A New Aromatic Amide from the Roots of Zanthoxylum tessmannii (Rutaceae)

Phytochemical investigation of the methanolic extract of the roots of Zanthoxylum tessmannii Zepernick and Timler (Rutaceae) led to the isolation and characterization of one new aromatic amide named tessmamide ( 1 ) along with twelve known compounds, N‐benzoyltyramine methyl ether ( 2 ), 7,8,9‐trimethoxycoumarin ( 3 ), 7,8‐dimethoxycoumarin ( 4 ), integrifoliodiol ( 5 ), robustin ( 6 ), skimmianine ( 7 ), lupeol ( 8 ), lupenone ( 9 ), a mixture of stigmasterol and β‐sitosterol, and a mixture of their glucosides. The structures of all compounds were determined by comprehensive spectroscopic analyses (1D‐ and 2D‐NMR, EI‐MS, and ESI‐MS) and comparison with known analogs. The determination of the radical scavenging activity using the 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) assay gave moderate antioxidant values for the crude extracts of the roots of Zanthoxylum tessmannii (IC₅₀ 0.8 mg/mL), tessmamide ( 1 ; IC₅₀ 31.8 μm ), and 7,8,9‐trimethoxycoumarin ( 3 ; IC₅₀ 29.3 μm ), compared to the standard ascorbic acid (IC₅₀ 11.6 μm ).     

Synthesis and Cytotoxicity Evaluation of Panaxadiol Derivatives

In this study, 13 panaxadiol (PD) derivatives were synthesized via reactions with aromatic compounds and amino acids. Following this, the cytotoxicity of these compounds was evaluated against four cancer cell lines (human hepatoma cells HepG‐2, human lung cancer cells A549, human breast cancer cells MCF‐7, and human colon cancer cells HCT‐116) and one normal cell lines (human gastric epithelial cells GES‐1). The results showed that the panaxadiol derivatives 3 , 12 , and 13 showed significant inhibition of cellular proliferation against cancer cells compared with PD, and the panaxadiol derivative 12 had the lowest IC₅₀ value for A549 (IC₅₀=18.91±1.03 μm ). For MCF‐7 cells, most compounds exhibited good inhibition of cellular proliferation, and the panaxadiol derivative 13 showed the strongest inhibitory effect (IC₅₀=8.62±0.23 μm ), which significantly increased the cytotoxicity of PD and was stronger than the positive control (mitomycin). For normal cells, all compounds exhibited low or no toxic effects; thus, these derivatives can be used to develop novel antiproliferative agents.     

Activities of Wogonin Analogs and Other Flavones against Flavobacterium columnare

In our on‐going pursuit to discover natural products and natural product‐based compounds to control the bacterial species Flavobacterium columnare, which causes columnaris disease in channel catfish (Ictalurus punctatus), we synthesized flavone and chalcone analogs, and evaluated these compounds, along with flavonoids from natural sources, for their antibacterial activities against two isolates of F. columnare (ALM‐00‐173 and BioMed) using a rapid bioassay. The flavonoids chrysin ( 1a ), 5,7‐dihydroxy‐4′‐methoxyflavone ( 11 ), isorhamnetin ( 26 ), luteolin ( 27 ), and biochanin A ( 29 ), and chalcone derivative 8b showed strong antibacterial activities against F. columnare ALM‐00‐173 based on minimum inhibition concentration (MIC) results. Flavonoids 1a, 8, 11, 13 (5,4′‐dihydroxy‐7‐methoxyflavone), 26 , and 29 exhibited strong antibacterial activities against F. columnare BioMed based upon MIC results. The 24‐h 50% inhibition concentration (IC₅₀) results revealed that 27 and 29 were the most active compounds against F. columnare ALM‐00‐173 (IC₅₀ of 7.5 and 8.5 mg/l, resp.), while 26 and 29 were the most toxic compound against F. columnare BioMed (IC₅₀ of 9.2 and 3.5 mg/l, resp.). These IC₅₀ results were lower than those obtained for wogonin against F. columnare ALM‐00‐173 and F. columnare BioMed (28.4 and 5.4 mg/l, resp.). However, based on MIC results, none of the compounds evaluated in this study were as active as wogonin (MIC 0.3 mg/l for each F. columnare isolate). Further modification of the wogonin structure to enhance antibacterial is of interest.     

