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Background/aim: Flavonoids represent a privileged scaffold for medicinal chemists because of versatile synthetic transformation into a large variety of functionalized derivatives and are known to exhibit a variety of biological activities and their potential as anticancer agents is being investigated. As part of our continuing investigation of flavonoid derivatives as potential anticancer substances, a series of 3-methylflavones were synthesized, and their antiproliferative activity was evaluated in leukemic HL60 cells., Materials and Methods: 3-Methylflavones were directly synthesized from the 2-propionylphenyl benzoate esters prepared from combination of 2'-hydroxypropiophenone with appropriate benzoic acid derivatives by the modified conditions of Yamaguchi esterification. The synthesized 3-methylflavones were tested in leukemic HL60 cells to assess their antiproliferative activity., Results: Among the synthesized compounds, 3,3'-dimethylflavone showed the most potent activity (IC 50 =76 μM), although the introduction of C3-methyl group in flavone tended to reduce the biological activity., Conclusion: Synthesis of a series of 3-methylflavones as anticancer agents conducted and their antiproliferative activity evaluated. Although the one carbon homologation at C3 position of flavones weakened their activity, atropisomerism can be highlighted as the remarkable phenomenon of 3-methylflavones., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A series of chrysin derivatives were designed, synthesized, and evaluated for their antibacterial activity against four different bacterial strains. We have synthesized new propyl-substituted and butyl-substituted chrysin-piperazine derivatives, which show marvellous inhibition against E. coli and S. aureus . The free hydroxyl group at the C-5 position of chrysin improved therapeutic efficacy in vivo and was a beneficial formulation for chemotherapy. All synthesized compounds were confirmed by various spectroscopic techniques such as IR, NMR, HPLC, and mass spectrometry. The compounds exhibited moderate to good inhibition, and their structure-activity relationship (SAR) has also been illustrated. Among the synthesised compounds, compounds 4 and 10 were the most active against S. pyogenes and E. coli , with 12.5 g/mL MICs; additionally, compound 12 exhibits significant activity on both the S. aureus and E. coli stains. Based on the promising activity profile and docking score of compound 12 , it was selected for 100 ns MD simulation and post-dynamic binding free energy analysis within the active sites of S. aureus TyrRS (PDB ID: 1JIJ) and E. coli DNA GyrB (PDB ID: 6YD9) to investigate the stability of molecular contacts and to establish how the newly synthesized inhibitors fit together in the most stable conformations.Communicated by Ramaswamy H. Sarma.

Neocyclomorusin ( 1 ), a natural bioactive pyranoflavone mainly isolated from plants of the Moraceae family, was synthesized for the first time using a Friedel-Crafts reaction, a Baker-Venkataraman (BK-VK) rearrangement, a selective epoxidation, and a novel S N 2-type cyclization as the key steps. The present protocol was also successfully applied for the total synthesis of oxyisocyclointegrin ( 2 ). Structurally related natural products morusin ( 23 ) and cudraflavone B ( 24 ) were also prepared. We investigated the antibacterial activities of these natural compounds against both Gram-negative and Gram-positive strains. The prenylated flavones, morusin ( 23 ) and cudraflavone B ( 24 ), showed comparable activity to ampicillin and kanacycin A against Staphylococcus aureus . Both morusin ( 23 ) and cudraflavone B ( 24 ) showed better antibacterial activities than ampicillin against the Gram-positive bacteria Staphylococcus epidermidis and Bacillus subtilis . Both neocyclomorusin ( 1 ) and oxyisocyclointegrin ( 2 ) displayed disappointing antimicrobial activities against Escherichia coli , Staphylococcus aureus , Staphylococcus epidermidis , and Bacillus subtilis strains.

American trypanosomiasis (Chagas disease) caused by the Trypanosoma cruzi parasite, is a severe health problem in different regions of Latin America and is currently reported to be spreading to Europe, North America, Japan, and Australia, due to the migration of populations from South and Central America. At present, there is no vaccine available and chemotherapeutic options are reduced to nifurtimox and benznidazole. Therefore, the discovery of new molecules is urgently needed to initiate the drug development process. Some acetophenones and chalcones, as well as chromane-type substances, such as chromones and flavones, are natural products that have been studied as trypanocides, but the relationships between structure and activity are not yet fully understood. In this work, 26 compounds were synthesized to determine the effect of hydroxyl and isoprenyl substituents on trypanocide activity. One of the compounds showed interesting activity against a resistant strain of T. cruzi , with a half effective concentration of 18.3 µM ± 1.1 and an index of selectivity > 10.9.

Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone ( AMF ) is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of AMF have led to a series of AMF derivatives ( 9a-h ) and apigenin-piperazine/piperidine hybrids ( 14a-p , 15a-p , 17a-h , and 19a-f ), respectively. Among these compounds, 15l exhibited a potent PARP-1 inhibitory effect (IC 50 = 14.7 nM) and possessed high selectivity to PARP-1 over PARP-2 (61.2-fold). Molecular dynamics simulation and the cellular thermal shift assay revealed that 15l directly bound to the PARP-1 structure. In in vitro and in vivo studies, 15l showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. 15l·2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l·2HCl may serve as a lead compound for chemosensitizers and the (BRCA-1)-deficient cancer therapy.

Flavones are valuable scaffolds in medicinal chemistry, especially as they display activity as antioxidants and neuroprotective agents. The need to incorporate a fluorine atom on flavones has driven much of the recent synthetic work in this area. We now report a route for the production of 3-fluorinated derivatives of 3',4',5'-trihydroxyflavone and 3',4',5'-trimethoxyflavone. Biological evaluation of these agents, along with their non-fluorinated counterparts, demonstrate that antioxidant activity may be enhanced whereas neuroprotective activity is conserved. Also, the 3-fluoro-3',4',5'-trihydroxyflavone can act as an NMR probe to detect structural changes during its action as a radical scavenger., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Norwogonin is a natural flavone with three phenolic hydroxyl groups in skeletal structure and has excellent antioxidant activity. However, the neuroprotective effect of norwogonin remains unclear. Here, we investigated the protective capacity of norwogonin against oxidative damage elicited by hypoxia in PC12 cells., Methods: The cell viability and apoptosis were examined by MTT assay and Annexin V-FITC/PI staining, respectively. Reactive oxygen species (ROS) content was measured using DCFH-DA assay. Lactate dehydrogenase (LDH), malondialdehyde (MDA) and antioxidant enzyme levels were determined using commercial kits. The expression of related genes and proteins was measured by real-time quantitative PCR and Western blotting, respectively., Results: We found that norwogonin alleviated hypoxia-induced injury in PC12 cells by increasing the cell viability, reducing LDH release, and ameliorating the changes of cell morphology. Norwogonin also acted as an antioxidant by scavenging ROS, reducing MDA production, maintaining the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and decreasing the expression levels of HIF-1α and VEGF. In addition, norwogonin prevented cell apoptosis via inhibiting the expression levels of caspase-3, cytochrome c and Bax, while increasing the expression levels of Bcl-2 and the ratio of Bcl-2/Bax., Conclusions: Norwogonin attenuates hypoxia-induced injury in PC12 cells by quenching ROS, maintaining the activities of antioxidant enzymes, and inhibiting mitochondrial apoptosis pathway.

