3-Hydroxyisoflavanones from the stem bark of Dalbergia melanoxylon: Isolation,antimycobacterial evaluation and molecular docking studies

Two new 3-hydroxyisoflavanones, (S)-3,4′,5-trihydroxy-2′,7-dimethoxy-3′-prenylisoflavanone (trivial name kenusanone F 7-methyl ether) and (S)-3,5-dihydroxy-2′,7-dimethoxy-2″,2″-dimethylpyrano[5″,6″:3′,4′]isoflavanone (trivial name sophoronol-7-methyl ether) along with two known compounds (dalbergin and formononetin) were isolated from the stem bark of Dalbergia melanoxylon. The structures were elucidated using spectroscopic techniques. Kenusanone F 7-methyl ether showed activity against Mycobacterium tuberculosis, whereas both of the new compounds were inactive against the malaria parasite Plasmodium falciparum at 10 μg/ml. Docking studies showed that the new compounds kenusanone F 7-methyl ether and sophoronol-7-methyl ether have high affinity for the M. tuberculosis drug target INHA.     

Transport of folate compounds into Lactobacillus Casei

Transport of folate, 5-methyl tetrahydrofolate, and amethopterin into Lactobacillus casei occurs against a concentration gradient, is pH and temperature dependent, requires glucose, exhibits saturation kinetics, is maximal when cells are harvested in late-log phase, and is repressed by excess folate in the growth medium. K_m values are 0.35, 0.90, and 0.21 μm for the influx of folate, 5-methyl tetrahydrofolate, and amethopterin, respectively. Dihydrofolate, tetrahydrofolate, 5-formyl tetrahydrofolate, 5-methyl tetrahydrofolate, aminopterin, and amethopterin are inhibitors of folate influx. Countertransport of 5-methyl tetrahydrofolate is enhanced by various other folate compounds. Uptake of folate, 5-methyl tetrahydrofolate, and amethopterin is inhibited to the same degree by increasing concentrations of iodoacetate. These results indicate that a single system is responsible for transport of a variety of folate compounds into L. casei.     

Structural manipulation of aporphines via C10 nitrogenation leads to the identification of new 5-HT7AR ligands

Aporphine alkaloids containing a C10 nitrogen motif were synthesized and evaluated for affinity at 5-HT_1AR, 5-HT_2AR, 5-HT₆R and 5-HT_7AR. Three series of racemic aporphines were investigated: 1,2,10-trisubstituted, C10 N-monosubstituted and compounds containing a C10 benzofused aminothiazole moiety. The 1,2,10-trisubstituted series of compounds as a group displayed modest selectivity for 5-HT_7AR and also had moderate 5-HT_7AR affinity. Compounds from the C10 N-monosubstituted series generally lacked affinity for 5-HT_2AR and 5-HT₆R and showed strong affinity for 5-HT_1A or 5-HT_7AR. Compounds in this series that contained an N6-methyl group were up to 27-fold selective for 5-HT_7AR over 5-HT_1AR, whereas compounds with an N6-propyl substituent showed a reversal in this selectivity. The C10 benzofused aminothiazole analogues showed a similar binding profile as the C10 N-monosubstituted series i.e. strong affinity for 5-HT_1AR or 5-HT_7AR, with selectivity between the two receptors being similarly influenced by N6-methyl or N6-propyl substituents. Compounds 29 and 34a exhibit high 5-HT_7AR affinity, excellent selectivity versus dopamine receptors and function as antagonists in 5-HT_7AR cAMP-based assays. Compounds 29 and 34a have been identified as new lead molecules for further tool and pharmaceutical optimization.     

Onognaphalin,a further 5-methyl coumarin from Onoseris gnaphalioides

From the roots of Onoseris gnaphalioides in addition to a known 5-methyl coumarin a new type was isolated. The aerial parts contain a glucoside of 4-hydroxy-5-methyl coumarin. From Gerbera ambigua a compound related to the possible precursor of the 5-methyl coumarins was isolated.     

Flavone 5-O-glucosides from Daphne sericea

The aerial parts of Daphne sericea yielded two new flavonoids, luteolin 7-methyl ether 5-β-d-glucoside and luteolin 7,3′-dimethyl ether 5-β-d-glucoside, as well as luteolin 7-methyl ether, isovitexin, apigenin and its 7-β-d-glucoside.     

