Embelin Derivatives Research Articles

Synthesis of Quinoline and Dihydroquinoline Embelin Derivatives as Cardioprotective Agents.

A set of new dihydroquinoline embelin derivatives was obtained from the reaction of the natural benzoquinone embelin (1) with anilines and aromatic aldehydes in the presence of AgOTf. The synthesis of these compounds involves the formation of a Knoevenagel adduct, followed by nucleophilic addition of aniline and subsequent electrocyclic ring closure. The scope of the reaction regarding the aldehydes and anilines was determined. Quinoline derivatives were also obtained from the corresponding dihydroquinolines under oxidation with DDQ. The cardioprotective activity of the synthesized compounds was screened using a doxorubicin-induced cardiotoxicity model in H9c2 cardiomyocytes. Some structure-activity relationships were outlined, and the best activities were achieved with quinoline-embelin derivatives having a 4-nitrophenyl group attached at the pyridine ring. The obtained results indicated that embelin derivatives 4i, 6a, 6d, 6k, and 6m could have potential as cardioprotective agents, as they attenuated a DOX-induced cardiotoxicity effect acting on oxidative stress and apoptosis.

Investigation of embelin synthetic hybrids as potential COVID-19 and COX inhibitors: Synthesis, spectral analysis, DFT calculations and molecular docking studies

Embelin (2, 5-dihydroxy-3-undecyl-1,4-benzoquinone), a benzoquinone isolated from fruits of Embelia ribes has miscellaneous biological potentials including; anticancer, anti-inflammation, antibiotic, and anti-hyperglycemic activities. Also, embelin down-regulates the overexpression of inflammatory pathways like NF-kB, TACE, TNF-α, and other cytokines. Furthermore, embelin fascinated synthetic interest as a pharmacologically active compound. The present article involves the design, synthesis, DFT calculations, and molecular docking studies of embelin derivatives as cyclooxygenase inhibitors. The structure of these derivatives is confirmed by the various spectral analyses such as IR, NMR, and Mass. The DFT calculations were carried out for the molecules (1-8) using CAM-B3LYP hybrid functional with a 6-31+g(d) all-electron basis set using the Gaussian 09 package. Second-order harmonic vibrational calculations are used to check the minimum nature of the geometry. Further, HOMO and LUMO analyses were used for the charge transfer interface between the structures. Based on our previous work and structural activity relationship study, foresaid embelin derivatives were evaluated for in vitro COX-1 and COX-2 inhibitory activity. The compounds 3, 4, 7, and 8 demonstrated excellent COX inhibitions with IC50 values of 1.65, 1.54, 1.56, and 1.23 μM compared to standard drugs Celecoxib and Ibuprofen. Finally, the molecular docking studies carried out with Covid-19 and cyclooxygenase with all the newly synthesized embelin derivatives.

Embelin and Its Derivatives: Design, Synthesis, and Potential Delivery Systems for Cancer Therapy.

Embelin is a naturally occurring benzoquinone that inhibits the growth of cancer cells, making it a potent anticancer drug. However, the low water solubility of embelin restricts its clinical applicability. This review provides a concise summary and in-depth analysis of the published literature on the design and synthesis of embelin derivatives possessing increased aqueous solubility and superior therapeutic efficacy. In addition, the potential of drug delivery systems to improve the anticancer capabilities of embelin and its derivatives is discussed.

Modular Synthesis and Antiproliferative Activity of New Dihydro-1H-pyrazolo[1,3-b]pyridine Embelin Derivatives.

A set of new dihydro-1H-pyrazolo[1,3-b]pyridine and pyrazolo[1,3-b]pyridine embelin derivatives was synthesized through a multicomponent reaction from natural embelin, 3-substituted-5-aminopyrazoles and aldehydes. The synthesized compounds were evaluated against three hematologic tumor cell lines, HEL (acute erythroid leukemia), K-562 (chronic myeloid leukemia) and HL-60 (acute myeloid leukemia), and five breast cancer cell lines (SKBR3, MCF-7, MDA-MB-231, BT-549, HS-578T). The primate non-malignant kidney Vero cell line was used as the control of cytotoxicity. From the obtained results, some structure–activity relationships were outlined. Furthermore, in silico prediction of physicochemical properties and ADME parameters were determined for the derivatives with the best antiproliferative values.

