, skin protective, and mosquito larvicidal activities. Conclusion More experimental reports on phytochemistry and pharmacology are required. In vivo pharmacological studies on the mechanisms of action of the active compounds are urgently required since most of the results obtained so far have been from in vitro assays.

Anti-inflammatory activity of phenolics from Hypericum japonicum

Two new phenolics, one xanthonoid (1) and one phloroglucinol derivative (2), together with eighteen known phenolics (3–20), were isolated from the aerial parts of Hypericum japonicum. Their structures were established by extensive spectral analysis, and the absolute configuration of compound 1 was determined by comparison of the calculated and experimental circular dichroism spectra. An anti-inflammatory activity assay revealed that compound 1 exhibited effective inhibitory effects on NO generation in LPS-stimulated RAW 264.7 macrophages, with an IC50 value of 6.34 μg/mL.

Phloroglucinol derivatives with α-glucosidase inhibitory activities from Syzygium fluviatile

Four new phloroglucinol derivatives (1 − 4) were isolated from the leaves of Syzygium fluviatile. Their structures were elucidated by means of extensive spectroscopic data. Among them, compounds 1 and 3 showed significant inhibitory activity against α-glucosidase with IC50 values of 10.60 and 5.07 µM, respectively. The structure-activity relationship was also discussed briefly.

Bioactive secondary metabolites isolated from the soft coral derived Penicillium sp. SCSIO 41038

Chemical investigation of the Penicillium sp. SCSIO 41038 led to the isolation and characterization of one new cyclopiazonic acid-type alkaloid, speradine I (1), and one new phloroglucinol derivative, speradine J (8), along with 13 known compounds. Their structures were determined on the basis of extensive spectroscopic analysis, and by a comparison with data from the literature. All the compounds were evaluated for their antitumor (22Rv1 and PC-3) and enzyme inhibitory activity against acetylcholinesterase (AChE) in vitro.