Acyl Phloroglucinol Research Articles

Free radical scavenging behaviour of the plant-beneficial secondary metabolite 2,4-diacetylphloroglucinol derivatives under physiological conditions: A joint experimental and theoretical study

Undoubtedly, natural products (NPs) offer a crucial foundation for crafting novel biologically relevant scaffolds. Among these, 2,4-diacetylphloroglucinol (DAPG) stands out as a polyketide compound produced by Pseudomonads spp, showcasing substantial antimicrobial activity. This study focuses on synthesising derivatives of DAPG and delving into their structural characteristics, tautomerism, and antiradical properties. Through density functional theory (DFT) calculations at the B3LYP/def2-SVP level, we examined the thermodynamic parameters governing the double H+/e−radical trapping processes. These investigations encompassed both gas phase and physiological environments (lipid-like and aqueous solution media). Comparative analyses were conducted with its analogue (2,4-diisobutyrylphloroglucinol, DBPG), its parent compound (phloroglucinol, PG), and a commercial antioxidant standard (2-butylated hydroxyanisole, 2-BHA). This study unveils that DAPG exhibits a preference for double-sequential proton loss electron transfer (dSPLET) as the favoured mechanism within physiological environments. Additionally, we computed redox potentials and equilibrium constants to discuss the effectiveness of the overall scavenging process against diverse reactive oxygen, nitrogen, and sulphur species (ROS, RNS, and RSS). Further insights were gained through molecular docking studies, evaluating the potential inhibition against several ROS-generating enzymes such as xanthine oxidase (XO), lipoxygenase (LO), CYP2C9 (CP450), and NADPH-oxidase (NO). Comprehensive discussions regarding the effects of modifications on PG rings were also conducted. In addition, bioinformatic POM (Petra/Osiris/Molinspiration) analyses were reported to aid in clarifying the experimental data and DFT calculations. Ultimately, this study advocates for the development of potent acyl phloroglucinols (ACPLs)-based antiradical agents, shedding light on how structural characteristics influence their radical scavenging potential.

Investigation of the dual role of acyl phloroglucinols as a new hope for antibacterial and anti-SARS-CoV-2 agents employing integrated in vitro and multi-phase in silico approaches

With the rapid spread of multi-drug-resistant bacteria and more infectious or aggressive variants of SARS-CoV-2, it is critical to develop drugs that can quickly adapt to evolving bacterial and viral mutations. In this study, encouraged by nature, we synthesized a series of phloroglucinol (PG) derivatives, acyl phloroglucinols (ACPLs) 2a-4c by mimicking the structure of the natural antifungal 2,4-diacetylphloroglucinol 3a (2,4-DAPG). According to the quantum chemical calculation, these compounds were expected to be exceptionally favourable for intermolecular interaction with protein receptors. Intriguingly, the in vitro study of Staphylococcus aureus (S. aureus) ATCC 25923 and Escherichia coli (E. coli) ATCC 25922, showed that the four ACPLs 3a–4a had good antibacterial activity and selectivity against gram-positive bacteria, S. aureus. These results were then supported by in silico molecular docking and molecular dynamics simulations (MDs) between these potent compounds and the S. aureus FtsA protein (PDB ID: 3WQU). Furthermore, with the aid of the knowledge base Virus-CKB along with the molecular docking study, it was found that the three ACPLs 4a–4c showed potential inhibitors against SARS-CoV-2 PLpro (PDB ID: 7CMD). Additionally, 100 ns of MDs was carried out in order to assess the stability behaviour of ACPLs at the docked site. Moreover, in silico ADME/T and drug likeness of all studied ACPLs were also predicted. Finally, shape-based screening of FDA-approved drugs was performed using the most prominent synthesized ACPLs as a template, enabling us to include several medications that could be utilized as antibacterial and antiviral drug candidates. Communicated by Ramaswamy H. Sarma

Colupulone, colupone and novel deoxycohumulone geranyl analogues as larvicidal agents against Culex pipiens.