Background: Flavonoids are naturally occurring compounds with versatile healthpromoting effects against various diseases., Objective: This aim of this paper is to synthesize and evaluate the biological activity of novel flavone derivatives against cancer., Methods: A new series of 2-hydroxy-α,β-unsaturated ketones 2a-h, was synthesized via the reaction of N-substituted-indole-3-carboxaldehyde 1a-h with 2-hydroxy acetophenone in the presence of piperidine. The oxidative cyclization of 2a-h using hydrogen peroxide/KOH and/or dimethyl sulfoxide/I2 produced the corresponding 2-(N-substituted-1H-indol-3-yl)-3-hydroxy-4H-chromen- 4-ones 3a-h and 2-(N-substituted-1H-indol-3-yl)-4H-chromen-4-ones 4a-h, respectively. Antiproliferative activities for synthesized series were investigated against HCT-116 colon and MCF- 7 breast cancer cell lines. Molecular downstream effects were evaluated using RT-PCR. Moreover, molecular docking was carried out to pinpoint the binding mode of the most active compounds into the active site of Akt enzyme (PDB ID: 3QKK)., Results: All compounds exhibited an anti-proliferative activity range of 52-97% and 67.2-99% against HCT-116 and MCF-7, respectively. Compounds 3b, 3h, 3g and 4h had a minimal inhibitory effect on normal BJ1 cells indicating their safety profile. Compounds 3b and 4h, in particular, exhibited the most potent antiproliferative activity against HCT116 and MCF7, meanwhile compounds 3g, 3h and 4g showed potent to moderate activity. Compound 3b had IC50 of 78.3 μM and 53.9 μM against HCT-116 and MCF-7 respectively with comparable IC50 for doxorubicin of 65.1 μM and 45.02 μM. Compound 3b exhibited significant down-regulation for Akt and significant up-regulation of CAS9 and CDKN1genes in all tested cell lines., Conclusion: The synthesized flavone derivatives and particularly compound 3b exhibited promising anticancer activity through Akt inhibition., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The design of a series of novel flavone derivatives was synthesized as potential broad-spectrum antipsychotics by using multi-receptor affinity strategy between dopamine receptors and serotonin receptors. Among them, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin- 1-yl) butoxy)-2,2-dimethylchroman-4-one ( 6j ) exhibited a promising preclinical profile. Compound 6j not only showed high affinity for dopamine D 2 , D 3 , and serotonin 5-HT 1A , 5-HT 2A receptors, but was also endowed with low to moderate activities on 5-HT 2C , α 1 , and H 1 receptors, indicating a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In vivo behavioral studies suggested that 6j has favorable effects in alleviating the schizophrenia-like symptoms without causing catalepsy. Taken together, compound 6j has the potential to be further developed as a novel atypical antipsychotic.

Acetylcholinesterase (AChE) and β-secretase (BACE-1) have become attractive therapeutic targets for Alzheimer's disease (AD). Flavones are flavonoid derivatives with various bioactive effects, including AChE and BACE-1 inhibition. In the present work, a series of 14 flavone derivatives was synthesized in relatively high yields (35-85%). Six of the synthetic flavones ( B4 , B5 , B6 , B8 , D6 and D7 ) had completely new structures. The AChE and BACE-1 inhibitory activities were tested, giving pIC 50 3.47-4.59 (AChE) and 4.15-5.80 (BACE-1). Three compounds ( B3 , D5 and D6 ) exhibited the highest biological effects on both AChE and BACE-1. A molecular docking investigation was conducted to explain the experimental results. These molecules could be employed for further studies to discover new structures with dual action on both AChE and BACE-1 that could serve as novel therapies for AD.

Hot water extraction of D-arabinofuranosylvitexin from the raw leaves of commercially available Basella alba "Tsurumurasaki" and subsequent acidic hydrolysis was improved to be a procedure using a high-pressure steam sterilizer to afford vitexin. The amount was estimated to be 14.1 mg from 1 g of dry weight of the raw leaves, whose recovery was calculated to be 95% based on the estimated content of D-arabinofuranosylvitexin in B. alba raw leaves. The product was dehydratively cyclized between hydroxy groups on the carbohydrate and flavone skeletons under modified Mitsunobu reaction conditions in N,N -dimethylformamide to give chafuroside B, which is known to be a bioactive Oolong tea polyphenol. Through these transformations, 10.2 mg of chafuroside B could be semisynthesized from 1 g of dry weight of the raw leaves, and the efficiency was improved compared to that from the extraction from Oolong tea (3.4 μg from 1 g of dry weight).

