Aurones: A Golden Resource for Active Compounds.

Deemed as poorly represented in nature, aurones have been often overlooked by researchers compared to other members of the flavonoid superfamily. However, over the past two decades, they have been reassessed by the scientific community, who are increasingly appreciating their ability to modulate several biological pathways. This review summarizes the recent literature on this class of compounds, which has been analyzed from both a chemical and a functional point of view. Original articles, reviews and editorials featured in Pubmed and Scifinder over the last twenty years have been taken into account to provide the readers with a view of the chemical strategies to obtain them, their functional properties, and their potential of technological use. The resulting comprehensive picture aims at raising the awareness of these natural derivatives as effective drug candidates, fostering the development of novel synthetic analogues.

Structural revision of sesbagrandiflorains A and B, and synthesis and biological evaluation of 6-methoxy-2-arylbenzofuran derivatives.

Sesbagrandiflorains A (1) and B (2), isolated from the stem bark of the Indonesian fabaceous plant Sesbania grandiflora, were reported to be 6-methoxy-2-(2´,3´-dihydroxy-5´-methoxyphenyl)-1-benzofuran-3-carbaldehyde and 6-hydroxy-2-(2´,3´-dihydroxy-5´-methoxyphenyl)-1-benzofuran-3-carbaldehyde, respectively. However, based on reevaluation of their 1D and 2D NMR data, the chemical structures of 1 and 2 have been revised to 4-hydroxy-2-(4´-hydroxy-2´-methoxyphenyl)-6-methoxybenzofuran-3-carbaldehyde and 4-hydroxy-2-(4´-hydroxy-2´-hydroxyphenyl)-6-methoxybenzofuran-3-carbaldehyde, respectively. In addition, seven new derivatives of 1 have been synthesized from the natural product in good yields (65 - 93%). The chemical structures of the synthetic compounds-one diester (6), four ethers (7-10), one secondary amine (11), and one oxime (12)-were confirmed by MS and NMR analysis. Compound 6 exhibited moderate antibacterial activity against the plant pathogen Rhodococcus fascians with a MIC of 0.1 mg/mL. Compounds 8 and 12 demonstrated respectable cytotoxicity against A375 melanoma cancer cells line with the relative IC50 values of 22.8 and 32.7 µM, respectively.

Recent advances on synthesis and biological activities of aurones.

Aurones are naturally occurring structural isomerides of flavones that have diverse bioactivities including antiviral, antibacterial, antifungal, anti-inflammatory, antitumor, antimalarial, antioxidant, neuropharmacological activities and so on. They constitute an important class of pharmacologically active scaffolds that exhibit multiple biological activities via diverse mechanisms. This review article provides an update on the recent advances (2013-2020.4) in the synthesis and biological activities of these derivatives. In the cases where sufficient information is available, some important structure-activity relationships (SAR) of their biological activities were presented, and on the strength of our expertise in medicinal chemistry and careful analysis of the recent literature, for the potential of aurones as medicinal drugs is proposed.

(±)-trans-2-phenyl-2,3-dihydrobenzofurans as leishmanicidal agents: Synthesis, in vitro evaluation and SAR analysis.

Leishmaniasis, a neglected tropical disease caused by parasites of the genus Leishmania, causes a serious burden of disease around the world, represents a threat to the life of millions of people, and therefore is a major public health problem. More effective and non-toxic new treatments are required, especially for visceral leishmaniasis, the most severe form of the disease. On the backdrop that dihydrobenzofurans have previously shown antileishmanial activity, we present here the synthesis of a set of seventy trans-2-phenyl-2,3-dihydrobenzofurans and evaluation of their in vitro activity against Leishmania donovani as well as a discussion of structure-activity relationships. Compounds 8m-o and 8r displayed the highest potency (IC50 < 2 µmol/L) and interesting selectivity of the antileishmanial activity over cytotoxicity against mammalian cells (SI > 4.6). Nonetheless, structural optimization as further requirement was inferred from the high clearance of the most potent compound (8m) observed during determination in vitro of its metabolic stability. On the other hand, chiral separation of 8m and subsequent biological evaluation of its enantiomers demonstrated no effect of chirality on activity and cytotoxicity. Holistic analysis of in silico ADME-like properties and ligand efficiency metrics by a simple scoring function estimating druglikeness highlighted compounds 16c, 18 and 23 as promising candidates for further development. Overall, the potential of trans-2-phenyl-2,3-dihydrobenzofurans as leishmanicidal agents was confirmed.

From Seeds of Apium graveolens Linn. to a Cerebral Ischemia Medicine: The Long Journey of 3-n-Butylphthalide.

3-n-Butylphthalide (NBP) as well as its derivatives and analogues (NBPs), in racemic or enantiomerically pure forms, possess potent and diverse pharmacological properties and have shown a great potential therapeutic interest for many human conditions, especially for cerebral ischemia. This Perspective outlines the synthesis and therapeutic applications of NBPs.