Efficient Multicomponent Synthesis of Diverse Antibacterial Embelin-Privileged Structure Conjugates

A library of embelin derivatives has been synthesized through a multicomponent reaction from embelin (1), aldehydes and privileged structures such as 4-hydroxycoumarin, 4-hydroxy-2H-pyran-2-one and 2-naphthol, in the presence of InCl3 as catalyst. This multicomponent reaction implies Knoevenagel condensation, Michael addition, intramolecular cyclization and dehydration. Many of the synthesized compounds were active and selective against Gram-positive bacteria, including one important multiresistant Staphylococcus aureus clinical isolate. It was found how the conjugation of diverse privileged substructure with embelin led to adducts having enhanced antibacterial activities.

Design, synthesis and α-glucosidase inhibition study of novel embelin derivatives

Embelin is a naturally occurring para-benzoquinone isolated from Embelia ribes (Burm. f.) of the Myrsinaceae family. It was first discovered to have potent inhibitory activity (IC50 = 4.2 μM) against α-glucosidase in this study. Then, four series of novel embelin derivatives were designed, prepared and evaluated in α-glucosidase inhibition assays. The results show that most of the embelin derivatives synthesised are effective α-glucosidase inhibitors, with IC50 values at the micromolar level, especially 10d, 12d, and 15d, the IC50 values of which are 1.8, 3.3, and 3.6 μM, respectively. Structure–activity relationship (SAR) studies suggest that hydroxyl groups in the 2/5-position of para-benzoquinone are very important, and long-chain substituents in the 3-position are highly preferred. Moreover, the inhibition mechanism and kinetics studies reveal that all of 10d, 12d, 15d, and embelin are reversible and mixed-type inhibitors. Furthermore, docking experiments were carried out to study the interactions between 10d and 15d with α-glucosidase.

Design, synthesis and biological evaluation of new embelin derivatives as CK2 inhibitors

A new series of furan embelin derivatives was synthesized and characterized as ATP-competitive CK2 inhibitors. The new compounds were efficiently synthesized using a multicomponent approach from embelin (1), aldehydes and isonitriles through a Knoevenagel condensation/Michael addition/heterocyclization. Several compounds with inhibitory activities in the low micromolar or even submicromolar were identified. The most active derivative was compound 4l (2-(tert-butylamino)-3-(furan-3-yl)-5-hydroxy-6-undecylbenzofuran-4,7-dione) with an IC50 value of 0.63 μM. It turned out to be an ATP competitive CK2 inhibitor with a Ki value determined to be 0.48 μM. Docking studies allowed the identification of key ligand-CK2 interactions, which could help to further optimize this family of compounds as CK2 inhibitors.

Synthesis and Antibacterial Screening of Novel Derivatives of Embelin

Embelin, a naturally occurring compound extracted from Embelia ribes is used in Ayurvedic system of medicine owing to its wide spectrum of biological activities. In the present work, we have aimed at improving the efficacy of Embelin by appropriate structural modifications. A few novel derivatives of Embelin have been prepared. The antibacterial screening of these derivatives were carried out and compared with a well known antibiotic, Streptomycin. The derivatives exhibited better activity than Streptomycin and the lead molecule, Embelin.

Recent developments in synthesis of embelin heterocyclic derivatives and their biological applications

Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) has attracted a great deal of synthetic attention as a biologically active heterocyclic compound in the last decades. The high reactivity of its carbonyl groups, active methylene group, and hydroxyl groups represents challenges to many organic reactions for the synthesis of various embelin derivatives. This review summarizes for the first time the most recent and relevant approaches towards the synthesis of embelin-linked heterocyclic derivatives.

Chemical and Biological Aspects of the Natural 1,4-Benzoquinone Embelin and its (semi-)Synthetic Derivatives.

Like the impressive biological properties of embelin, its chemical aspects have raised the interest of scientists in the field as well. A detailed understanding of the chemistry of embelin is necessary to fully exploit it medicinally. Search for embelin isolation and its chemical modifications was carried out using web-based literature searching tools such as Pubmed and Scifinder. Pertinent literature is covered up to 2016. Structures of bioactive embelin derivatives are provided. Pure embelin, obtained from Embelia ribes berries extraction or by total synthesis, was applied for a number of biological assays. Semi-synthetic and total synthetic approaches led to new high affinity embelin-derived inhibitors of crucial protein targets and to new embelin derivatives with improved pharmacological properties (e.g., with better water-solubility or as applications for drug carrier systems). This review provides a summary of the rich chemistry of embelin and the latest developments in the field of optimized (semi-)synthetic embelin derivatives including their biological activities.