The formation and isolation of benzisothiazole rings from the reactions of oxime-thiophenolate ligands

The reaction of [Ni(eftp)] [eftp = N,N-ethylene(6-formyl-4-methyliminatothiophenolato)] with hydroxylamine hydrochloride in the presence of potassium acetate in MeOH resulted in the formation of [Ni(L)₂], L = 2-mercapto-5-methyl-3-({2-[(5-methyl-benzo[d]isothiazol-7-ylmethylene)-amino]-ethylimino}-methyl)-benzonitrile. A single-crystal X-ray diffraction structural determination showed that the oxime groups of the proposed new binucleating ligand had reacted to produce a nitrile and an isothiazole ring, while two ligand molecules combined with one Ni(II) ion to form a new complex with a cis-S₂N₂ square-planar geometry. Also, the reaction of 2,6-diformyl-4-methylphenyl disulfide with hydroxylamine in MeCN resulted in the synthesis of 5-methyl-2-oxy-benzo[d]isothiazole-7-carbaldehyde oxime, where an isothiazole ring had formed via the cleavage of the disulfide bond. Again, a single-crystal X-ray diffraction study confirmed the presence of a benzisothiazole product.     

Synthesis of halogenated 4-quinolones and evaluation of their antiplasmodial activity

Treatment of 4-hydroxyquinolines with (2-methyl)allyl bromide in the presence of K₂CO₃ resulted in the formation of novel N-[(2-methyl)allyl]-4-quinolones through selective N-alkylation. Further reaction of N-(2-methylallyl)-4-quinolones with bromine or N-bromosuccinimide yielded the corresponding 3-bromo-1-(2,3-dibromo-2-methylpropyl)-4-quinolones and 3-bromo-1-(2-methylallyl)-4-quinolones, respectively. Furthermore, a copper-catalyzed C–N coupling of the latter 3-bromo-4-quinolones with (5-chloro)indole afforded novel 3-[(5-chloro)indol-1-yl]-4-quinolone hybrids. Antifungal and antiplasmodial assays of all new 4-quinolones were performed and revealed no antifungal properties but moderate antiplasmodial activities. All 15 compounds displayed micromolar activities against a chloroquine-sensitive strain of Plasmodium falciparum, and the five most potent compounds also showed micromolar activities against a chloroquine-resistant strain of P. falciparum with IC₅₀-values ranging between 4 and 70 μM.     

Neue sesquiterpene und acetylenverbindungen aus Cineraria-arten

The investigation of several members of the South African genus Cineraria affords, in addition to known compounds, several new eremophilene derivatives together with modified types all derived from a carbon skeleton where the 5-methyl has migrated to C-6. Some of these compounds are transformed to unusual enol lactones. Furthermore some derivatives of himachalene are present. All species also contain C₁₁-acetylenes, most of which are new. Senecio deltoideus also contains some of these compounds. The chemotaxonomic situation is discussed.     

Effect of fenarimol on sterol biosynthesis in suspension cultures of bramble cells

Bramble suspension cultures normally contain Δ⁵-sterols (sitosterol, campesterol and isofucosterol). When the cells were grown in a medium supplemented with fenarimol, 14α-methyl sterols accumulated. Eight 14α-methyl sterols, including two new compounds, 4α,14α-dimethyl-stigmasta-8,Z-24(28)-dien-3β-ol and 14α-methyl-stigmasta-8,Z-24(28)-dien-3β-ol, were identified. Fenarimol probably inhibited the 14α-methyl demethylation. Cell lines growing permanently in 2 fenarimol-supplemented medium were obtained.     

Structure guided inhibitor designing of CDK2 and discovery of potential leads against cancer

On the basis of stereo specific information obtained from crystal structures of CDK2, indole and chromene analogues were designed by suitably substituting the pharmacophores on their moiety and docked with target protein for calculating binding affinities. The binding affinities are represented in glide score. (5E)-5-[(1-methyl-1H-indol-3-yl)methylidene]-2,4,6-trioxotetrahydro-2H-pyrimidin-1-ide (I₁), (5E)-5-(1H-indol-3-ylmethylidene)-2,4,6-trioxotetrahydro-2H-pyrimidin-1-ide (I₂) and 2-amino-4-(4-methyl phenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (C₉) were selected for synthesis and biological testing based on vital interactions. (5E)-5-(1H-indol-3-ylmethylidene)-2,4,6-trioxotetrahydro-2H-pyrimidin-1-ide(I₂) and 2-amino-4-(4-methyl phenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (C₉) were proved to be active against MCF-7 and HeLa cell lines.     

Synthesis,characterization, toxicity,cytogenetic and in vivo antitumor studies of 1,1-dithiolate Cu(II) complexes with di-, tri-, tetra- amines and 1,3-thiazoles. Structure–activity correlation

A series of new mixed-ligand neutral copper(II) complexes of the general type [Cu(amine)(i-MNT)] and [Cu(tz)(i-MNT)] was prepared and characterized by elemental, spectroscopic methods, μ_eff, Λ_μ measurements and molecular modeling studies. The acute toxicity, the cytogenetic and the in vivo antitumor activity of the new complexes, is related to their chemical and physicochemical properties. Among the Cu(II) compounds tested the complex with 2-amino-5-methyl thiazole increases significantly the life span of leukemia P388 bearing mice in vivo.     

6-methoxyflavonoids from Brickellia laciniata (compositae)

One new and fourteen known flavonoids, including thirteen containing 6-methoxy groups, were isolated from Brickellia laciniata. The new flavonol is quercetagetin 6,4′-dimethyl ether. Among the known compounds identified were the 4′-methyl and 7,4′-dimethyl ethers of eupafolin and luteolin 4′-methyl ether, and the flavonols: patuletin, spinacetin, eupatolitin, eupatin, centaureidin, casticin, patuletin 3-glucoside and 3-galactoside, eupatolitin 3-galactoside, patuletin 3-SO₃K and eupatin 3-SO₃Ca_1/2.     

Cd(II) and Cu(II) complexes of polydentate Schiff base ligands: synthesis, characterization, properties and biological activity

We report the synthesis of the Schiff base ligands, 4-[(4-bromo-phenylimino)-methyl]-benzene-1,2,3-triol (A₁), 4-[(3,5-di-tert-butyl-4-hydroxy-phenylimino)-methyl]-benzene-1,2,3-triol (A₂), 3-(p-tolylimino-methyl)-benzene-1,2-diol (A₃), 3-[(4-bromo-phenylimino)-methyl]-benzene-1,2-diol (A₄), and 4-[(3,5-di-tert-butyl-4-hydroxy-phenylimino)-methyl]-benzene-1,3-diol (A₅), and their Cd(II) and Cu(II) metal complexes, stability constants and potentiometric studies. The structure of the ligands and their complexes was investigated using elemental analysis, FT-IR, UV-Vis, ¹H and ¹³C NMR, mass spectra, magnetic susceptibility and conductance measurements. In the complexes, all the ligands behave as bidentate ligands, the oxygen in the ortho position and azomethine nitrogen atoms of the ligands coordinate to the metal ions. The keto-enol tautomeric forms of the Schiff base ligands A₁-A₅ have been investigated in polar and non-polar organic solvents. Antimicrobial activity of the ligands and metal complexes were tested using the disc diffusion method and the strains Bacillus megaterium and Candida tropicalis.Protonation constants of the triol and diol Schiff bases and stability constants of their Cu²⁺ and Cd²⁺ complexes were determined by potentiometric titration method in 50% DMSO-water media at 25.00 ± 0.02 °C under nitrogen atmosphere and ionic strength of 0.1 M sodium perchlorate. It has been observed that all the Schiff base ligands titrated here have two protonation constants. The variation of protonation constant of these compounds was interpreted on the basis of structural effects associated with the substituents. The divalent metal ions of Cu²⁺ and Cd²⁺ form stable 1:2 complexes with Schiff bases.The Schiff base complexes of cadmium inhibit the intense chemiluminescence reaction in dimethylsulfoxide (DMSO) solution between luminol and dioxygen in the presence of a strong base. This effect is significantly correlated with the stability constants K_CdL of the complexes and the protonation constants K_OH of the ligands; it also has a nonsignificant association with antibacterial activity.     

Specificity for the glucose-6-P inhibition site of hexokinase

Inhibition of the three animal hexokinase isozymes by the following glucose-6-P analogs has been determined: α-glucose-1,6-P₂, α- and β-methyl glucose-6-P, α- and β-glucose-6-P, 2-Cl- and 4F-glucose-6-P, 5-deoxyglucose-6-P, glucose-6-sulfate, and δ-gluconolactone-6-P. Although both anomers of glucose-6-P were about equally active inhibitors, the β-methyl derivative was inactive. Generally the α-methyl and α-PO₃^? derivatives were good inhibitors though weaker than glucose-6-P except in the case of hexokinase II for which α-glucose-1,6-P₂ was an excellent inhibitor.     

Flavonoids of Plagiochila asplenioides

Besides an apigenin- and a luteolin-di-C-glycoside, 5 previously unknown di-C-glycosides of tricetin were identified in the gametophytic and sporophytic tissues of Plagiochila asplenioides. Two of them were new 6,8-di-C-hexopyranosyltricetins, and two were new 6-C- hexopyranosyl-8-C-pentopyranosyltricetins. 6-C-Hexopyranosyl-8-C-pentopyranosyltricetin-5′-methyl ether was also found.     

Ammonia-lyase and O-methyl transferase activities related to lignification in wheat leaves infected with botrytis

The deposition of lignin around wounds in wheat leaves infected with the non-pathogenic fungus Botrytis cinerea, was preceded by increases in ammonia-lyase and O-methyl transferase activities. The increases were localised in the lignifying tissues. Phenylalanine ammonia-lyase and tyrosine ammonia-lyase increased concurrently and were inseparable by gel filtration or DEAE cellulose chromatography, the two activities probably being the function of a single protein. Infection-specific isoenzymes for either of the ammonia-lyase activities were absent. Increases in caffeic acid O-methyl transferase and 5-hydroxyferulic acid O-methyl transferase activities closely followed those of the ammonia- lyases. It is unlikely that the increased proportion of syringyl groups found in infection-induced lignin is controlled by O-methyl transferase activity. A modified method for the estimation of O-methyl transferase activity in crude wheat extracts is described.     

Effects of pH on benzimidazole fluorescence

Four benzimidazoles (unsubstituted, 5-methyl, 2-ethyl, and 2-ethyl-5-methyl) have been characterized by fluorescence spectroscopy. At low pH (<6), activation at 270 nm caused fluorescence at 305 nm; at high pH (<8), activation at 270 nm caused fluorescence at 365 nm. The relative proportion of peak fluorescence at either 305 or 365 nm was correlated with the pK_a values of the four benzimidazoles. It was concluded that the protonated specie of benzimidazole was fluorescent at 365 nm and the unprotonated specie was also fluorescent at 305 nm.     

Alcaloïdes d'Alstonia quaternata

Eleven alkaloids have been isolated from Alstonia quaternata. Three of them, namely 11-methoxy-epi-3α-yohimbine, 10,11-dimethoxy-picrinine designated quaternine, and 19,20-epoxy-N_(a)-methyl, desacetyl, desformo, 2βH-dihydroakuammiline designated quaternoxine, are new alkaloids.     

Anti-AIDS agents 84. Synthesis and anti-human immunodeficiency virus (HIV) activity of 2′-monomethyl-4-methyl- and 1′-thia-4-methyl-(3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs

In a continuing investigation into the pharmacophores and structure–activity relationship (SAR) of (3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) as a potent anti-HIV agent, 2′-monomethyl substituted 1′-oxa, 1′-thia, 1′-sulfoxide, and 1′-sulfone analogs were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. Among them, 2′S-monomethyl-4-methyl DCK (5a)³ and 2′S-monomethyl-1′-thia-4-methyl DCK (7a) exhibited potent anti-HIV activity with EC₅₀ values of 40.2 and 39.1 nM and remarkable therapeutic indexes of 705 and 1000, respectively, which were better than those of the lead compound DCK in the same assay. In contrast, the corresponding isomeric 2′R-monomethyl-4-methyl DCK (6) and 2′R-monomethyl-1′-thia-4-methyl DCK (8) showed much weaker inhibitory activity against HIV-1 replication. Therefore, the bioassay results suggest that the spatial orientation of the 2′-methyl group in DCK analogs can have important effects on anti-HIV activity of this compound class.