As climate change proceeds, the management of the population of mosquitoes becomes more and more challenging. Insect adulticides and larvicides constitute significant control techniques, with the latter being considered the leading mosquito control method. However, the development of mosquito resistance development and the adverse side effects caused by the extensive use of synthetic insecticides have turned research towards the discovery of environmentally-friendly solutions. Plants and bacteria have historically proven to be a good source of insecticidally active compounds, which may possess novel modes of action to overcome current resistance mechanisms and could also possess favorable human and environmental safety profiles. A previous study demonstrated that the naturally occurring prenylated acyl phloroglucinol deoxycohumulone is a potent larvicidal agent against Culex pipiens. Herein the structural characteristics that improve it are explored by evaluating colupulone and novel geranylated analogues. Colupulone, a prenylated acyl phloroglucinol isolated from Humulus lupulus, colupone, and novel geranylated acyl phloroglucinol congeners, were synthesized and evaluated against Cx. pipiens larva. Results indicated that selected derivatives exhibited superior potency than deoxycohumulone (LC50 43.7mg L-1 ). Thus, strong activity was observed for colupulone (LC50 19.7mg L-1 ), and some novel geranyl analogues of deoxycohumulone reaching at LC50 17.1mg L-1 , while colupone and similar compounds were almost inactive. The results determined the relationship between the target activity and the chemical structure of the tested compounds, and they revealed significantly improved larvicidal candidates. These results highlight the potential of the acyl phloroglucinol chemistry for further development of mosquito larvicides. © 2022 Society of Chemical Industry.

AKTIVITAS ANTIKANKER SENYAWA ASILFLOROGLUSINOL DARI BIJI Melicope incana TERHADAP SEL KANKER PAYUDARA MCF-7

Melicope incana is one of the plant species that belongs to family Rutaceae. Melicope produces phenolic compounds, including alkaloids, acylphloroglucinol, flavonoids, and coumarins. This study aims to isolate the acyl phloroglucinol derivatives found in M. incana seeds. Extraction of acylphloroglucinol derivatives with methanol using the maceration method at room temperature. Separation and purification using a combination of gravity column chromatography, and radial chromatography. Two acylphloroglucinol compounds have been isolated, namely 3'-geranyl-2',4',6'-trihydroxy acetophenone ( 1 ) and 3'-isoprenyl-2',4',6'-trihydroxy acetophenone ( 2 ). The structure of the two compounds was determined based on UV, IR, 1D, and 2D NMR spectroscopic analysis. Anticancer activity of compounds 1-2 against breast cancer cells MCF-7 showed IC 50 values of 48.98 and 4.30 µg /mL, respectively.

Tube-shaped molecular structures built from acylphloroglucinols: an ab initio and DFT study

Molecular structures containing a cavity encounter a variety of applications, from hosts to ions or to smaller molecules to building units for nanomaterials. Previous computational studies of bowl-shaped structures built from acylphloroglucinol (ACPL) units had shown that ACPLs can form the deepest cavities among hydroxybenzenes. The current work considers tube-shaped structures built from ACPL units. To ensure that the two rims have equal size, the orientations of the even-number units are alternated, so that each rim contains alternating RCO and OH-only groups from neighbouring units. Tubes with 4 and 6 units and different R chains have been calculated at the HF/6-31G(d,p) and DFT/B3LYP/6-31+G(d,p) levels. In each rim, the space between two consecutive RCO groups contains three consecutive intramolecular hydrogen bonds (IHBs). The computable properties of the calculated tubes are analysed in detail, with particular attention to the tubes’ geometric features (including the size of the hollow inner part) and to the characteristics and roles of the IHBs. It is inferred that the characteristics of these tubes (including the tight texture of their ‘walls’, the electron-richness of their cavities, and the possibility of expanding their size through the addition of more monomeric units) suggest potential interest for practical applications.

Littordials A–E, novel formyl-phloroglucinol-β-caryophyllene meroterpenoids from the leaves of Psidium littorale

Littordials A–E (1–5), featuring unusual acyl phloroglucinol units, were isolated from the leaves of Psidium littorale. 2, 3 and 5 exhibited significant cytotoxic activities on MDA-MB-231 and B16 cell lines.