Caesalpanins A–C,Three Dimeric Cassane Diterpenoids from the Seeds of Caesalpinia sappan L.

Three dimeric cassane diterpenoids, caesalpanins A–C, were isolated from the seeds of Caesalpinia sappan L., as well as three known compounds. Their structures were determined via analysis of 1D‐, 2D‐NMR, and HR‐ESI‐MS data. Caesalpanins A and B were the second and third compounds that presented a nitrogen‐containing cassane diterpenoid dimer linked through one ether bond between C‐19 and C‐20′. Caesalpanin B exhibited moderate cytotoxic activity against MCF‐7 cell lines with IC₅₀ value of 29.98 μm . Caesalpanins A and B had weak inhibitory effects against LPS‐induced nitric oxide (NO) production in RAW 264.7 macrophages at 50 μm with inhibitory rate of 36.01 % and 32.93 %, respectively.     

Experimental and molecular docking investigation on DNA interaction of N‐substituted phthalimides: antibacterial,antioxidant and hemolytic activities

A series of Schiff base molecules derived from a phthalimide scaffold was investigated as efficient antibacterial, antioxidant and DNA‐interacting agents. The spectroscopic characterization of these derivatives was studied in detail using elemental analysis and spectroscopic techniques. The DNA‐binding profile of title molecules against Ct‐DNA (calf thymus) was investigated by absorbance, fluorescence, hydrodynamics and thermal denaturation investigations. The bacterial inhibition potential of these molecules was investigated against Escherichia coli and Staphylococcus aureus. Molecule 3c emerged as the most active against S. aureus (IC₅₀: 14.8 μg/mL), whereas compounds 3a and 3b displayed potential antibacterial activities against E. coli (IC₅₀: 49.7 and 67.6 μg/mL). Molecular docking studies of these compounds against GlcN‐6‐P synthase were carried out to rationalize antibacterial efficiency of these molecules. These newly synthesized molecules were screened for their scavenging capacity against 2,2‐diphenyl‐1‐picryl‐hydrazyl (DPPH) and H₂O₂ free radicals and the results were compared with ascorbic acid as synthetic antioxidant. The title molecules 3a, 3b and 3e showed less than 20% hemolysis, which indicated their significant non‐toxic behavior.     

Bioactive Neolignans and Other Compounds from Magnolia grandiflora L.: Isolation and Antiplasmodial Activity

Bioassay‐guided fractionation of a methanol extract of Magnolia grandiflora against Plasmodium falciparum yielded two new ( 1 and 2 ) and six known ( 3 – 8 ) bioactive compounds. The structures of the new compounds were assigned by mass spectrometric and 1D‐ and 2D‐NMR data. Known compounds were identified by comparison of ¹H‐NMR and MS data with literature data. The two known neolignans 3 and 4 showed moderate antiplasmodial activity with the IC₅₀ values of 2.8 ± 0.1 and 3.4 ± 0.1 μm , respectively. Weak antiplasmodial activity was recorded for compounds 1 , 2 , 5 , 6 , 7 , and 8 , with the IC₅₀ values of 38 ± 2, 23 ± 2, 16.5 ± 0.2, 86 ± 1, 44 ± 4, and 114 ± 9 μm , respectively.     

1,3,4-oxadiazole/chalcone hybrids: Design,synthesis, and inhibition of leukemia cell growth and EGFR,Src, IL-6 and STAT3 activities

A new series of 1,3,4-oxadiazole/chalcone hybrids was designed, synthesized, identified with different spectroscopic techniques and biologically evaluated as inhibitors of EGFR, Src, and IL-6. The synthesized compounds showed promising anticancer activity, particularly against leukemia, with 8v being the most potent. The synthesized compounds exhibited strong to moderate cytotoxic activities against K-562, KG-1a, and Jurkat leukemia cell lines in MTT assays. Compound 8v showed the strongest cytotoxic activity with IC₅₀ of 1.95 µM, 2.36 µM and 3.45 µM against K-562, Jurkat and KG-1a leukemia cell lines, respectively. Moreover; the synthesized compounds inhibited EGFR, Src, and IL-6. Compound 8v was most effective at inhibiting EGFR (IC₅₀ = 0.24 μM), Src (IC₅₀ = 0.96 μM), and IL-6 (% of control = 20%). Additionally, most of the compounds decreased STAT3 activation.     