7-O-galloyltricetiflavan (GTF), a natural flavonoid, is known to exert anti-oxidation and neuroprotective activity, which are related to the prevention of Alzheimer's disease (AD). In this study, three series of GTF hybrids have been designed, synthesized and evaluated as multifunctional agents for treatment AD. The biological assays indicated that most of them showed strong inhibitory effect on self-induced β-amyloid (Aβ) aggregation, and a significant ability to inhibit ChEs. Among them, compound A15 exhibited best inhibition of Aβ aggregation (78.81% at 20 μM), potent AChE inhibitory potencies (IC 50 , 0.56 μM), and compound C4 presented the highest ability to inhibit BuChE (IC 50 , 5.77 μM). Furthermore, kinetic, molecular modeling and molecular dynamics studies revealed that A15 and C4 could interact with the catalytic active site of AChE and BuChE, respectively. In addition, compounds A15 and C4 could cross the blood-brain barrier in vitro. More importantly, A15 and C4 also showed excellent neuroprotective activities against H 2 O 2 -induced human neuroblastoma SH-SY5Y cells damage and nearly no toxicity on SH-SY5Y cells. All of these outstanding in vitro results indicated A15 and C4 as the leading structure worthy of further investigation., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: A series of eight new flavone derivatives containing a piperazine chain with different substitution were synthesized and their structures were determined., Methods: Their antiradical and antioxidant activities were evaluated using superoxide anion radical, hydroxyl radical, 2,2-diphenyl-1-picrylhydrazyl radical, 2,2'-azino-di(3-ethylbenzthiazoline sulphonate) radical cation (ABTS + ) scavenging (as measure total antioxidant status TAS), ferric reducing antioxidant power (TAC), and hydrogen peroxide decomposition. The antioxidant activities of the synthesized compounds were compared with standard antioxidants trolox, ascorbic acid, butylated hydroxytoluene (BHT) as positive controls, reference antibiotics (doxycycline, dicloxacillin), and medicinal plants (Menthae piperita, Cistus incanus). Chemiluminescence, spectrophotometry, electron spin resonance (ESR) spectroscopy in conjunction with 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) as the spin trap were the measurement techniques., Results: The results show that the synthesized compounds exhibit weak, albeit a wide spectrum of antiradical and antioxidant activities. The TAS values were measured as trolox equivalents, ranging from 209.6 ± 6.1 to 391.1 ± 8.2 µM TE/g; the TAC values were in ranges from 10.8 ± 0.5 to 49.5 ± 0.5 µM TE/g being higher than that of dicloxacillin (241.0 ± 16.5 and 9.73 ± 0.8 µM TE/g, respectively), but lower than ascorbic acid, BHT, doxycycline, and medicinal plants. Best antioxidant activities were found for the piperazinyl analogues with methoxy group on phenyl piperazine ring., Conclusion: We suggest that the synthesized compounds may be used as lead molecules for optimization of molecular structure to maximize the antioxidant potency., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We designed a series of substituted flavones and aurones as non-competitive H1N1 neuraminidase (NA) inhibitors and anti-influenza agents. The molecular docking studies showed that the designed flavones and aurones occupied 150-cavity and 430-cavity of H1N1-NA. We then synthesized these compounds and evaluated these for cytotoxicity, reduction in H1N1 virus yield, H1N1-NA inhibition and kinetics of inhibition. The virus yield reduction assay and H1N1-NA inhibition assay demonstrated that the compound 1f (4-methoxyflavone) had the lowest EC 50 of 9.36 nM and IC 50 of 8.74 μM respectively. Moreover, kinetic studies illustrated that compounds 1f and 2f had non-competitive inhibition mechanism., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Flavonoids are compounds based on a 2-phenylchromonone scaffold. Flavonoids can be divided into flavonoids, flavonols, dihydroflavones, anthocyanins, chalcones and diflavones according to the oxidation degree of the central tricarbonyl chain, the connection position of B-ring (2-or 3-position), and whether the tricarbonyl chain forms a ring or not. There are a variety of biological activities about flavonoids, such as anti-inflammatory activity, anti-oxidation and anti-tumor activity, and the antiinflammatory activity is apparent. This paper reviews the anti-inflammatory activities and mechanisms of flavonoids and their derivatives reported in China and abroad from 2011 till date (2011-2020), in order to find a good drug scaffold for the study of anti-inflammatory activities., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Flavonoid is a family of compounds present in the everyday consumption plants and fruits, contributing to a balanced diet and beneficial health effects. Being a scaffold for new drugs and presenting a wide range of applicability in the treatment of illnesses give them also an impact in medicine. Among the several types of flavonoids, flavone and isoflavone derivatives can be highlighted due to their prevalence in nature and biological activities already established. The standard synthetic route to obtain both halogenated flavones and isoflavones is through the use of already halogenated starting materials. Halogenation of the flavone and isoflavone core is less common because it is more complicated and involves some selectivity issues., Objective: Considering the importance of these flavonoids, we aim to present the main and more recent synthetic approaches towards their halogenation., Methods: The most prominent methodologies for the synthesis of halogenated flavones and isoflavones were reviewed. A careful survey of the reported data, using mainly the Scopus database and halogenation, flavones and isoflavones as keywords, was conducted., Results: Herein, a review is provided on the latest and more efficient halogenation protocols of flavones and isoflavones. Selective halogenation and the greener methodologies, including enzymatic and microbial halogenations, were reported. Nevertheless, some interesting protocols that allowed the synthesis of halogenated flavone and isoflavone derivatives in specific positions using halogenated reagents are also summarized., Conclusion: Halogenated flavones and isoflavones have risen as noticeable structures; however, most of the time, the synthetic procedures involve toxic reagents and harsh reaction conditions. Therefore, the development of new synthetic routes with low environmental impact is desirable., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Three substituted flavone derivatives have been synthesized from substituted O-hydroxy acetophenones and 4-trifluoromethyl benzaldehyde in good yield. These compounds were characterized by NMR spectroscopy and single crystal X-ray Diffraction. Compound F1 and F3 were re-crystallized from their concentrated solutions in chloroform ethyl acetate mixture while F2 was re-crystallized in ethyl acetate n-hexane mixture. Compound F1 and F3 are monoclinic (space group P2 1 /c) with lattice parameters: [a, b, c (A) / β (°)] = 13.332 (2), 15.616 (2) / 6.2898 (8) and 13.9716 (15), 7.1868 (7), 13.6912 (14) / 91.113(6) respectively. Compound F2 is Triclinic (space group P-1) and has lattice parameters: [a, b, c (Å) / α, β, γ (°)] = 6.5002 (6), 8.3801 (9), 13.5989 (14) / 89.348(5), 85.141(4), 84.521(5). Antioxidant, antibacterial and cytotoxic profile was investigated. The compounds showed moderate to less activity on 1,1-diphenyl-2-picryl-hydrazyl (DPPH), Hydrogen peroxide (H /2 /O /2 ) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) models of radical scavenging activity while promising antibacterial potentials were recorded. Furthermore, these molecules can also be used as potential candidates for new antitumor agents.

Flavones are important bioactive compounds, many of which are effective in cancer therapy for their ability to target enzymes related to DNA repair and cell proliferation. In this report, the interaction of a synthetic nitroflavone, 2,4-nitrophenylchromen-4-one (4NCO) with human poly (ADP-ribose) polymerase 1 (hPARP1) was investigated to explore its inhibitory action. Its interaction with hPARP1 was compared with that of other inhibitors through molecular docking studies. Further insight into the 4NCO-hPARP1 interaction was obtained from competitive docking and molecular dynamic simulation studies. In silico mutagenesis studies and per-residue interaction energy calculations were carried out. Quantitative Structure Activity Relationship analysis was also performed to calculate its predictive percent inhibitory activity. Our results indicated that 4NCO exhibited competitive mode of binding to hPARP1. It formed a stable interaction with the protein thereby hindering any further molecular interaction to render it inactive with a predictive inhibition of 96%. It also had good ADMET properties and showed best Autodock binding free energy values compared to other known inhibitors. 4NCO showed good hPARP1 inhibitory properties with higher bioavailability and lower probability of getting effluxed. Development of inhibitors against hPARP1 is important for cell proliferative disorders, where 4NCO can be predicted as a potential new drug., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: "Cell-cycle hypothesis" is emerging in recent years to suggest that aberrant cell cycle re-entry of differentiated neurons leads to a remarkable genetic disequilibrium which is likely to be the primary cause of neuronal apoptosis. DNA polymerase-β is involved in neuronal DNA replication during cell cycle re-entry, thus constituting a promising target for Alzheimer's disease treatment. Recently, 5-methoxyflavone was identified as a candidate molecule endowed with good biological activity and selectivity on the DNA pol-β in multiple in vitro AD models. In vivo assays, especially the brain uptake of 5-methoxyflavone, is need to be evaluated for further development for AD treatment. We report herein the synthesis of 11 C-labeled 5-methoxyflavone, and the evaluation of in vivo properties of 5-[ 11 C]methoxyflavone in rodents., Methods: The strategy for synthesis of 5-[ 11 C]methoxyflavone was developed by treating precursor 5-hydroxyflavone with [ 11 C]CH 3 I and KOH in anhydrous DMF. 5-[ 11 C]Methoxyflavone was purified, then evaluated in mice by using PET/CT imaging., Results: The 5-[ 11 C]methoxyflavone was synthesized conveniently in an average decay corrected yield of 22% (n = 3) with a radiochemical purity >99%. The average molar radioactivity of 5-[ 11 C]methoxyflavone was 383 GBq/μmol. The average concentration was 0.107 μg/mL. PET/CT imaging in mice showed 5-[ 11 C]methoxyflavone rapidly passed through the blood-brain barrier with 8.36 ± 0.61%ID/g at 2 min post injection, and the radioactivity accumulation in brain was still noticeable with 2.48 ± 0.59%ID/g at 28 min post injection. The clearance rate was 3.37 (brain 2 min /brain 28 min ratio). The blood and muscle uptakes were low. The lung displayed high initial uptake and subsequent rapid clearance, while the liver and kidney displayed a relatively slow clearance. Real-time imaging showed that 5-[ 11 C]methoxyflavone accumulated immediately in the heart, then transferred to the liver and intestine, and was not observed in lower digestive tract., Conclusions: 5-[ 11 C]Methoxyflavone was synthesized conveniently in one step. The results of PET/CT imaging in C57BL/6 mice suggested 5-[ 11 C]methoxyflavone possesses appropriate pharmacokinetic properties and favorable brain uptake, thus being proved to be suitable for further development for AD treatment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Seventeen new flavone derivatives substituted at the 4'-OH position were designed, synthesized and evaluated for their anticancer and antibacterial activities. Among them, compounds 3 , 4 , 6f , 6e , 6b , 6c and 6k demonstrated the most potent antiproliferative activities against a human erythroleukemia cell line (HEL) and a prostate cancer cell line (PC3). The results also showed that the IC 50 value of compounds 3 , 4 , 6f , 6e , 6b , 6c and 6k were close to that of the anticancer drug cisplatin (DDP) and lower than that of apigenin. All of the derivatives did not present antibacterial activities. The structure-activity relationships evaluation showed that the configuration of methyl amino acid might affect their biological activities.

In a search for novel multifunctional anti-Alzheimer agents, a congeneric set of seventeen flavone-8-acrylamide derivatives (8a─q) were synthesized and evaluated for their cholinesterase inhibitory, antioxidant, neuroprotective and modulation of Aβ aggregation activities. The target compounds showed effective and selective inhibitory activity against the AChE over BuChE. In addition, the target compounds also showed moderate anti-oxidant activity and strong neuroprotective capacities, and accelerated dosage-dependently the Aβ aggregation. Also, we presented here a complete study on the interaction of 8a, 8d, 8e, 8h and 8i with AChE. Through fluorescence emission studies, the binding sites number found to be 1, binding constants were calculated as 2.04 × 10 4 , 2.22 × 10 4 , 1.18 × 10 4 , 9.8 × 10 3 and 3.2 × 10 4 M -1 and free energy change as -5.83, -5.91, -5.51, -5.41 and -6.12 kcal M -1 at 25 °C which were well agreed with the computational calculations indicating a strong binding affinity of flavones and AChE. Furthermore, the CD studies revealed that the secondary structure of AChE became partly unfolded upon binding with 8a, 8d, 8e, 8h and 8i., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A series of flavonoid derivatives, flavones (F1-F3) and flavonols (OF1-OF3) were synthesized. Their structures were confirmed through various spectroscopic techniques and elemental analysis. These were then tested for cytotoxic activity against mouse fibroblast (NIH 3T3), human endothelial cervical (HeLa) and breast (MCF7) cell lines in vitro by MTT assay. The flavonol series showed prominent potentials than the flavones. The compound OF2 in flavonols exhibited greater potentials MCF7 cell with IC50 value of 0.96μM and OF3 has 1.04μM. In contrast, the OF3 exhibited higher activity against HeLa cell with IC50 value of 0.51μM and OF2 has 1.06μM. The compounds OF2 and OF3 exhibited activity against mouse fibroblast (NIH 3T3) cell with IC50 values 2.48 and 1.24μM. The OF1 was found to be moderate to inactive against all cells. Cytotoxic screening of the tested flavones, F1 to F3 were also active against all cells but the activity was less in comparison to flavonol series of compounds suggestion the possible involvement of hydroxyl (OH) at position 3 in case of flavonols. These results indicated a cheering scaffold that may lead to innovation of potent anti-breast cancer activity.

3',4',7-Trimethoxyflavone (TMF) has been reported to show a potent reversal effect on drug resistance mediated by breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2). In this study, we designed and synthesized five derivatives with either a hydroxy group or a fluorine atom at C-5 and several kinds of capping moiety at the C-7 hydroxy group, on the same 3',4'-dimethoxy-substituted flavone skeleton. We subsequently evaluated the efficacies of these compounds against BCRP-expressing human leukaemia K562/BCRP cells. Reversal of drug resistance was expressed as the concentration of compound causing a twofold reduction in drug sensitivity (RI 50 ). Of the synthesized compounds, the reversal effect of 5-hydroxy-3',4',7-trimethoxyflavone (HTMF, RI 50 7.2 nm) towards 7-ethyl-10-hydroxycamptothecin (SN-38) was stronger than that of TMF (RI 50 18 nm). Fluoro-substituted 5-fluoro-3',4',7-trimethoxyflavone (FTMF, RI 50 25 nm) and monoglycosylated 7-(β-glucosyloxy)-5-hydroxy-3',4'-dimethoxyflavone (GOHDMF, 91 nm) also exhibited reversal effects, whereas the di- and triglycoside derivatives did not. TMF, HTMF and FTMF at 0.01-10 μm upregulated the K562/BCRP cellular accumulation of Hoechst 33342 nuclear staining dye. In addition, western blotting revealed that treatment of K562/BCRP cells with 0.1 μm TMF, HTMF or FTMT suppressed the expression of BCRP. HTMF showed the strongest inhibition of BCRP-mediated efflux and suppression of BCRP expression of the three effective synthesized flavones., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cancer still represents a major global health problem. All currently available anticancer agents have disadvantages like resistance or side effects. Therefore, introduction of novel anticancer agents is needed. Intrigued by the high success rate for natural products-based drug discovery, we designed and synthesized antiproliferative chemical entities as hybrids of two natural products; 3,5,4'-trimethoxystilbene and 5,6,7-trimethoxyflavone. To probe the spectrum of the synthesized compounds, in vitro evaluation was conducted against nine panels representing major cancer diseases. The results revealed the hybrid analogs 4f, 4h, 4k and 4q as promising broad-spectrum anticancer lead compounds eliciting high growth inhibition of several cell lines representing multiple cancers diseases. Evaluation of the promising lead compounds against normal human cell lines suggested a selective cytotoxic effect on cancer cells. Mechanistic investigation of the cytotoxic activity of compound 4f in human cervical cancer HeLa cells showed that it triggers cell death through induction of apoptosis. As a whole, this study presents the natural products hybrid analogs 4f, 4h, 4k and 4q as potential lead compounds for further development of novel anticancer therapeutics., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Traditional chemotherapeutics of low-molecular weight diffuse passively across intact membrane structures of normal healthy cells found in tissues and organ systems in a non-specific unrestricted manner which largely accounts for the induction of most sequelae which restrict dosage, administration frequency, and duration of therapeutic intervention. Molecular strategies that offer enhanced levels of potency, greater efficacy and broader margins-of-safety include the discovery of alternative candidate therapeutics and development of methodologies capable of mediating properties of selective "targeted" delivery., Materials and Methods: The covalent immunopharmaceutical, dexamethasone-(C21-phosphoramidate)-[anti- EGFR] was synthesized utilizing organic chemistry reactions that comprised a multi-stage synthesis regimen. Multiple forms of analysis were implemented to vadliate the successful synthesis (UV spectrophotometric absorbance), purity and molar-incorporation-index (UV spectrophotometric absorbance, chemical-based protein determination), absence of fragmentation/polymerization (SDS-PAGE/chemiluminescent autoradiography), retained selective binding-avidity of IgG-immunoglobulin (cell-ELISA); and selectively "targeted" antineoplastic cytotoxicity (biochemistry-based cell vitality/viability assay)., Results: The botanicals carnosic acid, ginkgolide-B and tangeretin, each individually exerted maximum antineoplastic cytotoxicity levels of 58.1%, 5.3%, and 41.1% respectively against pulmonary adenocarcinoma (A549) populations. Dexamethasone-(C21-phosphoramidate)-[anti-EGFR] formulated at corticosteroid/ glucocorticoid equivalent concentrations produced anti-neoplastic cytotoxicity at levels of 7.7% (10-9 M), 26.9% (10-8 M), 64.9% (10-7 M), 69.9% (10-6 M) and 73.0% (10-5 M). Ccarnosic acid, ginkgolide-B and tangeretin in simultaneous dual-combination with dexamethasone-(C21-phosphoramidate)-[anti-EGFR] exerted maximum anti-neoplastic cytotoxicity levels of 70.5%, 58.6%, and 69.7% respectively., Discussion: Carnosic acid, ginkgolide-B and tangeretin botanicals exerted anti-neoplastic cytotoxicity against pulmonary adenocarcinoma (A549) which additively contributed to the anti-neoplastic cytotoxic potency of the covalent immunopharmaceutical, dexamethasone-(C21-phosphoramidate)-[anti-EGFR]. Carnosic acid and tangeretin were most potent in this regard both individually and in dual-combination with dexamethasone-(C21- phosphoramidate)-[anti-EGFR]. Advantages and attributes of carnosic acid and tangeretin as potential monotherapeutics are a wider margin-of-safety of conventional chemotherapeutics which would readily complement the selective "targeted" delivery properties of dexamethasone-(C21-phosphoramidate)-[anti-EGFR] and possibly other covalent immunopharmaceuticals in addition to providing opportunities for the discovery of combination therapies that provide heightened levels of anti-neoplastic efficacy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The antitumor activity of natural flavonoids has been exhaustively reported. Previously it has been demonstrated that prenylation of flavonoids allows the discovery of new compounds with improved antitumor activity through the activation of caspase-7 activity. The synthesis of twenty-five flavonoids ( 4 ⁻ 28 ) with one or more alkyl side chains was carried out. The synthetic approach was based on the reaction with alkyl halide in alkaline medium by microwave (MW) irradiation. The in vitro cell growth inhibitory activity of synthesized compounds was investigated in three human tumor cell lines. Among the tested compounds, derivatives 6 , 7 , 9 , 11 , 13 , 15 , 17, and 18 revealed potent growth inhibitory activity (GI 50 < 10 μM), being the growth inhibitory effect of compound 13 related with a pronounced caspase-7 activation on MCF-7 breast cancer cells and yeasts expressing human caspase-7. A quantitative structure-activity relationship (QSAR) model predicted that hydrophilicity, pattern of ring substitution/shape, and presence of partial negative charged atoms were the descriptors implied in the growth inhibitory effect of synthesized compounds. Docking studies on procaspase-7 allowed predicting the binding of compound 13 to the allosteric site of procaspase-7.

Members of the aurora kinase family are Ser/Thr kinases involved in regulating mitosis. Multiple promising clinical trials to target aurora kinases are in development. To discover flavones showing growth inhibitory effects on cancer cells, 36 flavone derivatives were prepared, and their cytotoxicity was measured using a long-term clonogenic survival assay. Their half-maximal growth inhibitory effects against HCT116 human colon cancer cells were observed at the sub-micromolar level. Pharmacophores were derived based on three-dimensional quantitative structure⁻activity calculations. Because plant-derived flavones inhibit aurora kinase B, we selected 5-methoxy-2-(2-methoxynaphthalen-1-yl)-4 H -chromen-4-one (derivative 31 ), which showed the best half-maximal cell growth inhibitory effect, and tested whether it can inhibit aurora kinases in HCT116 colon cancer cells. We found that derivative 31 inhibited the phosphorylation of aurora kinases A, aurora kinases B and aurora kinases C, suggesting that derivative 31 is a potential pan-aurora kinase inhibitor. The results of our analysis of the binding modes between derivative 31 and aurora A and aurora B kinases using in-silico docking were consistent with the pharmacophores proposed in this study.

Expression of cytochrome P450-1A1 (CYP1A1) is suppressed under physiologic conditions but is induced (a) by polycyclic aromatic hydrocarbons (PAHs) which can be metabolized by CYP1A1 to carcinogens, and (b) in majority of breast cancers. Hence, phytochemicals or dietary flavonoids, if identified as CYP1A1 inhibitors, may help in preventing PAH-mediated carcinogenesis and breast cancer. Herein, we have investigated the cancer chemopreventive potential of a flavonoid-rich Indian medicinal plant, Pongamia pinnata (L.) Pierre. Methanolic extract of its seeds inhibits CYP1A1 in CYP1A1-overexpressing normal human HEK293 cells, with IC 50 of 0.6 µg/mL. Its secondary metabolites, the furanoflavonoids pongapin/lanceolatin B, inhibit CYP1A1 with IC 50 of 20 nM. Although the furanochalcone pongamol inhibits CYP1A1 with IC 50 of only 4.4 µM, a semisynthetic pyrazole-derivative P5b, has ∼10-fold improved potency (IC 50 , 0.49 μM). Pongapin/lanceolatin B and the methanolic extract of P. pinnata seeds protect CYP1A1-overexpressing HEK293 cells from B[a]P-mediated toxicity. Remarkably, they also block the cell cycle of CYP1A1-overexpressing MCF-7 breast cancer cells, at the G 0 -G 1 phase, repress cyclin D1 levels and induce cellular-senescence. Molecular modeling studies demonstrate the interaction pattern of pongapin/lanceolatin B with CYP1A1. The results strongly indicate the potential of methanolic seed-extract and pongapin/lanceolatin B for further development as cancer chemopreventive agents., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: Synthesis of novel 2(2-hydroxyphenyl) pyrimidine/benzothiazole piperazinyl-substituted flavones end evaluate their antioxidant activity., Results: Six novel 2-(2-hydroxyphenyl) pyrimidine/benzothiazole-substituted flavones were synthesized, their structures were confirmed by elementary and spectral analyses. The compounds were evaluated for their in vitro antioxidant potency by employing various antioxidant assays., Conclusion: All tested compounds acted as scavengers of free radicals like hydroxyl (15-45%), 2,2-diphenyl-1-picrylhydrazyl • (17-48%) at 1.25 and 0.5 mM concentrations respectively. The total antioxidant status activity values of the compounds ranged from 234.1 to 464.1 μm trolox equivalent/g, the total antioxidant capacity - from 24.9 to 52.7 μm trolox equivalent per gram. Compounds incorporating the benzothiazole group on the piperazine ring were more effective antioxidants than those with the 2-(2-hydroxyphenyl) pyrimidine group.

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., Competing Interests: The authors declare no conflict of interest.

Baicalin and its aglycone baicalein derived from Scutellaria baicalensis exhibited potent anticancer effects in various types of cancer cell lines. However, the unfavorable pharmaceutical properties became the main obstacle for their potential clinical development. With the aim of development of novel anticancer agents based on the skeleton of baicalin, a series of novel negletein derivatives were designed and synthesized. Among them, compound 8 (FZU-02,006) with an N,N-dimethylamino ethoxyl moiety at the C-6 position exhibited significant enhanced antiproliferative effect against HL-60 cells in vitro through regulating multisignaling pathways. These results revealed that compound 8 with the improved aqueous solubility (as HCl salt, >1 mg/ml) and enhanced antileukemia potency might serve as a promising lead for further development., (© 2017 John Wiley & Sons A/S.)

The synthesis of hydroxyflavone derivatives is described. The acyl derivatives of 3-, 6-, 7-hydroxyflavones (compounds 2, 4, 6, respectively) and chrysin (5,7-dihydroxyflavone, 7) were obtained in high yields and evaluated in vitro for their cytotoxic activity against several cancer cell lines of different origin: MCF-7 (breast cancer), A549 (nonsmall cell lung cancer), MES-SA (uterine sarcoma), LoVo (colon cancer), drug-resistant human cancer cells (MES-SA/DX5, LoVo/DX) and also towards non-cancer cell line MCF-10A (normal breast epithelial cells). The flavones modified with acyl group showed higher antiproliferative activity than free hydroxyflavones. The highest activity was noted for 3-acetoxyflavone (2), which proved active against LoVo, LoVo/DX, and MES-SA cell lines (IC50 from 4.7 μM to 7.8 μM, respectively). The highest ability to overcome the barrier of resistance (resistance index=0.82) against the drug-resistant MES-SA/DX5 cells compared to the parental drug-sensitive MES-SA cell line was found for 7-acetoxyflavone (6).

The BDNF mimetic compound 7,8-dihydroxyflavone (7,8-DHF), a potent small molecular TrkB agonist, displays prominent therapeutic efficacy against Alzheimer's disease (AD). However, 7,8-DHF has only modest oral bioavailability and a moderate pharmacokinetic (PK) profile. To alleviate these preclinical obstacles, we used a prodrug strategy for elevating 7,8-DHF oral bioavailability and brain exposure, and found that the optimal prodrug R13 has favorable properties and dose-dependently reverses the cognitive defects in an AD mouse model. We synthesized a large number of 7,8-DHF derivatives via ester or carbamate group modification on the catechol ring in the parent compound. Using in vitro absorption, distribution, metabolism, and excretion assays, combined with in vivo PK studies, we identified a prodrug, R13, that prominently up-regulates 7,8-DHF PK profiles. Chronic oral administration of R13 activated TrkB signaling and prevented Aβ deposition in 5XFAD AD mice, inhibiting the pathological cleavage of APP and Tau by AEP. Moreover, R13 inhibited the loss of hippocampal synapses and ameliorated memory deficits in a dose-dependent manner. These results suggest that the prodrug R13 is an optimal therapeutic agent for treating AD., Competing Interests: The authors declare no conflict of interest.

Thioflavone derivatives are the thio analogs of the core constituent of the natural product class of flavones. Based on the position and oxidation level of sulfur, they can be divided into three major categories: 4-thioflavones, 1-thioflavones and 1-thioflavones 1,1-dioxide. In recent years, great efforts have been made to develop an approach for the synthesis of thioflavones, especially 1- thioflavones with high functional group compatibility, high yields, low toxicity as well as proceeding under a mild condition, and a variety of synthetic protocols have been developed, the method of choice being dependent on the nature of substrates. As isosteric analogs of biologically active flavones, thioflavones also exhibit various pharmaceutical properties, such as antimicrobial, anticancer and neuroprotective activities. Replacement of the oxygen atom on flavone skeleton by a sulfur atom resulted in modified biological effects due in most part to the change of the structural properties. However, these varying effects depend on the substituents present and the test species. To provide a comprehensive vision of this class of compounds, this review primarily focuses on the structure, synthetic methods, biological properties as well as structure-activity relationships of thioflavones., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: A new series of 13 piperazinyl flavone derivatives has been synthesized and examined for their in vitro antiradical and antioxidant activities in response to the pharmacy industry's increasing demand for new non-toxic anti-inflammatory and anticancer drugs., Method: Their antioxidant activity was evaluated by the reactive oxygen species (ROS) scavenging assays, 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH•) and 2,2'-azino-bis(3- ethylbenzothiazoline-6-sulphonic acid) radical cation (ABTS+•) scavenging assays, and the ferric reducing antioxidant potency (TAC) method, and was compared to known positive controls, herbal infusions, and penicillins. Chemiluminescence, spectrophotometry, electron spin resonance (ESR) and 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) as the spin trap were the measurement techniques., Result: It was seen that synthesized compounds have a wide spectrum of antioxidant property. Some of the test compounds proved to be extremely efficient scavengers of H2O2 exhibiting, in some cases, EC50 of about 2 µM. The values of antioxidant status (TAS) were in the range of 49 ± 3.9 to 1283 ± 51.3 µM TE/g (TE = Trolox equivalent) and were lower than that of butylated hydroxytoluene (BHT) (1304 ± 43.2 µM TE/g) and green tea (1356 ± 40.0 µM TE/g), but for several synthesized compounds, they were higher than chamomille infusion and penicillins. Ferric reducing antioxidant powers (TAC) for the piperazinyl flavone derivatives were in the range 7 ± 0.5 to 104 ± 0.6 µM TE/g and were weaker than that of BHT (217 ± 5.3 µM TR/g )., Conclusion: Carboxylic or hydroxamic acid substituted piperazinyl flavones are potentially active as antioxidants, thus may be suggested as pharmacologically interesting ones., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Flavones exhibit a variety of beneficial effects and are well known for their medicinal importance in several diseases, including cardiovascular, neurodegenerative and cancer. The inclusion of the piperazine ring to the flavone backbone is an important strategy in drug discovery but only a few studies have synthesized piperazinyl flavone compounds to test their biological activity. While there is a major focus on the antioxidant properties of drugs in therapy of several diseases of inflammatory origin, we synthesized a series of the novel piperazinyl flavone analogues bearing the phenyl ring with different substituents. The analogues were evaluated for in vitro antioxidant activity against superoxide anion radical, hydroxyl radical, 2,2-diphenyl-1-picrylhydrazyl radical, and hydrogen peroxide scavenging properties. The total antioxidant status based on the absorbance of the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) radical cation (ABTS +• ) and total antioxidant capacity using the Fe(III)-ferrozine complex were also monitored. The results of the above studies showed that the compounds synthesized were found possessed moderate radical scavenging potential, and that their interaction with reactive oxygen species is complex and depends on their structural conformation and the type of substituent R in the piperazine ring being attached. Best antiradical activity were found for the compounds with methoxy groups on the phenyl ring of substituent R, whereas the presence of methoxy or trifluoromethyl groups in substituent R resulted in higher ABTS +• and ion Fe(III) reduction. These compounds are promising molecules to be used for their antioxidant properties and may be regarded, after improvement of the antioxidant potential, to control diseases of free radical etiology., (Copyright © 2017 John Wiley & Sons, Ltd.)

Hispidulin is a naturally occurring flavone known to have various Central nervous system (CNS) activities. Proposed synthetic approaches to synthesizing hispidulin have proven unsatisfactory due to their low feasibility and poor overall yields. To solve these problems, this study developed a novel scheme for synthesizing hispidulin, which had an improved overall yield as well as more concise reaction steps compared to previous methods reported. Additionally, using the same synthetic strategy, d -labelled hispidulin was synthesized to investigate its metabolic stability against human liver microsome. This work may produce new chemical entities for enriching the library of hispidulin-derived compounds., Competing Interests: The authors declare no conflict of interest.

Flavonoids are naturally occurring polyphenolic compounds and are among the most promising anticancer agents. A series of flavonols and their 3-methyl ether derivatives were synthesized and assessed for cytotoxicity. It was found that 3'-hydroxy-3,4'-dimethoxyflavone (flavonoid 7a) displayed strong cytotoxicity against human SK-MEL-1 melanoma cells and blocked tubulin polymerization, but had no significant cytotoxic effects against quiescent or proliferating human peripheral blood mononuclear cells. Our analyses showed that flavonoid 7a induces G 2 -M cell cycle arrest and apoptosis in melanoma cells which is associated with cytochrome c release and activation of both extrinsic and intrinsic apoptotic pathways of cell death., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Flavonoids are phenolic compounds that have always attracted pharmaceutical researchers and food manufacturers. Nature has indirectly provided us flavones in our daily diet i.e. tea, fruits, juices and vegetables. Flavones have got special position in research field of natural and synthetic organic chemistry due to their biological capabilities. Flavone derivative has been synthesized in good yield from ketone and corresponding aldehydes. The structures have been established by different spectroscopic techniques like 1 H NMR, 13 C NMR, IR and elemental analysis. The compounds were then screened for its acute toxicity and antinociceptive response in mice models with writhings induced by acetic acid, tail immersion and formalin-induced nociception assay procedures and structure activity relationship was established. The compounds were safe up to a maximum dose of 1200 mg/kg body weight in mice. The effects following pretreatment with naloxone were also studied to reveal the involvement of opioid receptors in the antinociceptive action. The flavone derivatives showed significant reduction in number of abdominal constrictions, increase in paw licking response time in both phases and a significant raise in latency time in nociception models. Moreover, the antinociceptive response was significantly attenuated by pretreatment with naloxone suggesting the involvement of opioid system in the antinociceptive action. The promising effects were shown by halogenated flavone. The flavone derivatives showed analgesic response in all models of nociception suggesting the involvement of opioid system in the antinociceptive action.

A series of scutellarein-O-acetamidoalkylbenzylamines derivatives were designed based on a multitarget-directed ligands strategy for the treatment of Alzheimer's disease. Among these compounds, compound T-22 demonstrated excellent acetylcholinesterase inhibitory, moderate inhibitory effects on self-induced Aβ 1-42 aggregation, Cu 2+ -induced Aβ 1-42 aggregation, human AChE-induced Aβ 1-40 aggregation and disassembled Cu 2+ -induced aggregation of the well-structured Aβ 1-42 fibrils, and also acted as potential antioxidant and biometals chelator. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that T-22 interacted with both the catalytic active site and peripheral anionic site of AChE. Moreover, compound T-22 showed a good neuroprotective effect against H 2 O 2 -induced PC12 cell injury and low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated T-22 significantly reversed scopolamine-induced memory deficit in mice. Taken together, the data showed that T-22 was an interesting multifunctional lead compound worthy of further study for AD., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Agonism of the 5-HT 2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT 2A and 5-HT 2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT 2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT 2C . SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT 2C with high selectivity over the related 5-HT 2A and 5-HT 2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT 2C antagonist.

A new series of semisynthetic flavone-based small molecules mimicking antimicrobial peptides has been designed from natural icaritin to combat drug-resistant Gram-positive bacterial infections. Compound 6 containing two arginine residues exhibited excellent antibacterial activity against Gram-positive bacteria, including MRSA, and very low toxicity to mammalian cells, resulting in a high selectivity of more than 511, comparable to that of several membrane-active antibiotics in clinical trials. Our data show for the first time that icaritin derivatives effectively kill bacteria. Meanwhile, this is the first study deploying a biomimicking strategy to design potent flavone-based membrane targeting antimicrobials. 6 showed rapid bactericidal activity by disrupting the bacterial membrane and can circumvent the development of bacterial resistance. Importantly, 6 was highly efficacious in a mouse model of corneal infection caused by MRSA and Staphylococcus aureus.

Corylifol A, a member of the isoflavone subclass of isoflavonoids, has long been considered to have various biological activities. Here, we sought to synthesize corylifol A glucosides by the in vitro glucosylation reaction using the UDP-glycosyltransferase YjiC from Bacillus licheniformis DSM 13, and obtained two novel glucosides: corylifol A-4',7-di-O-beta-d-glucopyranoside (1) and corylifol A-4'-O-beta-d-glucopyranoside (2). To improve the yield of the products, the reaction time, concentration of UDP-glucose, and pH of the buffer were optimized. The Michaelis constant (K m ) was calculated to be 2.88 mM, and the maximal velocity (V max ) was calculated to be 77.32 nmol/min/mg for UDP-glycosyltransferase. Meanwhile, the water-solubility of compounds 1 and 2 was approximately 27.03 and 15.13 times higher, respectively, than that of their parent compound corylifol A. Additionally, the corylifol A glycosylated products exhibited the highest stability at pH 9.6 and better temperature stability than corylifol A at 40, 60, 80 and 100 °C. In addition, cytotoxicity activity assays against three human tumor cell lines, only corylifol A showed moderate anti-proliferative activity. Overall, this work demonstrates that glycosylation can enhance the water solubility and stability of promising compounds, with potential for further development and application., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

There is a constant need for new therapies against multidrug-resistant (MDR) cancer. Natural compounds are a promising source of novel anticancer agents. We recently showed that protoflavones display activity in MDR cancer cell lines that overexpress the P-glycoprotein (P-gp) drug efflux pump. In this study, 52 protoflavones, including 22 new derivatives, were synthesized and tested against a panel of drug-sensitive parental cells and their MDR derivatives obtained by transfection with the human ABCB1 or ABCG2 genes, or by adaptation to chemotherapeutics. With the exception of protoapigenone, identified as a weak ABCG2 substrate, all protoflavones bypass resistance conferred by these two transporters. The majority of the compounds were found to exhibit mild to strong (up to 13-fold) selectivity against the MCF-7 Dox and KB-V1 cell lines, but not to transfected MDR cells engineered to overexpress the MDR transporters. Our results suggest that protoflavones can overcome MDR cancer by evading P-gp-mediated efflux., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In an effort to identify novel anti-inflammatory compounds, a series of flavone derivatives were synthesized and biologically evaluated for their inhibitory effects on the production of nitric oxide (NO) and prostaglandin E 2 (PGE 2 ), representative pro-inflammatory mediators, in LPS-induced RAW 264.7 cells. Their structure-activity relationship was also investigated. In particular, we found that compound 3g displayed more potent inhibitory activities on PGE 2 production, similar inhibitory activities on NO production and less weak cytotoxicity than luteolin, a natural flavone known as a potent anti-inflammatory agent., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Described herein is a facile and efficient methodology toward the synthesis of Morusin scaffolds and Morusignin L scaffolds 4-9 and 12via a novel three-step approach (Michael addition or prenylation, cyclization and cyclization) and use a rapid, microwave-accelerated cyclization as the key step. Furthermore, their biological activities have been preliminarily demonstrated by in vitro evaluation for anti-osteoporosis activity. These Morusin, Morusignin L and newly synthesized compounds 5b, 6a, 8e, 8f greatly exhibited the highest potency, especially at the 10 -5 mol/L (P<0.01), and had good in vitro anti-osteoporosis activities using the commercially available standard drug Ipriflavone as a positive control. The mechanisms associated with anti-osteoporosis effects of these compounds may be through the inhibition of TRAP enzyme activity and bone resorption in osteoclasts, and promotion effect of osteoblast proliferation in vitro. The results indicated that Morusin scaffolds and Morusignin L scaffolds may be useful leads for further anti-osteoporosis activity screenings., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Substantial research has suggested that the configuration and the total number of functional groups on flavones influence their bioactivity. To investigate the changes in the biological activities of selenoflavones in relationship to structural changes, the development of a generally applicable synthetic method was a key. Until now, an efficient pathway for palladium-catalyzed direct arylation with the selenocyclic enone systems is not known in the literature. We herein introduce a simple direct C-H arylation of two difficult coupling partners, selenochromones and electron-rich aryl bromide, affording diverse polymethoxyselenoflavones with great efficiency and high selectivity.

Farnesoid X receptor (FXR), a nuclear receptor mainly distributed in liver and intestine, has been regarded as a potential target for the treatment of various metabolic diseases, cancer and infectious diseases related to liver. Starting from two previously identified chalcone-based FXR antagonists, we tried to increase the activity through the design and synthesis of a library containing chalcones, flavones and chromenes, based on substitution manipulation and conformation (ring closure) restriction strategy. Many chalcones and four chromenes were identified as microM potent FXR antagonists, among which chromene 11c significantly decreased the plasma and hepatic triglyceride level in KKay mice., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Most of the available antimicrobial drugs have developed resistance, some of them suffer from severe toxicity and side effects. So, there is a need to discover novel compound(s) which should not only be potent, but also less toxic and cost effective., Objectives: The aim of the study is to develop new synthetic antimicrobial agents (Anti-bacterial and anti-fungal) such as 3-substituted flavone/flavanone derivatives, which should be significantly potent with low toxicity., Method: An attempt was made to synthesize a newer series of 3-methyl flavanone derivatives together with the synthesis of a series of 3- hydroxyl flavone analogues. The structures of the test compounds were elucidated and established by UV, IR, 1H-NMR, 13C-NMR and mass spectrometry. The synthesized compounds were subjected for in vitro antimicrobial screening using cup plate methods, followed by the determination of zone of inhibitions., Result: Two series (each 10) of 3-methyl flavanone and 3-hydroxy flavone derivatives were synthesized. The structures of the test compounds were characterized and established by various spectroscopic methods. The synthesized compounds were screened for in vitro antibacterial and antifungal activity against different strains (3-Gram positive, 3-Gram negative and 2- fungal strains)., Conclusion: Some of the 3- hydroxyl flavones derivatives (1b, 3b, 4b, and 5b) and 3- methyl flavanone derivatives (3a, 1a, 2a and 4a) were found to elicit potent antimicrobial activity. The study revealed that 3-hydroxy flavone derivatives were found to be most active against Gram negative, while 3-methyl flavanone derivatives were active against Gram positive bacteria., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

A concise and highly enantioselective synthesis of the natural flavans kazinol U and (2S)-7,3'-dihydroxy-4'-methoxyflavan is reported for the first time. The key transformation is a single-step conversion of a racemic flavanone to a flavan by means of an asymmetric transfer hydrogenation/deoxygenation cascade with kinetic resolution.