Molecular modeling and in vitro approaches towards cholinesterase inhibitory effect of some natural xanthohumol, naringenin, and acyl phloroglucinol derivatives

BackgroundMany natural products, particularly phenolic compounds, have been reported to have a strong inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the key enzymes in the pathology of Alzheimer's disease (AD). HypothesisTherefore, we hypothesized that some xanthahumol, naringenin, and acyl phloroglucinol derivatives (1–14) isolated from Humulus lupulus L. (hops) may have an inhibitory potential against AChE and BChE. MethodsInhibitory potential of compounds 1–14 were tested against AChE and BChE using ELISA microtiter assay. Different molecular docking simulations, including IFD and GOLD protocols, were implemented to verify the interactions between the ligands and the active site amino acids and also their binding energies inside the catalytic crevices of AChE and BChE. ADME/Tox analysis were used to determine pharmacological activities of the compounds. ResultsAmong them, 3‑hydroxy‑xanthohumol (IC50 = 51.25 ± 0.88 µM) and xanthohumol (IC50 = 71.34 ± 2.09 µM), displayed a moderate AChE inhibition in comparison to that of the reference (galanthamine, IC50 = 2.52 ± 0.15 µM). In addition to 3‑hydroxy‑xanthohumol (IC50 = 63.07 ± 3.76 µM) and xanthohumol (IC50 = 32.67 ± 2.82 µM), 8-prenylnaringenin (IC50 = 86.58 ± 3.74 µM) also showed micromolar-range inhibition against BChE (galanthamine, IC50 = 46.58 ± 0.91 µM). Rest of the compounds were found to be either inactive or having inhibition below 50%. Prediction of pharmacokinetic studies suggested that all the ligands revealed acceptable drug-like profiles. Docking simulations demonstrate not only the prediction of ligand binding energies of the compounds inside the catalytic domains of the targets, but also highlight the critical amino acids contributing to stabilizations of the ligands. ConclusionOur findings revealed that xanthohumol in particular could be considered as lead molecule to explore new cholinesterase inhibitors for AD.

Progress on PPAPs cyclization: Guttiferone A as a case study

Guttiferone A and cyclized analogs are naturally occurring polycyclic polyprenylated acyl phloroglucinols possessing antiparasitic activities. Naturally occurring xanthones possess increased activity, but are either rare or difficult to synthesize. In this paper, three optimized methodologies to access natural, hydroxylated and non-natural xanthonic skeletons from guttiferone A are described. These compounds will serve as starting materials for further SAR studies.

A concise review on Phytochemistry and Pharmacological properties of Eucalyptus tereticornis Smith.

Eucalyptus (Myrtaceae) is genus of very diverse flowering trees, which is produced hard and durable heartwood and an important eucalyptol essential oil. Eucalyptus tereticornis Smith leaf is the important source of Eucalyptus oil, which is used as a pharmaceutical, antiseptic, repellent, flavoring and fragrance. The oil comprised of mainly monoterpene like α-pinene and 1,8-cineole as major constituents. Apart from essential oil, the leaf is also reported to presence of various non-volatile phytoconstituents viz; acyl phloroglucinol derivatives, triterpenoids, tannins, lignins, long chain fatty acids, flavonoids and other phenolic compounds. The leaves are also good source of important triterpenoids such as ursolic acid and betulinic acid, which has wide range of pharmacological activities and therapeutic uses. Various analytical methods have been reported for identification and quantification of phytoconstituents in the leaf of E. tereticornis . The leaf extract and oil of E. tereticornis showed various pharmacological activities like antihypergycemic, antibacterial antifungal, antioxidant larvicidal and myorelaxant property. The review attempts to highlight various available literature with respect to the chemical constitutes and their analysis by various chromatographic methods, uses and reported various pharmacological activities.

Isolation of Guttiferones from Renewable Parts of Symphonia globulifera by Centrifugal Partition Chromatography

The aim of this study was to investigate the species Symphonia globulifera, a source of polycyclic polyprenylated acyl phloroglucinols such as guttiferone A, which is known to exhibit a variety of biological activities including noticeable antileishmanial properties. Our goal was the identification and the quantification of guttiferone A in different renewable parts of S. globulifera and its preparative isolation. To the best of our knowledge, there is no data concerning its mechanism of action. Consequently, it is particularly interesting to isolate it in gram quantities in order to establish structure activity relationship studies. After performing high-performance liquid chromatography profiles detecting the presence of guttiferone A and proceeding to its quantification, a centrifugal partition chromatography methodology using a two-phase solvent system of cyclohexane/ethyl acetate/methanol/water (20 : 1 : 20 : 1, v/v/v/v) was applied to each extract. In conclusion, a centrifugal partition chromatography system has been developed to ensure a fast, reliable, and scalable way to isolate, with a high level of purity, guttiferone A from five renewable parts of S. globulifera. Moreover, this methodology can be extended to the isolation of other polycyclic polyprenylated acyl phloroglucinols such as guttiferones B, C, and D.