Copper-Catalyzed Enantioselective Hydroalkoxylation of Alkenols for the Synthesis of Cyclic Ethers.

The copper-catalyzed enantioselective intramolecular hydroalkoxylation of unactivated alkenes for the synthesis of tetrahydrofurans, phthalans, isochromans, and morpholines from 4- and 5-alkenols is reported. The substrate scope is complementary to existing enantioselective alkene hydroalkoxylations and is broad with respect to substrate backbone and alkene substitution. The asymmetric induction and isotopic labeling studies support a polar/radical mechanism involving enantioselective oxycupration followed by C-[Cu] homolysis and hydrogen atom transfer. Synthesis of the antifungal insecticide furametpyr was accomplished.

Synthesis and Biological Evaluation of (+)-Usnic Acid Derivatives as Potential Anti-Toxoplasma gondii Agents.

Six series of (+)-usnic acid derivatives were synthesized. The IC50 values of these compounds were determined in T. gondii infected HeLa cells (µM) and in HeLa cells (µM), and their selectivity indexes (SI) were calculated. In vitro, most of the derivatives tested in this study exhibited more anti activity than that of the parent compound (+)-usnic acid and the positive control drugs. Among these derivatives, methyl (E)-(1-(6-acetyl-7,9-dihydroxy-8,9b-dimethyl-1,3-dioxo-3,9b-dihydrodibenzo[b,d]furan-2(1H)-ylidene)ethyl)phenylalaninate (D3) showed the most effective anti-T. gondii activity (selectivity >2.77). In comparison with the clinically used positive control drugs sulfadiazine (selectivity 1.15), pyrimethamine (selectivity 0.89), spiramycin (selectivity 0.72), and the lead compound (+)-usnic acid (selectivity 0.96), D3 showed better results in vitro. Furthermore, D3 and (E)-6-acetyl-7,9-dihydroxy-8,9b-dimethyl-2-(1-(quinolin-6-ylamino)ethylidene)dibenzo[b,d]furan-1,3(2H,9bH)-dione (F3) had greater inhibitory effects on T. gondii (inhibition rates 76.0% and 64.6%) in vivo in comparison to spiramycin (inhibition rate 55.2%); in the peritoneal cavity of mice, the number of tachyzoites was significantly reduced (p < 0.001) in vivo. Additionally, some biochemical parameters were measured and spleen indexes were comprehensively evaluated, and the results indicated that mice treated with both compound D3 and compound F3 showed reduced hepatotoxicity and significantly enhanced antioxidative effects in comparison to the normal group. Granuloma and cyst formation were effected by the inhibition of compound D3 and compound F3 in liver sections. Overall, these results indicated that D3 and F3 for use as anti-T. gondii agents are promising lead compounds.

Green synthesis and antioxidant activity of novel series of benzofurans from euparin extracted of Petasites hybridus.

A novel class of benzofuran derivatives is prepared from the isocyanide-based MCR, euparin and aldehydes in the presence of ZnO-nanorods as a catalyst in excellent yields at room temperature under solvent-free conditions as a green reaction medium. Also, the antioxidant activities of some synthesised compounds such as 4a, 4b, 10a and 10b were evaluated by DPPH radical scavenging and ferric reduction activity potential (FRAP) assays. Compound 10b, was shown moderate radical scavenging activity and very good reducing activity compared to standards (BHT and TBHQ).

Inhibitory Effect of New Semisynthetic Usnic Acid Derivatives on Human Tyrosyl-DNA Phosphodiesterase 1.

Usnic acid, a lichen secondary metabolite produced by a whole number of lichens, has attracted the interest of researchers owing to its broad range of biological activity, including antiviral, antibiotic, anticancer properties, and it possessing a certain toxicity. The synthesis of new usnic acid derivatives and the investigation of their biological activity may lead to the discovery of compounds with better pharmacological and toxicity profiles. In this context, a series of new usnic acid derivatives comprising a terpenoid moiety were synthesized, and their ability to inhibit the catalytic activity of the human DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 was investigated. The most potent compounds (15A, 15B, 15G: , and 16A, 16B, 16G: ) had IC50 values in the range of 0.33 - 2.7 µM. The inhibitory properties were mainly dependent on the flexibility and length of the terpenoid moiety, but not strongly dependent on the configuration of the asymmetric centers. The synthesized derivatives showed low cytotoxicity against human cell lines in an MTT assay. They could be used as a basis for the development of more effective anticancer therapies when combined with topoisomerase 1 inhibitors.

Determination of Usnic Acid Responsive miRNAs in Breast Cancer Cell Lines.

OBJECTIVE: Breast Cancer (BC) is the most common type of cancer diagnosed in women. A common treatment strategy for BC is still not available because of its molecular heterogeneity and resistance is developed in most of the patients through the course of treatment. Therefore, alternative medicine resources as being novel treatment options are needed to be used for the treatment of BC. Usnic Acid (UA) that is one of the secondary metabolites of lichens used for different purposes in the field of medicine and its anti-proliferative effect has been shown in certain cancer types, suggesting its potential use for the treatment. METHODS: Anti-proliferative effect of UA in BC cells (MDA-MB-231, MCF-7, BT-474) was identified through MTT analysis. Microarray analysis was performed in cells treated with the effective concentration of UA and UA-responsive miRNAs were detected. Their targets and the pathways that they involve were determined using a miRNA target prediction tool. RESULTS: Microarray experiments showed that 67 miRNAs were specifically responsive to UA in MDA-MB-231 cells while 15 and 8 were specific to BT-474 and MCF-7 cells, respectively. The miRNA targets were mostly found to play role in Hedgehog signaling pathway. TGF-Beta, MAPK and apoptosis pathways were also the prominent ones according to the miRNA enrichment analysis. CONCLUSION: The current study is important as being the first study in the literature which aimed to explore the UA related miRNAs, their targets and molecular pathways that may have roles in the BC. The results of pathway enrichment analysis and anti-proliferative effects of UA support the idea that UA might be used as a potential alternative therapeutic agent for BC treatment.

Convenient Synthesis and Physiological Activities of Flavonoids in Coreopsis lanceolata L. Petals and Their Related Compounds.

Chalcones, flavanones, and flavonols, including 8-methoxybutin isolated from Coreopsis lanceolata L. petals, were successfully synthesized with total yields of 2⁻59% from O-methylpyrogallols using the Horner⁻Wadsworth⁻Emmons reaction as a key reaction. Aurones, including leptosidin, were also successfully synthesized with 5⁻36% total yields using the Aldol condensation reaction as a key reaction. Each chalcone, flavanone, flavonol, and aurone with the 3,4-dihydroxy groups in the B-ring showed high antioxidant activity. Additionally, each of the chalcones, flavanones, flavonols, and aurones with the 2,4-dihydroxy groups in the B-ring showed an excellent whitening ability.

Structure-Based Virtual Screening and Biochemical Evaluation for the Identification of Novel Trypanosoma brucei Aldolase Inhibitors.

INTRODUCTION: The glycolytic enzyme fructose-1,6-bisphosphate aldolase is a validated molecular target in human African trypanosomiasis (HAT) drug discovery, a neglected tropical disease (NTD) caused by the protozoan Trypanosoma brucei. Herein, a structure-based virtual screening (SBVS) approach to the identification of novel T. brucei aldolase inhibitors is described. Distinct molecular docking algorithms were used to screen more than 500,000 compounds against the X-ray structure of the enzyme. This SBVS strategy led to the selection of a series of molecules which were evaluated for their activity on recombinant T. brucei aldolase. The effort led to the discovery of structurally new ligands able to inhibit the catalytic activity of the enzyme. RESULTS: The predicted binding conformations were additionally investigated in molecular dynamics simulations, which provided useful insights into the enzyme-inhibitor intermolecular interactions. CONCLUSION: The molecular modeling results along with the enzyme inhibition data generated practical knowledge to be explored in further structure-based drug design efforts in HAT drug discovery.

Synthesis of ε-Viniferin Glycosides by Glucosyltransferase from Phytolacca americana and their Inhibitory Activity on Histamine Release from Rat Peritoneal Mast Cells.

Glycosylation of (+)-ε-viniferin was investigated using glucosyltransferase from Phytolacca americana (PaGT3) as a biocatalyst. (+)-ε-Viniferin was converted by PaGT3 into its 4b- and 13b-ß-D-glucosides, the inhibitory activities on histamine release from rat peritoneal mast cells of which were higher than that of (+)-ε-viniferin.

Synthesis of a Functionalized Benzofuran as a Synthon for Salvianolic Acid C Analogues as Potential LDL Antioxidants.

A palladium mediated synthesis of a common synthon for the syntheses of antioxidant analogues of naturally occurring salvianolic acids is presented. The synthetic route may be used to obtain analogues with a balanced lipophilicity/hydrophilicity which may result in potentially interesting LDL antioxidants for the prevention of cardiovascular diseases.

Assessment of flavaglines as potential chikungunya virus entry inhibitors.

Chikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus that recently caused large epidemics in islands in, and countries around, the Indian Ocean. There is currently no specific drug for therapeutic treatment or for use as a prophylactic agent against infection and no commercially available vaccine. Prohibitin has been identified as a receptor protein used by chikungunya virus to enter mammalian cells. Recently, synthetic sulfonyl amidines and flavaglines (FLs), a class of naturally occurring plant compounds with potent anti-cancer and cytoprotective and neuroprotective activities, have been shown to interact directly with prohibitin. This study therefore sought to determine whether three prohibitin ligands (sulfonyl amidine 1 m and the flavaglines FL3 and FL23) were able to inhibit CHIKV infection of mammalian Hek293T/17 cells. All three compounds inhibited infection and reduced virus production when cells were treated before infection but not when added after infection. Pretreatment of cells for only 15 minutes prior to infection followed by washing out of the compound resulted in significant inhibition of entry and virus production. These results suggest that further investigation of prohibitin ligands as potential Chikungunya virus entry inhibitors is warranted.

Facile, protection-free, one-pot synthesis of aureusidin.

A new, reliable, and convenient protection-free one-pot method for the synthesis of aureusidin (1) is described. The present synthetic approach involves the condensation of 4,6-dihydroxybenzofuranone with 3,4-dihydroxybenzaldehyde in the presence of concentrated HCl to afford aureusidin (1) in good yield with high purity. This procedure offers a short and simple route for the preparation of aureusidin (1), a bioactive natural product from several vegetal species, as well as for synthesis of other aurones.

Formal synthesis of (+)-3-epi-eupomatilone-6 and the 3,5-bis-epimer.

The formal synthesis of (+)-3-epi-eupomatilone-6 () and the 3,5-bis-epimer () has been accomplished. The key synthetic strategy involved the stereoselective construction of (3R,4S,5R)- and (3R,4S,5S)-trisubstituted γ-butyrolactones and from (2R,3R)-2,3-dimethyl-4-pentenoic acid derivative , which was readily obtained via stereoselective conjugate addition of vinylmagnesium chloride to a chiral α,ß-unsaturated N-acyl oxazolidinone (Evans' auxiliary) followed by α-methylation.

Immunomodulatory effects of 1-(6-hydroxy-2-isopropenyl-1-benzofuran-5-yl)-1-ethanone from Petasites hybridus and its synthesized benzoxazepine derivatives.

1-(6-Hydroxy-2-isopropenyl-1-benzofuran-5-yl)-1-ethanone (1), isolated from the roots of Petasites hybridus L., and a series of synthetic benzoxazepine derivatives of compound 1 (2-6) were evaluated for their immunomodulatory effects. The compounds were evaluated for their effects on the respiratory burst of human whole blood and isolated human polymorphonuclear leukocytes (PMNs) using luminol- and lucigenin-based chemiluminescence (CL) assays, and their effect on chemotactic migration of PMNs was assessed using the Boyden chamber technique. Compound 1 exhibited stronger inhibition than acetylsalicylic acid (ASA) on luminol-enhanced CL of PMNs. It also inhibited PMN chemotaxis with an IC50 value comparable to that of ibuprofen. Of the compounds tested, 5 was the most effective in inhibiting luminol-enhanced CL and also strongly inhibited lucigenin-enhanced CL with IC50 values lower than that of ASA. Compound 2 was the most active in inhibiting migration of PMNs and was five times stronger than ibuprofen. The results suggest that compound 1 and its synthesized benzoxazepine derivatives, especially compounds 2 and 5, were able to modulate the innate immune response of phagocytes at different steps, emphasizing their potential as leads for the development of new immunomodulatory agents.

Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity.

The NS5A protein plays a critical role in the replication of HCV and has been the focus of numerous research efforts over the past few years. NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays, making them attractive components for inclusion in all oral combination regimens. Early work in the NS5A arena led to the discovery of our first clinical candidate, MK-4882 [2-((S)-pyrrolidin-2-yl)-5-(2-(4-(5-((S)-pyrrolidin-2-yl)-1H-imidazol-2-yl)phenyl)benzofuran-5-yl)-1H-imidazole]. While preclinical proof-of-concept studies in HCV-infected chimpanzees harboring chronic genotype 1 infections resulted in significant decreases in viral load after both single- and multiple-dose treatments, viral breakthrough proved to be a concern, thus necessitating the development of compounds with increased potency against a number of genotypes and NS5A resistance mutations. Modification of the MK-4882 core scaffold by introduction of a cyclic constraint afforded a series of tetracyclic inhibitors, which showed improved virologic profiles. Herein we describe the research efforts that led to the discovery of MK-8742, a tetracyclic indole-based NS5A inhibitor, which is currently in phase 2b clinical trials as part of an all-oral, interferon-free regimen for the treatment of HCV infection.

Total synthesis of bisbibenzyl dibenzofuran asterelin A via intramolecular oxidative coupling.

Total synthesis of asterelin A was accomplished by applying intramolecular Suzuki-Miyaura and oxidative couplings to the formation of an 18-membered macrocyclic ring and a dibenzofuran, respectively.