Two New Limonoids from the Fruits of Melia azedarach (Meliaceae)

Two new limonoids, trichilinin M ( 1 ) and ohchinin benzoate ( 2 ), along with two known limonoids, 12-hydroxyamoorastatone ( 3 ) and mesendanin H ( 4 ), were isolated from the fruits of Melia azedarach Linn. The structures of new limonoids were determined by analyses of HR-ESI-MS, 1D and 2D NMR (HSQC, HMBC and NOESY) data. All compounds were evaluated against human pancreatic cancer PANC1 cells and the results showed that compounds 3 – 4 exhibited substantial cytotoxic activity ( 3 : IC₅₀=4.55 μM; 4 : IC₅₀=7.54 μM), and compounds 1 – 2 exhibited moderate cytotoxicity ( 1 : IC₅₀=27.06 μM; 2 : IC₅₀=21.17 μM).     

Synthesis and Anticancer Activity of 3‐(Substituted Aroyl)‐4‐(3,4,5‐trimethoxyphenyl)‐1H‐pyrrole Derivatives

A series of 3‐(substituted aroyl)‐4‐(3,4,5‐trimethoxyphenyl)‐1H‐pyrrole derivatives were synthesized and determined for their anticancer activity against eleven cancer cell lines and two normal tissue cell lines using MTT assay. Among the synthesized compounds, compound 3f was the most potent compound against A375, CT‐26, HeLa, MGC80‐3, NCI‐H460 and SGC‐7901 cells (IC₅₀ = 8.2 – 31.7 μm ); 3g , 3n and 3a were the most potent compounds against CHO (IC₅₀ = 8.2 μm ), HCT‐15 (IC₅₀ = 21 μm ) and MCF‐7 cells (IC₅₀ = 18.7 μm ), respectively. Importantly, all the target compounds showed no cytotoxicity towards the normal tissue cell (IC₅₀ > 100 μm ). Thus, these compounds with the potent anticancer activity and low toxicity have potential for the development of new anticancer chemotherapy agents.     

Effect of chlorinated aliphatic hydrocarbons on the acetoclastic methanogenic activity of granular sludge

The toxicity of chlorinated aliphatic hydrocarbons on acetoclastic methanogens in anaerobic granular sludge was determined using a standardized anaerobic bioassay method. Most of the chloroaliphatics tested were strong inhibitors of methanogenesis. Tri- and tetrachloride derivatives of methane and ethane were the most highly toxic compounds tested, with concentrations of less than 18 mg/l resulting in 50% inhibition (IC₅₀) of the methanogenic activity. Dichlorinated compounds were less toxic, with IC₅₀ values ranging from 40 mg/l to 100 mg/l. On the other hand, perchlorinated derivatives of ethane and ethene were scarcely inhibitory at concentrations near their maximum water solubility. The toxicity caused by chlorinated aliphatic hydrocarbons was reversible. The comparison of structurally related compounds indicated that unsaturated chloroaliphatics were less toxic than their saturated counterparts. A reverse correlation between the electric dipole moment of these compounds and their methanogenic toxicity is discussed. Received: 9 July 1996 / Received revision: 11 October 1996 / Accepted: 18 October 1996     

Nitric Oxide Production‐Inhibitory Activity of Limonoids from Azadirachta indica and Melia azedarach