Acylphloroglucinol Biosynthesis in Strawberry Fruit.

Phenolics have health-promoting properties and are a major group of metabolites in fruit crops. Through reverse genetic analysis of the functions of four ripening-related genes in the octoploid strawberry (Fragaria × ananassa), we discovered four acylphloroglucinol (APG)-glucosides as native Fragaria spp. fruit metabolites whose levels were differently regulated in the transgenic fruits. The biosynthesis of the APG aglycones was investigated by examination of the enzymatic properties of three recombinant Fragaria vesca chalcone synthase (FvCHS) proteins. CHS is involved in anthocyanin biosynthesis during ripening. The F. vesca enzymes readily catalyzed the condensation of two intermediates in branched-chain amino acid metabolism, isovaleryl-Coenzyme A (CoA) and isobutyryl-CoA, with three molecules of malonyl-CoA to form phlorisovalerophenone and phlorisobutyrophenone, respectively, and formed naringenin chalcone when 4-coumaroyl-CoA was used as starter molecule. Isovaleryl-CoA was the preferred starter substrate of FvCHS2-1. Suppression of CHS activity in both transient and stable CHS-silenced fruit resulted in a substantial decrease of APG glucosides and anthocyanins and enhanced levels of volatiles derived from branched-chain amino acids. The proposed APG pathway was confirmed by feeding isotopically labeled amino acids. Thus, Fragaria spp. plants have the capacity to synthesize pharmaceutically important APGs using dual functional CHS/(phloriso)valerophenone synthases that are expressed during fruit ripening. Duplication and adaptive evolution of CHS is the most probable scenario and might be generally applicable to other plants. The results highlight that important promiscuous gene function may be missed when annotation relies solely on in silico analysis.

Role of mitochondria in the leishmanicidal effects and toxicity of acyl phloroglucinol derivatives: nemorosone and guttiferone A.

Nemorosone (Nem) and guttiferone A (GutA) are acyl phloroglucinol derivatives (APD) that are present in different natural products. For both compounds anti-cancer and anti-microbial properties have been reported. In particular, an anti-leishmanial activity of both compounds was demonstrated. The aim of this study was to explore the possible role of mitochondria in the anti-leishmanial activity of Nem and GutA in comparison with their action on mammalian mitochondria. Both APD inhibited the growth of promastigotes of Leishmania tarentolae (LtP) with half maximal inhibitory concentration (IC50) values of 0·67 ± 0·17 and 6·2 ± 2·6 μ m; while IC50 values for cytotoxicity against peritoneal macrophages from BALB/c mice were of 29·5 ± 3·7 and 9·2 ± 0·9 μ m, respectively. Nemorosone strongly inhibited LtP oxygen consumption, caused species-specific inhibition (P < 0·05) of succinate:ubiquinone oxidoreductase (complex II) from LtP-mitochondria and significantly increased (P < 0·05) the mitochondrial superoxide production. In contrast, GutA caused only a moderate reduction of respiration in LtP and triggered less superoxide radical production in LtP compared with Nem. In addition, GutA inhibited mitochondrial complex III in bovine heart submitochondrial particles, which is possibly involved in its mammalian toxicity. Both compounds demonstrated at low micromolar concentrations an effect on the mitochondrial membrane potential in LtP. The present study suggests that Nem caused its anti-leishmanial action due to specific inhibition of complexes II/III of mitochondrial respiratory chain of Leishmania parasites that could be responsible for increased production of reactive oxygen species that triggers parasite death.

Cytotoxic activity of acyl phloroglucinols isolated from the leaves of Eucalyptus cinerea F. Muell. ex Benth. cultivated in Egypt.