Antidiabetic activity of Embelia ribes, embelin and its derivatives: A systematic review and meta-analysis.

Embelia ribes (ER) has been documented in Ayurveda for treating various diseases, including diabetes mellitus (DM). The present systematic review and meta-analysis evaluated the efficacy and safety of ER and its active bio-marker, embelin and its derivatives in the treatment of DM. Literature search was performed in PubMed/MEDLINE, EMBASE, Scopus, ScienceDirect, Scifinder, and Google Scholar. Using Review Manager, meta-analysis of ER/embelin/derivatives of embelin versus diabetic control was performed with inverse-variance model, providing mean differences (MDs) and 95% confidence intervals (CIs). Heterogeneity was determined by I2 statistic. A total of 13 studies were included in the systematic review and meta-analysis, and were conducted in experimental rats. ER and embelin significantly (P≤0.01) resorted blood glucose (MD, -231.30; CI, -256.79, -205.82; and MD, -154.70; CI, -168.65, -140.74) and glycosylated haemoglobin (MD, -6.36; CI, -8.33, -4.39; and MD,-4.68; CI, -7.76, -1.60), respectively. Meta-analysis findings also reported considerable restoration of insulin, lipid profile, haemodynamic parameters, serum and oxidative stress markers. The derivatives of embelin, 6-bromoembelin and vilangin, also improved diabetic condition. In addition, treatments also ameliorated body weight changes due to diabetes. The present systematic review and meta-analysis supports scientific evidence for the antidiabetic activity of ER/embelin/derivatives of embelin. However, further research is warranted in clinical trials to validate the present findings.

Microwave-Assisted Organocatalytic Intramolecular Knoevenagel/Hetero Diels-Alder Reaction with O-(Arylpropynyloxy)-Salicylaldehydes: Synthesis of Polycyclic Embelin Derivatives.

A highly efficient and regioselective approach to new polycyclic embelin derivatives through a domino Knoevenagel condensation/intramolecular hetero Diels-Alder reaction using O-(arylpropynyloxy)-salicylaldehydes in the presence of ethylenediamine diacetate (EDDA) is reported. This organocatalyzed protocol is compatible toward a wide range of aryl-substituted alkynyl ethers with electron-donating and electron-withdrawing groups. When other active methylene compounds were subjected to this domino reaction the corresponding adducts were obtained in high yield.

Hypoglycemic activity of 6-bromoembelin and vilangin in high-fat diet fed-streptozotocin-induced type 2 diabetic rats and molecular docking studies

AimsThis paper investigates the hypoglycemic activity of two derivatives of embelin (1) viz. 6-bromoembelin (2) and vilangin (3), in high-fat diet - STZ induced diabetic rats. Main methodsThe effects of 6-bromoembelin (2) and vilangin (3) on insulin resistance, β-cell dysfunction and glucose transport in high-fat diet (HFD) fed-streptozotocin (STZ) (40mg/kg) induced type 2 diabetic rats were evaluated. The binding modes of 6-bromoembelin (2) and vilangin (3) into PPARγ, PI3K, Akt, and GLUT4 were also studied using Autodock 4.2 and ADT 1.5.6 programs. Key findingsAt the dose of 30mg/kg, the plasma glucose, plasma insulin and body weight were reduced by both embelin derivatives in diabetic rats. Additionally the altered lipid profiles and hexokinase, glucose-6-phosphatase and fructose-1,6-bisphosphatase levels were brought to normal. Compared to diabetic control group, there was a significant increase in the expression of PPARγ in epididymal adipose tissue. Inhibition of adipogenic activity and mild activation of PPARγ levels in the skeletal muscle and liver were observed. In epididymal adipose tissue, the compounds increased the insulin-mediated glucose uptake through the activation and translocation of GLUT4 in PI3K/p-Akt signaling cascade. SignificanceThe derivatives of embelin such as 6-bromoembelin (2) and vilangin (3) may be useful in the prevention and treatment of obesity-linked type 2 diabetes mellitus.

Domino Synthesis of Embelin Derivatives with Antibacterial Activity.