Seventy‐three limonoids isolated from three Meliaceae plants, Azadirachta indica, A. indica var. siamensis, and Melia azedarach, or semi‐synthesized from the Meliaceae limonoids, were evaluated for their inhibitory activity against nitric oxide (NO) production in mouse macrophage RAW 264.7 cells induced by lipopolysaccharide (LPS), as a primary screening test for anti‐inflammatory agents. Of the compounds tested, 21 compounds exhibited inhibitory activity (IC₅₀ 4.6 – 58.6 μm ) without any significant toxicity (IC₅₀ > 100 μm ) which were more potent than l ‐NMMA (NO‐production inhibitory activity, IC₅₀ 65.6 μm ; cytotoxicity, IC₅₀ > 100 μm ), and among which, nine compounds, i.e., 17‐hydroxy‐15‐methoxynimbocinol ( 6 ), ohchinin ( 20 ), 1‐cis‐cinnamoyl‐1‐decinnamoylohchinin ( 24 ), salannin ( 27 ), methyl nimbidate ( 32 ), isosalannin ( 55 ), nimbolinin D ( 58 ), mesendanin E ( 69 ), and 7‐deacetylgedunin ( 73 ) exhibited potent inhibitory activity (IC₅₀ 4.6 – 29.3 μm ). In particular, compounds 6 (IC₅₀ 7.3 μm ), an azadirone‐type limonoid, and 73 (IC₅₀ 4.6 μm ), a gedunin‐type limonoid, exhibited remarkable activity. Western blot analysis revealed that 27 and 73 reduced the expression levels of the inducible NO synthase and cyclooxygenase‐2 proteins in a concentration‐dependent manner. These findings suggest that limonoids of A. indica, A. indica var. siamensis, and M. azedarach, and their semi‐synthetic derivatives may be effective against inflammation.     

Bioactive metabolites from the sponge Suberea sp

Two new brominated compounds, subereaphenol K ( 2 ) and 2‐(3,5‐dibromo‐1‐ethoxy‐4‐oxocyclohexa‐2,5‐dien‐1‐yl)acetamide ( 3 ), together with subereaphenol B (methyl 2‐(2,4‐dibromo‐3,6‐dihydroxyphenyl)acetate; 1 ) with a revised structure, and five dibromotyrosine‐derived metabolites, 4 – 8 , were isolated from the sponge Suberea sp. and characterized by 1D‐ and 2D‐NMR spectroscopic and HR‐MS spectrometric data. Compounds 1, 2, 6 , and 8 exhibited various weak or moderate bioactivities, including antimicrobial and cytotoxic activities. Furthermore, compounds 1 and 2 inhibited human recombinant phosphodiesterase 4 (PDE4) with IC₅₀ values of 2 μM , whereas compounds 6 and 8 were less active.     

Inhibition analysis of inhibitors derived from lignocellulose pretreatment on the metabolic activity of Zymomonas mobilis biofilm and planktonic cells and the proteomic responses

Lignocellulose pretreatment produces various toxic inhibitors that affect microbial growth, metabolism, and fermentation. Zymomonas mobilis is an ethanologenic microbe that has been demonstrated to have potential to be used in lignocellulose biorefineries for bioethanol production. Z. mobilis biofilm has previously exhibited high potential to enhance ethanol production by presenting a higher viable cell number and higher metabolic activity than planktonic cells or free cells when exposed to lignocellulosic hydrolysate containing toxic inhibitors. However, there has not yet been a systematic study on the tolerance level of Z. mobilis biofilm compared to planktonic cells against model toxic inhibitors derived from lignocellulosic material. We took the first insight into the concentration of toxic compound (formic acid, acetic acid, furfural, and 5‐HMF) required to reduce the metabolic activity of Z. mobilis biofilm and planktonic cells by 25% (IC₂₅), 50% (IC₅₀), 75% (IC₇₅), and 100% (IC₁₀₀). Z. mobilis strains ZM4 and TISTR 551 biofilm were two‐ to three fold more resistant to model toxic inhibitors than planktonic cells. Synergetic effects were found in the presence of formic acid, acetic acid, furfural, and 5‐HMF. The IC₂₅ of Z. mobilis ZM4 biofilm and TISTR 551 biofilm were 57 mm formic acid, 155 mm acetic acid, 37.5 mm furfural and 6.4 mm 5‐HMF, and 225 mm formic acid, 291 mm acetic acid, 51 mm furfural and 41 mm 5‐HMF, respectively. There was no significant difference found between proteomic analysis of the stress response to toxic inhibitors of Z. mobilis biofilm and planktonic cells on ZM4. However, TISTR 551 biofilms exhibited two proteins (molecular chaperone DnaK and 50S ribosomal protein L2) that were up‐regulated in the presence of toxic inhibitors. TISTR 551 planktonic cells possessed two types of protein in the group of 30S ribosomal proteins and motility proteins that were up‐regulated.     

