Xanthone Derivatives Research Articles

Chiral Derivatives of Xanthones with Antimicrobial Activity.

According to the World Health Organization, the exacerbated use of antibiotics worldwide is increasing multi-resistant infections, especially in the last decade. Xanthones are a class of compounds receiving great interest in drug discovery and development that can be found as natural products or obtained by synthesis. Many derivatives of xanthones are chiral and associated with relevant biological activities, including antimicrobial. The aim of this review is to compile information about chiral derivatives of xanthones from natural sources and their synthesized examples with antimicrobial activity.

Structures, Activities and Drug-Likeness of Anti-Infective Xanthone Derivatives Isolated from the Marine Environment: A Review.

Marine organisms represent almost half of total biodiversity and are a very important source of new bioactive substances. Within the varied biological activities found in marine products, their antimicrobial activity is one of the most relevant. Infectious diseases are responsible for high levels of morbidity and mortality and many antimicrobials lose their effectiveness with time due to the development of resistance. These facts justify the high importance of finding new, effective and safe anti-infective agents. Among the variety of biological activities of marine xanthone derivatives, one that must be highlighted is their anti-infective properties. In this work, a literature review of marine xanthones with anti-infective activity, namely antibacterial, antifungal, antiparasitic and antiviral, is presented. Their structures, biological activity, sources and the methods used for bioactivity evaluation are described. The xanthone derivatives are grouped in three sets: xanthones, hydroxanthones and glycosylated derivatives. Moreover, molecular descriptors, biophysico-chemical properties, and pharmacokinetic parameters were calculated, and the chemical space occupied by marine xanthone derivatives is recognized. The chemical space was compared with marketed drugs and framed accordingly to the drug-likeness concept in order to profile the pharmacokinetic of anti-infective marine xanthone derivatives.

Carboxyxanthones: Bioactive Agents and Molecular Scaffold for Synthesis of Analogues and Derivatives.

Xanthones represent a structurally diverse group of compounds with a broad range of biological and pharmacological activities, depending on the nature and position of various substituents in the dibenzo-γ-pyrone scaffold. Among the large number of natural and synthetic xanthone derivatives, carboxyxanthones are very interesting bioactive compounds as well as important chemical substrates for molecular modifications to obtain new derivatives. A remarkable example is 5,6-dimethylxanthone-4-acetic acid (DMXAA), a simple carboxyxanthone derivative, originally developed as an anti-tumor agent and the first of its class to enter phase III clinical trials. From DMXAA new bioactive analogues and derivatives were also described. In this review, a literature survey covering the report on carboxyxanthone derivatives is presented, emphasizing their biological activities as well as their application as suitable building blocks to obtain new bioactive derivatives. The data assembled in this review intends to highlight the therapeutic potential of carboxyxanthone derivatives and guide the design for new bioactive xanthone derivatives.

Retracted Article: Synthesis of xanthone derivatives and anti-hepatocellular carcinoma potency evaluation: induced apoptosis.

Twenty-one xanthone derivatives (XDs) were synthesized by a microwave-assisted technique. Their in vitro inhibition potency against the growth of four cancer cell lines was evaluated. XD-1 ∼ [6,9,10-trihydroxy-3,3-dimethyl-5-(2-methylbut-3-en-2-yl)-3H,7H-pyrano[2,3-c]xanthen-7-one] was confirmed as the most active agent against HepG2 cell line growth with IC50 of 18.6 ± 2.31 μM. Apoptosis analysis indicated different contributions of early/late apoptosis and necrosis to cell death for XD-1. XD-1 arrested HepG2 cells on the G0/G1 phase, as indicated by the decreased expressions of cyclin D and CDK2 and the increased expressions of p21. Western blot implied that XD-1 regulated p53/MDM2 to a better healthier state. Moreover, XD-1-induced cell apoptosis was mitochondrion-mediated, as evidenced by caspase activation and involved the PI3K/AKT/mTOR signaling pathway. All the evidence supports that XD-1 is a significant anti-cancer agent for HCC.