A series of dihydropyran embelin derivatives was synthesized through a direct and highly efficient approach based on a domino Knoevenagel intramolecular hetero-Diels-Alder reaction from natural embelin (1), using unsaturated aldehydes in the presence of organocatalysts such as ethylendiamine diacetate or l-proline. The aliphatic aldehydes yielded exclusively trans adducts, while mixtures of trans and cis isomers were found in reactions with aromatic aldehydes, with the cis form always predominating. Some of the compounds obtained were active and selective against Gram-positive bacteria, including multiresistant Staphylococcus aureus clinical isolates.

Synthesis and anti-proliferative activities of new derivatives of embelin

Embelin (1), a benzoquinone isolated from Embelia ribes is known to possess variety of biological activities. Despite of several promising biological activities, preclinical efforts on embelin were hampered because of its poor aqueous solubility. In order to address the solubility issue, herein, we have synthesized a series of Mannich products of embelin by treating it with various secondary amines. The synthesized compounds were screened for antiproliferative and antimicrobial activities. In cytotoxicity screening, the benzyl-piperidine linked derivative 8m was found to possess better antiproliferative activity compared to parent natural product embelin against a panel of cell lines including HCT-116, MCF-7, MIAPaCa-2 and PC-3 with IC50 values of 30, 41, 34 and 36μM, respectively. The mechanistic study of compound 8m revealed that it exhibits cytotoxicity via induction of apoptosis and mitochondrial membrane potential loss. Further, the compounds were tested for antimicrobial activity where dimethylamino- 8a and piperidine linked derivative 8b displayed antibacterial activity against Staphylococcus aureus with MIC values of 8 and 16μg/mL, respectively. Mannich derivatives did now show improved aqueous solubility, however their hydrochloride salts 8a·HCl, 8b·HCl and 8m·HCl showed significantly improved aqueous solubility without affecting biological activities of parent Mannich derivatives.

Synthesis and Evaluation of Analgesic and Anti-inflammatory Activities of Most Active Antioxidant Derivatives of Embelin

Objective: To evaluate antioxidant, analgesic and anti-inflammatory properties of embelin and its derivatives. Methods: In the present study embelin was condensed with various aliphatic substituted primary amines, hydrazines and amino acids to yield seven new and five reported derivatives. All these compounds along with embelin were evaluated for in vitro

ChemInform Abstract: Multicomponent Synthesis of Antibacterial Dihydropyridin and Dihydropyran Embelin Derivatives.

AbstractCoupling of embelin with aldehydes and the primary enaminones (III) provides a new, straightforward one‐pot approach to dihydropyridine derivatives of type (IV).

Hemisynthesis of Selected Embelin Analogs and Investigation of their Proapoptotic Activity Against Cancer Cells

Embelin is a natural product, inhibitor of XIAP (X-chromosome-linked Inhibitor of APoptosis) with strong proapoptotic properties on cancer cells. In order to clarify the role of two OH groups on benzoquinone core, we have prepared by hemisynthesis close analogs of embelin, where these OH groups have been replaced in a systematic manner by OMe and OAc groups. Proapoptotic activities of six embelin derivatives have been studied as single agent, or in combination with TRAIL, and their abilities to interact with XIAP have been evaluated by Surface Plasmon Biacore. Our results show that these new embelin analogs have good proapoptotic properties against selected cancer cells, often higher than the natural product itself. Further, this activity is not directly mediated by XIAP. Altogether these preliminary results demonstrate that for active embelin analogs, the two OH groups are not absolutely required for anticancer activity, opening new possibilities for the design of proapoptotic derivatives in these series.

Multicomponent Synthesis of Antibacterial Dihydropyridin and Dihydropyran Embelin Derivatives

A series of dihydropyran and dihydropyridin embelin derivatives were synthesized through a novel and straightforward one-pot protocol based on a three-component reaction with embelin, aldehydes, and cyclic enaminones as synthetic imputs. The type of substituent on the nitrogen atom of the β-enaminone is key to obtain nitrogenated or oxygenated rings. The obtained compounds were active against Gram-positive bacteria, including multiresistant Staphylococcus aureus clinical isolates.

Synthesis and biological evaluation of hydrophilic embelin derivatives

In continuance of our search for newer anti-cancer agents we were interested on embelin, a XIAP (X-linked inhibitor of apoptosis protein) inhibitor. This natural benzoquinone bear a lipophilic chain and we report here the synthesis of hydrophilic analogues of embelin. To allow a large flexibility in the nature of the hydrophilic group, three amines with different length of carbon chain bearing a protected benzoquinone were prepared. The cytotoxic effects of these derivatives were evaluated on KB cell line.