Two acyl phloroglucinol compounds namely; Sideroxylonal B (1) and Macrocarpal A (2) were isolated from the Sideroxylonal-Rich Extract (SRE) of the juvenile leaves of Eucalyptus cinerea; F. Muell. ex Benth cultivated in Egypt. Identification of the isolated compounds was established on the basis of physico-chemical properties and spectral analysis (1D & 2D NMR). The two compounds were isolated for the first time from this species. The SRE alongside with the isolated compounds were tested against three human cancer cell lines; MCF7 (breast carcinoma cell line), HEP2 (laryngeal carcinoma), CaCo (colonic adenocarcinoma) and one type of normal human cell line;10 FS (fibroblast cells). The SRE, (1), and (2) showed cytotoxic activity with IC50 13.6 ± 0.62, 7.2 ± 0.5, 14.8 ± 0.55 μg mL−1 against HEP2 respectively, 11.6 ± 0.47, 4 ± 0.36, 11.4 ± 0.45 μg mL−1 against CaCo, respectively, and 8.6 ± 0.29, 4.4 ± 0.25, and 7.8 ± 0.3 μg mL−1 against MCF7, respectively. Meanwhile, the (SRE) together with (1) and (2) exhibited low cytotoxicity against normal cell line 10 FS, with IC50 55.4 ± 1.4, 43 ± 0.8 and 50.1 ± 1.12 μg mL−1, respectively. The antiprofilerative activity of the tested compounds was evaluated. The cell cycle profile of cells treated with Sideroxylonal-B and Macrocarpal-A indicates possible S-phase specific effects.

Hypericum in infection: Identification of anti-viral and anti-inflammatory constituents

The Iowa Center for Research on Botanical Dietary Supplements seeks to optimize Echinacea, Hypericum, and Prunella botanical supplements for human-health benefit, emphasizing anti-viral, anti-inflammatory, and anti-pain activities. This mini-review reports on ongoing studies on Hypericum. The Center uses the genetically diverse, well-documented Hypericum populations collected and maintained at the USDA-ARS North Central Regional Plant Introduction Station (NCRPIS), and the strength of research in synthetic chemistry at Iowa State University to tap natural diversity, to help discover key constituents and interactions among constituents that impact bioactivity and toxicity. The NCRPIS has acquired more than 180 distinct populations of Hypericum, with a focus on Hypericum perforatum L. (Hypericaceae), representing about 13% of currently recognized taxa. Center chemists have developed novel synthetic pathways for key flavones, acyl phloroglucinols, hyperolactones, and a tetralin that have been found in Hypericum, and these compounds are used as standards and for bioactivity studies. Both light-dependent and light-independent anti-viral activities have been identified by using bioactivity-guided fractionation of H. perforatum and a HIV-1 infection test system. Our Center has focused on light-independent activity, potentially due to novel chemicals, and polar fractions are undergoing further fractionation. Anti-inflammatory activity has been found to be light-independent, and fractionation of a flavonoid-rich extract revealed four compounds (amentoflavone, chlorogenic acid, pseudohypericin, and quercetin) that interacted in the light to inhibit lipopolysaccharide-induced prostaglandin E2 activity. The Center continues to explore novel populations of H. perforatum and related species to identify constituents and interactions of constituents that contribute to potential health benefits related to infection.

Reactions of Carbanions with 1,3-Benzodioxin-4-ones: Facile Routes to Flavones, Aurones, and Acyl Phloroglucinols

Two 1,3-benzodioxin-4-ones react with enolates, acetylides and aryllithium reagents to afford adducts that were converted ' into flavones, aurones, and an acyl phloroglucinol.

Carbon‐13 spectral analysis, tautomeric structures and conformations of four two‐ring methylene‐bridged phloroglucinol derivatives

AbstractThe 13C NMR spectra of phloropyron BB, desaspidin BB, albaspidin BB and margaspidin BB were recorded and the structures of the compounds investigated with the aid of chemical shifts and CH coupling constants. The filicinic acid ring of the first three compounds appeared to have a monoketonic structure with the carbonyl group in position 2 (acyl group in position 3). The pyronone ring of phloropyron BB also has a monoketonic structure, with the carbonyl function adjacent to the ring oxygen. The two rings of the first three compounds attain a conformation where a stabilizing hydrogen bond(s) is (are) formed between the two rings, as shown by the observed CH couplings to some of the hydroxyl protons. The spectrum of margaspidin BB, whichconsists of two aromatic acyl phloroglucinol rings, indicates less inter‐ring hydrogen bonding interactions.

New metabolites from the brown algal genus Cystophora

The dichloromethane-soluble secondary metabolites of four Cystophora species, C. monilifera, C. congesta, C. expansa and C. scalaris, are described. The structures of two new acyl phloroglucinols isolated from C. monilifera have been established by a combination of spectral and chemical methods.