Cytoprotective and Anti-genotoxic Effects of Xanthone Derivatives from Garcinia mangostana Against H2O2 Induced PBMC Cell and Blood Leukocytes Damage of Normal and Type 2 Diabetes Volunteers

Hyperglycemia is well-known for inducing cellular oxidative damage in type II diabetes (T2D) patients. This research addressed the cytoprotective and anti-genotoxic effect of xanthone derivatives from Garcinia mangostana against hydrogen peroxide (H2O2)-induced human peripheral blood mononuclear cell (PBMC) and blood leukocytes damage of the normal and T2D volunteers. The cytoprotective effects of an aqueous extract of xanthone (100 and 200 µg/mL) was assessed on cell viability and free radical scavenging activity using the trypan blue exclusion method on PBMC cells. Malondialdehyde (MDA) levels and lactate dehydrogenase (LDH) activity were measured as cellular oxidative damage markers and estimated from culture medium of PBMCs of normal and T2D volunteers. The anti-genotoxicity was assessed as the protective effect of xanthone against H2O2-induce DNA damage of blood leukocytes of the normal volunteers following comet assay technique. Xanthone and Gallic acid (control) concentrations 100, 200 and 100 µg/mL significantly (P < 0.05) protected from H2O2 (20 mM)-induced oxidative damage of PBMCs. It was confirmed by increased cell viability and free radical scavenging activity coupled with the decreased MDA and LDH levels in cell culture medium compared to H2O2 (20 mM)-treated group. In H2O2 (40 mM)-induced blood leukocytes of normal volunteers, different concentration xanthone (50 - 500 µg/mL) significantly (P < 0.05) improved the anti-genotoxicity effect compared to negative/positive control group by lowering comet formation. Xanthone treatments on PBMCs and blood leukocytes of the normal and T2D volunteers could attenuate the H2O2-induced cellular oxidative damage and cell death via exhibiting antioxidant and free radical scavenging activities.

Design, synthesis and cholinesterase inhibitory activity of α-mangostin derivatives

α-mangostin, a polyphenol xanthone derivative, was mainly isolated from pericarps of the mangosteen fruit (Garcinia mangostana L.). In present investigation, a series of derivatives were designed, synthesised and evaluated in vitro for their inhibitory activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among the synthesised xanthones, compounds 1, 9, 13 and 16 showed AChE selective inhibitory activity, 15 was a BuChE selective inhibitor while 2, 3, 5, 6, 7, 12 and 14 were dual inhibitors. The most potent inhibitor of AChE was 16 while 5 was the most potent inhibitor of BuChE with IC50 values of 5.26 μM and 7.55 μM respectively.

Xanthones as natural compounds with a wide spectrum of biological activity

One of the fields of research involving new substances with potential therapeutic effects is folk medicine. In indigenous cultures, including Far Eastern culture, medicine is based on beliefs and superstitions, passed down from generation to generation, concerning the effects of certain substances contained in plants, herbs or spices. Science very often uses traditional knowledge as a source of information. Observation of everyday life and customs of this culture became the starting point for this research on the plants of the family Clusiacaceae Lindl. Substances included in the different parts of these plants are used as anti-inflammatory, antipyretic, antiparasitic, antimicrobial, antifungal and anti-cancer drugs. Many studies have led to the isolation of compounds with different properties and uses, called xanthones. It is an interesting group which can be divided into natural and synthetic xanthone derivatives. On the other hand, xanthones are divided by the chemical structure and chemical ring synthesis. Many new xanthone derivatives are produced to evaluate the dependence of biological activity on the przeciwpasożytnichemical structure of these compounds. The most popular natural xanthones are α-mangostin and gambogic acid. Xanthones are tested in various aspects, but their most important feature is their strong antitumor activity. The distinct mechanism of action of xanthone derivatives and the limited number of side effects give great hope for the use of xanthones in anticancer therapy, as monotherapy drugs or as substances that support current chemotherapy.

Piperidine alkaloids and xanthone from the roots of Caulophyllum robustum Maxim

Two undescribed piperidine racemates, (±)-caulophines A and B (1 and 2), a new N-containing xanthone derivative (3), together with six known piperidines, were isolated from the roots of Caulophyllum robustum Maxim. Their structures were determined by extensive spectroscopic techniques. Compounds 3 and 7 exhibited weak cytotoxicities against human palace cancer hela cell line with inhibitory rates of 32.2% and 39.7%, respectively, at the concentration of 40 μM.

In-vitro and in-vivo Sunscreen Activity of Active Compounds Isolated from Fruits of Phaleria marcocarpha (Scheff.) Boerl

: Objective: Mahkota dewa fruits (Phaleria marcocarpha (Scheff.) Boerl) have been found to contain benzophenone and xanthone derivatives which have a protective effect against ultraviolet light. This study was aimed to evaluate the sunscreen activities of mahkoside A, mangiferin and 6, 4-dihydroxy- 4-methoxybenzophenone-2-O-β-D-glucopyranoside (6, 4-DHMP) isolated from Mahkota dewa fruits in-vitro and in-vivo. Methods: In-vitro sunscreen activity was evaluated using spectrophotometric method by measuring percentage transmission of erythema, percentage transmission of pigmentation and sun protection factor (SPF). The sunscreen activity assays in-vivo was conducted by observing the effect of erythema in rats after exposed to an exotera lamp for 24 h. Results: In-vitro assays showed that mahkoside A, mangiferin and 6, 4-dihydroxy-4-methoxybenzophenone-2-O-β-Dglucopyranoside at a concentration of 100 ppm had SPF value of 3.44, 2.82 and 3.08 respectively. In-vivo test results showed that mangiferin at concentrations of 12.5%, 25%, and 50% decreased the amount of erythema and erythema diameter significantly different than negative control (p Conclusion: Mahkoside A, mangiferin and 6, 4-DHMP possessed sunscreen activity in-vitro and in-vivo.Key words: Mahkoside A, Mangiferin, 6, 4-dihydroxy-4-methoxybenzophenone- 2-O-β-d-glucopyranoside, Phaleria marcocarpha, SPF, Erythema.

Structurally Diverse Polyketides From the Mangrove-Derived Fungus Diaporthe sp. SCSIO 41011 With Their Anti-influenza A Virus Activities.

Influenza A virus (IAV) is a severe worldwide threat to public health and economic development due to its high morbidity and mortality. Marine-derived fungi have been evidenced as a prolific source for the discovery of pharmacologically-active lead compounds. During the course of our search for novel bioactive substances from marine microorganisms, six new polyketides, including two octaketides (1–2), one chromone derivative (13), two highly substituted phthalides (17–18), and one α-pyrone derivative (21) along with 22 known congeners were isolated from a mangrove-associated fungus Diaporthe sp. SCSIO 41011. Their structures were determined by spectroscopic analysis and by comparison with literature data. And the absolute configurations were established according to the specific rotation or electron circular dichroism method. Antiviral evaluation results revealed that compounds 14, 15, 26, and 5-chloroisorotiorin displayed significant anti-IAV activities against three influenza A virus subtypes, including A/Puerto Rico/8/34 H274Y (H1N1), A/FM-1/1/47 (H1N1), and A/Aichi/2/68 (H3N2), with IC50 values in the range of 2.52–39.97 μM. The preliminary structure-activity relationships (SARs) are also discussed. These findings expand the chemical and bioactive diversity of polyketides derived from the genus Diaporthe, and also provide a basis for further development and utilization of chromone, xanthone, and chloroazaphilone derivatives as source of potential anti-viral chemotherapy agents.

Promiscuous enzyme-catalyzed cascade reaction: Synthesis of xanthone derivatives

Based on the screening of biocatalysts and reaction conditions including organic solvent, water content, lipase loading, reaction temperature and time, lipase TLIM exhibited the prominent promiscuity for the Knoevenagel-Michael cascade reactions of 1, 3-diketones with aromatic aldehydes to synthesize xanthone derivatives. This procedure provides satisfactory advantages such as environmental begin, simple work-up, generality, obtaining in excellent yields (80–97%), and potential for recycling of biocatalyst.

Preliminary antifungal activity assay of selected chlorine-containing derivatives of xanthone and phenoxyethyl amines.

The aim of this study was to evaluate antifungal activity in a diverse group of chlorine-containing xanthone and phenoxyethyl amine derivatives - and to select the most promising compounds for further studies. The antifungal efficacy of 16 compounds was tested with qualitative and quantitative methods against both reference and clinical strains of dermatophytes, moulds and yeasts. The disc-diffusion method has demonstrated that from 16 tested compounds, 7 possess good antifungal activity against dermatophytes and/or moulds while none of them has shown good efficacy against yeasts or bacterial strains. The most active compounds (2, 4, 10, 11, 12, 15, 16) were tested quantitatively by broth dilution method to obtain MIC values. The MIC values against dermatophytes ranged from 8 to 64μg/ml. Compound 2 was the most active one against dermatophytes (MIC 50 and MIC 90 were 8μg/ml). The MIC values for moulds ranged from 16 to 256μg/ml. Compound 4 was the most active one against moulds, with MIC 50 and MIC 90 values amounting to 32μg/ml. Among the tested compounds, compound 4 (derivative of xanthone) was the most active one and expressed good antifungal efficacy against clinical strains of dermatophytes and moulds. However, another xanthone derivative (compound 2) was the most active and selective against dermatophytes.

Synthesis and preliminary anti-inflammatory evaluation of xanthone derivatives

Abstract Xanthone derivatives of acetic, propionic and 2-methylpropionic acids were synthesized and assayed for their anti-inflammatory, analgesic and ulcerogenic activities. Compound 8 causes a dose-dependent diminution of paw edema (up to 61%) in the carrageenan model and at the highest tested dose reduces mechanical hyperalgesia in the Randall-Selitto test more effectively than the reference compound (~75% and ~32%, respectively). It shows high in vitro metabolic stability (Clint=12.5 μL/mg/min, t1/2=138.6 min) in the rat liver microsomes. None of the studied xanthone derivatives are ulcerogenic. The results of the present study suggest that compound 8 can be of interest in the future for the search for antinociceptive and antiedematous agents devoid of ulcerogenic effect.

Antimicrobial activity profiles of Amphiphilic Xanthone derivatives are a function of their molecular Oligomerization

Currently, membrane-targeting small antimicrobial peptidomimetics (SAP) are important in antibiotic development because bacteria appear to develop resistance to these surface-active compounds less readily. However, the molecular membrane-targeting action of SAPs has received little attention. In this study, we investigated the effect of oligomerization of amphiphilic xanthone, a model SAP, on its antimicrobial properties against both Gram-positive and Gram-negative bacteria. First, oligomer formation by an amphiphilic xanthone, compound 2 (also coded as AM052), was investigated via solution-state nuclear magnetic resonance (NMR) spectroscopy. Then, the effects of oligomerization on membrane disruption were further studied via biophysical approaches. The results showed that the antimicrobial activities of SAPs develop in several stages: oligomer formation in aqueous solution, initial binding of oligomers to the membrane-water interface followed by insertion into the membrane bilayer, aggregation of antimicrobial oligomers in the membrane, and induced membrane leakage. Ultimately, the presence of the oligomers in the bacterial membrane leads to decreased membrane fluidity and bacterial cell death. Interestingly, the early formation of large oligomers leads to stronger membrane disruption and more rapid bacterial killing. However, reduced antimicrobial activities against Gram-negative bacteria were observed for compounds that formed larger oligomers because the LPS layer acts as a barrier to large complexes. Taken together, our results suggest that oligomerization of SAPs has a strong impact on their antimicrobial properties.

Novel oxazolxanthone derivatives as a new type of α-glucosidase inhibitor: synthesis, activities, inhibitory modes and synergetic effect

Xanthone derivatives have shown good α-glucosidase inhibitory activity and have drawn increased attention as potential anti-diabetic compounds. In this study, a series of novel oxazolxanthones were designed, synthesized, and investigated as α-glucosidase inhibitors. Inhibition assays indicated that compounds 4–21 bearing oxazole rings exhibited up to 30-fold greater inhibitory activity compared to their corresponding parent compound 1b. Among them, compounds 5–21 (IC50 = 6.3 ± 0.4–38.5 ± 4.6 μM) were more active than 1-deoxynojirimycin (IC50 = 60.2 ± 6.2 μM), a well-known α-glucosidase inhibitor. In addition, the kinetics of enzyme inhibition measured by using Lineweaver–Burk analysis shows that compound 4 is a competitive inhibitor, while compounds 15, 16 and 20 are non-competitive inhibitors. Molecular docking studies showed that compound 4 bound to the active site pocket of the enzyme while compounds 15, 16, and 20 did not. More interestingly, docking simulations reveal that some of the oxazolxanthone derivatives bind to different sites in the enzyme. This prediction was further confirmed by the synergetic inhibition experiment, and the combination of representative compounds 16 and 20 at the optimal ratio of 4:6 led to an IC50 value of 1.9 ± 0.7 μM, better than the IC50 value of 7.1 ± 0.9 μM for compound 16 and 8.6 ± 0.9 μM for compound 20.

Effect of drying methods and solvent extraction on the phenolic compounds of Gynura pseudochina (L.) DC. leaf extracts and their anti-psoriatic property

Gynura pseudochina (L.) DC. is a local herb that has been used as an anti-inflammatory agent. To study the utilization of plant phenolics for psoriatic treatment, the effects of the drying process, solvent extraction process and age of the leaves on the total phenolic content (TPC), total flavonoid content (TFC), crude extract and anti-oxidant activity were evaluated. The phenolic composition in the plant extracts was investigated. The most efficient process was applied to obtain a suitable extract for in vitro studies. HaCaT cells subjected to non-TNF-α and TNF-α stimulation were utilized to evaluate the cytotoxicity and anti-RelA, anti-RelB and anti-IL-8 properties of the extracts. The results showed that freeze drying and microwave drying preserved high levels of TPC, TFC and anti-oxidant activity. The HPLC results indicated that 50% (v/v) methanol demonstrated a good efficiency for recovering phenolic compounds, specifically chlorogenic acid (CGA), caffeic acid (CA), p-coumaric acid (PCA) and rutin (RUT). CA content was increased with microwave drying. Microwave drying and mixed-aged leaves were utilized for further studies. Ethanol was used instead of methanol because the former is a safer solvent for health product application. The LC–MS/MS results revealed that 25% (v/v) and 99.9% (v/v) ethanol extracts of mixed-ages leaves dried using a microwave (MLM) contained phenolic acids, flavonoids, a xanthone derivative, a phenylpropanoid, a phenolic glycoside compound and a glycerol-phospholipid. The MLM extract additionally contained pyrrolizidine alkaloids (PAs) at a low concentration. Co-extraction with 25% and 50% (v/v) ethanol of the MLM extract (EMLM) was performed for recovering each phenolic compound. EMLM extracts and their marker compounds (CGA, CA, RUT and PCA) were not toxic to HaCaT cells subjected to non-TNF-α and TNF-α stimulation, except for CA. The EMLM extracts and certain concentrations of the marker compounds could inhibit the RelB canonical pathway and IL-8 production. All results support the possible application of G. pseudochina leaf extracts for psoriasis alleviation.

Preparation and mechanistic aspect of natural xanthone functionalized gold nanoparticle

Herein, a facile scale up and shape variable synthesis of gold nanoparticle (AuNP) and reaction mechanism by natural xanthone derivative (mangiferin) has been reported. Mangiferin (C19H18O11; 1,3,6,7-tetrahydroxyxanthone-C2-β-d-glucoside), a xanthone derivative is isolated from Mangifera indica L. leaves which efficiently reduces Au3+ ions to Au0 and stabilizes the formed AuNP. The structural, optical and plasmonic properties of synthesized AuNP have been investigated through different instrumental techniques like UV–Vis and FTIR spectroscopy, powder XRD, FESEM and TEM analysis. It is observed that variation of the concentration of Au3+ ions and mangiferin has a great effect on controlling size and shape of nanoparticles. The role of reaction temperature is also notable. An interesting observation is that with same concentration ratio of HAuCl4/mangiferin (0.025 mM/0.002%) at the room temperature kidney shaped AuNP is produced, whereas it is spherical at boiling temperature. Moreover, mangiferin allows high scale synthesis of AuNPs (0.025 mM to 10 mM) without changing the particles size and shape. The mechanistic investigation through UV–Vis, FTIR and GCMS analyses reveal the cleavage of glucose unit and oxidation of phenolic OH groups during AuNP formation. Non-toxicity of mangiferin conjugated AuNP on normal human breast cell line (MCF-10A) suggesting its future application as a drug delivery system and other related medicinal purposes.

Structure Elucidation of the Main Tetrahydroxyxanthones of Hypericum Seeds and Investigations into the Testa Structure.

Seeds from Hypericum species have recently been identified as an interesting source of xanthone derivatives. Extraction of seeds from H. perforatum with MeOH and subsequent concentration via polyamide adsorption yielded a fraction enriched in tetrahydroxyxanthones (THX), which were further semipurified by silica gel chromatography. Based on tentative structure assignment of the two main THX X1 and X2 by NMR a total synthesis was performed for both compounds (THX 1 and 2, respectively), starting with an Ullmann ether synthesis. The synthesized 1 and 2 were characterized via 1D- and 2D-NMR methods as well as by LC/HR-MS analysis and proven to be 1,4,6,7-THX (1) and 1,2,6,7-THX (2). Final structure assignment of the natural Hypericum THX constituents was accomplished by comparing chromatographic and spectroscopic data (LC/MSn and GC/MS) with those of 1 and 2 which were obtained by synthesis. Beyond, investigations into the seeds of H. perforatum and H. tetrapterum by scanning electron microscopy (SEM) provided insights of the structure of the testa (seed coat), which is established by two cell layers, with the lignified sclerenchyma presumably being the depository of the xanthones.

Design, synthesis and cardiovascular evaluation of some aminoisopropanoloxy derivatives of xanthone

A series of aminoisopropanoloxy derivatives of xanthone has been synthesized and their pharmacological properties regarding the cardiovascular system has been evaluated. Radioligand binding and functional studies in isolated organs revealed that title compounds present high affinity and antagonistic potency for α1-(compound 2 and 8), β-(compounds 1, 3, 4, 7), α1/β-(compounds 5 and 6) adrenoceptors. Furthermore, compound 7, the structural analogue of verapamil, possesses calcium entry blocking activity. The title compounds showed hypotensive and antiarrhythmic properties due to their adrenoceptor blocking effect. Moreover, they did not affect QRS and QT intervals, and they did not have proarrhythmic potential at tested doses. In addition they exerted anti-aggregation effect. The results of this study suggest that new compounds with multidirectional activity in cardiovascular system might be found in the group of xanthone derivatives.

Virtual screening, Docking, ADMET and System Pharmacology studies on Garcinia caged Xanthone derivatives for Anticancer activity

Caged xanthones are bioactive compounds mainly derived from the Garcinia genus. In this study, a structure-activity relationship (SAR) of caged xanthones and their derivatives for anticancer activity against different cancer cell lines such as A549, HepG2 and U251 were developed through quantitative (Q)-SAR modeling approach. The regression coefficient (r2), internal cross-validation regression coefficient (q2) and external cross-validation regression coefficient (pred_r2) of derived QSAR models were 0.87, 0.81 and 0.82, for A549, whereas, 0.87, 0.84 and 0.90, for HepG2, and 0.86, 0.83 and 0.83, for U251 respectively. These models were used to design and screened the potential caged xanthone derivatives. Further, the compounds were filtered through the rule of five, ADMET-risk and synthetic accessibility. Filtered compounds were then docked to identify the possible target binding pocket, to obtain a set of aligned ligand poses and to prioritize the predicted active compounds. The scrutinized compounds, as well as their metabolites, were evaluated for different pharmacokinetics parameters such as absorption, distribution, metabolism, excretion, and toxicity. Finally, the top hit compound 1G was analyzed by system pharmacology approaches such as gene ontology, metabolic networks, process networks, drug target network, signaling pathway maps as well as identification of off-target proteins that may cause adverse reactions.