Naphthalene Derivatives and Quinones from Ventilago denticulata and Their Nitric Oxide Radical Scavenging,Antioxidant, Cytotoxic,Antibacterial, and Phosphodiesterase Inhibitory Activities

New naphthalene derivatives ( 1 and 2 ) and a new isomer ( 3 ) of ventilagolin, together with known anthraquinones, chrysophanol ( 4 ), physcion or emodin 3‐methyl ether ( 5 ), and emodin ( 6 ), were isolated from vines of Ventilago denticulata. The isolated compounds exhibited cytotoxic activity with IC₅₀ values of 1.15 – 40.54 μg/ml. Compounds 1 – 3 selectively exhibited weak antibacterial activity (MIC values of 200.0 – 400.0 μg/ml), while emodin ( 6 ) displayed moderate antibacterial activity with MIC value of 25.0 μg/ml. The isolated compounds showed nitric oxide and DPPH radical scavenging activities. Compounds 1 – 3 and 6 exhibited weak xanthine oxidase inhibitory activity, while emodin ( 6 ) acted as an aromatase inhibitor with the IC₅₀ value of 10.1 μm . Compounds 1 and 2 exhibited phosphodiesterase 5 inhibitory activity with IC₅₀ values of 8.28 μm and 6.48 μm , respectively.     

In vitro effects of standard antioxidants on lactoperoxidase enzyme–A molecular docking approach

Lactoperoxidase (LPO), an antioxidant enzyme, is a natural antimicrobial system that eliminates the harmful effects of microorganisms in milk. It has a wide range of applications and is also preferred in cosmetic and clinical applications, as well as used in foods. The use of antioxidants is well recognized in the food and feed industries to improve the shelf life of products. This study aimed to determine the in vitro inhibition effects of Trolox, α‐tocopherol, butylated hydroxyanisole, butylated hydroxytoluene, and propyl gallate, which are commonly used as antioxidants in food and pharmaceutical products. For this purpose, LPO was first purified in a single step using sepharose‐4B‐l ‐tyrosine‐sulfanilamide affinity gel chromatography. Also, some inhibition parameters, including half‐maximal inhibitory concentration (IC₅₀), K_i values, and inhibition types, were calculated for each antioxidant molecule. The IC₅₀ values of these molecules, which exhibited competitive inhibition, varied between 377.7 and 3397.8 nM. Molecular docking studies were also performed for all compounds. According to the binding scores, α‐tocopherol was shown to exhibit the most effective inhibitor property (IC₅₀: 377.7 nM and K_i: 635.8 ± 16.8 nM) among the standard antioxidants used in this study. Inhibiting the LPO activity by standard antioxidants results in the weakening of the immune system during lactation, which is important for metabolism.     

Biological Activities of Phenolics from the Fruits of Phyllanthus emblica L. (Euphorbiaceae)

Seven phenolic compounds, 1 – 7 , including a new organic acid gallate, mucic acid 1‐ethyl 6‐methyl ester 2‐O‐gallate ( 7 ), were isolated from the MeOH extract of the fruits of Phyllanthus emblica L. (Euphorbiaceae). The structures were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. Upon evaluated for their antioxidant abilities by 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH), 2,2′‐azinobis(3‐ethylbenzthiazoline‐6‐sulfonic acid) (ABTS), and ferric reducing antioxidant power (FRAP) assays. The inhibitory activities against melanogenesis in B16 melanoma cells induced by α‐MSH, as well as cytotoxic activities against four human cancer cell lines were also evaluated. All phenolic compounds, 1 – 7 , exhibited potent antioxidant abilities (DPPH: IC₅₀ 5.6 – 12.9 μm ; ABTS: 0.87 – 8.43 μm Trolox/μm ; FRAP: 1.01 – 5.79 μm Fe²⁺/μm , respectively). Besides, 5 – 7 , also exhibited moderate inhibitory activities against melanogenesis (80.7 – 86.8% melanin content), even with no or low toxicity to the cells (93.5 – 101.6% cell viability) at a high concentration of 100 μm . Compounds 1 – 3 exhibited cytotoxic activity against one or more cell lines (IC₅₀ 13.9 – 68.4%), and compound 1 with high tumor selectivity for A549 (SI 3.2).     

Multi-target inhibitors against Alzheimer disease derived from 3-hydrazinyl 1,2,4-triazine scaffold containing pendant phenoxy methyl-1,2,3-triazole: Design,synthesis and biological evaluation

Alzheimer's disease (AD) is a complex neurological disorder with diverse underlying pathological processes. Several lines of evidence suggest that BACE1 is a key enzyme in the pathogenesis of AD and its inhibition is of particular importance in AD treatment. Ten new 3-hydrazinyl-1,2,4-triazines bearing pendant aryl phenoxy methyl-1,2,3-triazole were synthesized as multifunctional ligands against AD. We show that compounds containing Cl and NO₂ groups at the para position of the phenyl ring, namely compounds 7c (IC₅₀ = 8.55 ± 3.37 µM) and 7d (IC₅₀ = 11.42 ± 2.01 µM), possess promising BACE1 inhibitory potential. Furthermore, we assessed the neuroprotective activities of 7c and 7d derivatives in PC12 neuronal cell line, which showed moderate protection against amyloid β peptide toxicity. In addition, compound 7d demonstrated metal chelating activity and moderate antioxidant potential (IC₅₀ = 44.42 ± 7.33 µM). Molecular docking studies of these molecules revealed high-affinity binding to several amino acids of BACE1, which are essential for efficient inhibition. These results demonstrate that 1,2,4-triazine derivatives bearing an aryl phenoxy methyl-1,2,3-triazole have promising properties as therapeutic agents for AD.     

Cuceolatins A–D: New Bioactive Diterpenoids from the Leaves of Cunninghamia lanceolata

Four new diterpenoids named cuceolatins A–D, including three labdane‐type ( 1 – 3 ) and one abietane‐type ( 4 ) as well as three known labdane analogs ( 5 – 7 ), were reported from the leaves of Cunninghamia lanceolata. Structural assignments for these compounds were conducted by analyses of spectroscopic data, and their absolute configurations were determined by time‐dependent density functional theory (TD‐DFT) based electronic circular dichroism (ECD) calculations. Among them, the abietane‐type diterpenoid (11‐hydroxy‐12‐methoxyabieta‐8,11,13‐trien‐3‐one ( 4 )) showed significant cytotoxicity against human MDA‐MB‐231, MCF‐7, and HeLa tumor cell lines with IC₅₀ measurements of 4.3, 2.8 and 4.5 μm , respectively, while the labdane‐type diterpenoids with a 4α‐carboxy group ( 1 – 3 and 5 ) exhibited moderate antibacterial activity towards Bacillus subtilis and Staphylococcus aureus with IC₅₀ values all below 25 μm .     

Quinazolin‐4(3H)‐one‐Based Hydroxamic Acids: Design,Synthesis and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity

The present article describes the synthesis and biological activity of various series of novel hydroxamic acids incorporating quinazolin‐4(3H)‐ones as novel small molecules targeting histone deacetylases. Biological evaluation showed that these hydroxamic acids were potently cytotoxic against three human cancer cell lines (SW620, colon; PC‐3, prostate; NCI?H23, lung). Most compounds displayed superior cytotoxicity than SAHA (suberoylanilide hydroxamic acid, Vorinostat) in term of cytotoxicity. Especially, N‐hydroxy‐7‐(7‐methyl‐4‐oxoquinazolin‐3(4H)‐yl)heptanamide ( 5b ) and N‐hydroxy‐7‐(6‐methyl‐4‐oxoquinazolin‐3(4H)‐yl)heptanamide ( 5c ) (IC₅₀ values, 0.10–0.16 μm ) were found to be approximately 30‐fold more cytotoxic than SAHA (IC₅₀ values of 3.29–3.67 μm ). N‐Hydroxy‐7‐(4‐oxoquinazolin‐3(4H)‐yl)heptanamide ( 5a ; IC₅₀ values of 0.21–0.38 μm ) was approximately 10‐ to 15‐fold more potent than SAHA in cytotoxicity assay. These compounds also showed comparable HDAC inhibition potency with IC₅₀ values in sub‐micromolar ranges. Molecular docking experiments indicated that most compounds, as represented by 5b and 5c , strictly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA.