Reactions with acetoacetanilide: Synthesis and antibacterial activity of some new pyran,pyrano[2,3-c]pyrazole and pyrano[2,3-c]-pyridine derivatives

The reaction of acetoacetanilide (1) with the α-cyanocinnamonitrile derivatives2 yielded the Michael adducts4 which could be converted into the pyrano[2,3-c] pyrazole derivatives5 via their reaction with hydrazine hydrate. Cyclisation of4 afforded the cyanoaminopyrans9 which could in turn be converted into the corresponding pyridine derivatives10. The pyranopyrazoles9 reacted with different activated nitrile derivatives (3a-c) to give the pyrano[2,3-c]pyridine derivatives13, 16 and19 respectively. The biological activity of the synthesised heterocyclic derivatives was investigated and discussed.     

Synthesis of C-(2-furyl)-N-(4-nitrophenyl)methanohydrazonyl bromide. Reactions with nucleophiles and active methylene compounds

Synthesis of C-(2-furyl)-N-(4-nitrophenyl)methanohydrazonyl bromide2 is described. Treatment of2 with nucleophiles affords the corresponding substitution products3–7. Also, compound2 reacts with selenocyanate anion and thiocyanate anion and give the corresponding selenadiazoline and thiadiazoline8 and9, respectively. Moreover, reaction of2 with enolates of various active methylene compounds afforded the pyrazole derivatives17–20.     

Anticomplementary activity of stilbenes from medicinal plants

The anticomplementary activity of stilbenes from medicinal plants in Korea was investigatedin vitro. 3,5-Dihydroxy-4′-methoxystilbene (3) was most potent with IC₅₀ value of 1.5×10⁻⁴ M followed by rhapontigenin (4), oxyresverastrol (2), 2,3,4′,5-tetrahydroxystilbene-2-O-β-glucoside (9), rhaponticin (8), resverastrol (1), and piceid (7). The activity was found to be increased by a methylation on a hydroxy group of C-4′ of1, but decreased by further methylation on hydroxy groups of C-3 and C-5 and glucosylation on any hydroxy group of1. Addition of hydroxy group on C-2′ of1 or C-3′ of3 was little affected on the anticomplementary activity but the activity was increased byO-glucosylation on C-2 of1.     

Sesquiterpene components from the flower buds ofMagnolia fargesii

From the Chinese crude drugshin-i, the flower buds ofMagnolia fargesii, four sesquiterpene, oplopanone (1), oplodiol (2), homalomenol A (3) and 1β,4β,7α-trihydroxyeudesmane (4) were isolated. These structures were elucidated and the¹³C-NMR chemical, shifts of these compounds were revised by means of various 2D-NMR techniques.     

Synthesis and antifungal evaluation of 6-(N-arylamino)-7-methylthio-5,8-quinolinediones

A series of 6-(N-arylamino)-7-methylthio-5,8-quinolinedione derivatives4a-4l was newly synthesized for the evaluation of antifungal activity. 6-(N-Arylamino)-7-methylthio-5,8-quinolinediones were prepared by regioselective nucleophilic substitution of 6,7-dichloro-5,8-quinolinediones with arylamines in the presence of Ce³⁺, and Na₂S/dimethylsulfate. The MIC values of4a-4l were determined for antifungal susceptibilityin vitro againstCandida species by agar streak method. The derivatives4a-4l had generally potent antifungal activities against all human pathogenic fungi. Especially they had the most potent activity againstC. krusei at 12.5≈0.8 μg/ml. Compounds4d, 4g, 4h, 4j and4k had more potent antifungal activities than fluconazole. Compounds4g and4h completely inhibited the fungal growth at 0.8≈6.3 μg/ml against allCandida species, while fluconazole inhibited the growth at 25 μg/ml. The compounds such as4g and4h containing an N-(4-bromo-2-methylphenyl)- or N-(4-bromo-3-methylphenyl)amino substituent exhibited the most potent antifungal activities.     

Synthesis of some new 4-substituted antipyrines as potential antipyretic analgesics

4-Acetylantipyrine1 underwent condensation with 4-formyl-antipyrine2 to give3. Condensation of either3 with1 or1 with2 in a molar ratio of (2∶1) afforded4. Cyclization of4 in the presence of PPA and ammonium acetate or 4-aminoantipyrine in the presence of glacial acetic acid gave5–7, respectively. Claisen condensation of1 with ethyl acetate and diethyl oxalate afforded compounds8–10. The reaction of1 and2 with indole in ethanol/conc. hydrochloric acid was also investigated.     

Synthesis,characterization, and antimicrobial activity of some new coumarin derivatives

A number of new [(4-methyl-2-oxo-2H-chromen-7-yl)amino]methylcoumarins (5a–c), benzofuran (6), and benzoxazol (7) were synthesized through the reaction of 7-amino-4-methylcoumarin (1) with a number of organic halides. In addition, series of N-substituted 2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide (11a–h) and (12a–d) were prepared from the reaction of 2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide (8) with corresponding heteroaryl/alkyl halides (2–4, 9, and 10). The synthesized compounds were characterized by elemental analysis and by spectroscopic techniques such as ¹H-NMR, ¹³C-NMR, and mass spectrometry and were tested for their in vitro antimicrobial activity. The newly synthesized compounds exerted significant inhibitory activity against the growth of tested bacterial strains and a few of them are found to be potent antimicrobial agents.     

Cardiotoxicity of adrenochrome in isolated rabbit hearts assessed by epicardial NADH fluorescence

Noradrenaline in a micromolar concentration has recently been shown to contribute to ischemic tissue injury by direct cardiotoxic effects independent of functional alterations. Oxygen free radicals, generated during the auto-oxidation of catecholamines, are important mediators of catecholamine cardiotoxicity. However, the role of the oxidative products (aminochromes) is still unclear. We examined the effects of adrenochrome on functional parameters and on regional myocardial ischemia (MI) in isolated electrically-driven rabbit hearts with depleted catecholamine stores (reserpine 7.0 mg/kg i.p. 16 – 24 h before preparation, Langendorff, constant pressure: 70 cm H₂O, Tyrode solution, Ca⁺⁺ 1.8 mmol/l, 37°C). Repetitive MI, separated by a reperfusion period of 50 min, was induced by coronary artery branch ligature, and MI was quantitated from epicardial NADH fluorescence photography. Adrenochrome-treatment (10^– 6 M or 10^– 4 M) was started after a reperfusion period of 20 min. The left ventricular pressure (LVP) was significantly enhanced by adrenochrome (p <0.05), but it fell thereafter to below its initial value in hearts treated with adrenochrome 10^– 4 M. The global coronary flow (CF) was not affected by adrenochrome 10^– 6 M (P >0.05), but it was significantly decreased by adrenochrome 10^– 4 M (P <0.05). The relative CF (= CF/LVP × heart-rate) was numerically decreased by adrenochrome 10^– 6 M (p >0.05) and more markedly by adrenochrome 10^– 4 M (p <0.05). Whereas epicardial NADH fluorescence was similar after repetitive coronary artery occlusions in controls and in hearts treated with adrenochrome 10^– 6 M (p >0.05), it was significantly enhanced by adrenochrome 10^– 4 M (p <0.05). In isolated rabbit hearts, adrenochrome possesses deleterious effects on MI only at a very high concentration but not in a micromolar concentration. Therefore, it seems that aminochromes may be less cardiotoxic than catecholamines. Received: 28 February 1994 / Accepted: 2 May 1994     

Synthesis of higenamine,A cardiotonic principle of aconite root

Higenamine (I), a cardiotonic principle of Aconite root, was synthesized from 4-methoxy-phenylacetic acid (II) and β-(3, 4-dimethoxyphenyl)-ethylamine (IV). Condensation ofIV with 4-methoxyphenylacetyl chloride (III) was followed by cyclodehydration yielding 1-(4′-methoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline (VI). Reduction ofVI to 1, 2, 3, 4-tetrahydroisoquinoline (VII) and subsequent demethylation provided desired product higenamine, 1-(4′-hydroxybenzyl)-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline.     

Synthesis, spectral, and antimicrobial evaluation of some new 8-membered phosphorus heterocyclic compounds

Abstract  

Synthesis of 9-substituted-8, 9 10, 11-tetrahydro-7H-7, 11-diaza-9λ⁵-phosphacycloocta [d,e] naphthalene-9-sulfides/selenides (4–13) was accomplished in three steps. 1,8-diamino naphthalene (2) was reacted with tris (bromomethyl) phosphine (1) in the presence of triethylamine in dry tetrahydrofuran (THF) under N₂ atmosphere to form the corresponding intermediate (3). It was converted to the corresponding sulfide (4) and selenide (5) by the reaction with sulfur and selenium, respectively. The intermediates 4 and 5 were reacted with two achiral alcohols and two achiral amines to obtain the title compounds (6–13). The structures of the title compounds were established by elemental analysis and spectral data (IR, ¹H, ¹³C, ³¹P NMR, and FAB mass). The antimicrobial activity of these compounds was evaluated and they exhibited significant activity.     

Lactational exposure to methylmercury in the hamster

 Syrian Golden hamster dams were administered ²⁰³Hg-labelled methyl mercury (MeHg; 1.6 μmol/kg) 1 day after parturition and milk was collected twice during the 1st week. The excretion of ²⁰³Hg in milk and the uptake, retention and tissue distribution of ²⁰³Hg in the pups was studied using gamma counting. The fraction of inorganic Hg in milk and in the kidneys of the pups was determined following separation of inorganic Hg and MeHg by ion exchange chromatography. The concentration of ²⁰³Hg in milk on the 1st day after MeHg administration was 0.12 nmol/g. ²⁰³Hg was mainly (80–90%) excreted as MeHg during the first 6 days of lactation. The whole body and tissue concentration of ²⁰³Hg in the pups increased for 10–15 days and decreased thereafter. The content of ²⁰³Hg in the pelt and the fraction of inorganic Hg in the kidney increased throughout the study period (4 weeks). The excretion of MeHg in milk corresponded to at least 5% of the dose administered to the dam. Our study demonstrates that breast milk may be a significant source of MeHg exposure during the critical neonatal period. Received: 28 June 1994 / Accepted: 24 October 1994     

A new ferulic acid ester and other constituents from Dracocephalum peregrinum

A new ferulic acid ester, 1′-methyl-2′-hydroxyethyl ferulate (1), together with methylcaffeate (2), 4-hydroxy cinnamic acid (3), ferulic acid (4), caffeic acid (5), diosmetin (6), luteolin (7), 5,3′,4′-trihydroxy-3,7-dimethoxyflavone (8), eriodictyol (9), kaempferol (10), quercetin (11), acacetin-7-O-glcopyranoside (12), 4-(β-glucopyranosyloxy) benzoic acid (13), luteolin-7-O-(6″-feruloyl) glucopyranoside (14), luteolin-7-O-glucopyranoside (15), kaempferide-3-O-rhamnopyranoside (16), quercitrin (17), kaempferol-3-O-glucopyranoside (18), prunasin (19), quercetin-7-O-glucopyranoside (20), quercetin-3-O-glucopyranoside (21), plantaginin (22), linarin (23), luteolin-7-O-rutinoside (24), and chlorogenic acid (25) were isolated from the aerial parts of Dacocephalum peregrinum. The structure of 1 was elucidated on the basis of spectroscopic and HR-ESI-MS analyses. In addition, compound 1 exhibited mild inhibitory effect on NO production in LPS-stimulated RAW264.7 cells.     

Investigation of the reaction of 6-amino-3-methyl-4-oxo-3,4-dihydro-2-pyrimidinylhydrazine

The hydrazine derivative2 has been utilized for the synthesis of three different fused 1,2,4-triazolo [4,3-a] pyrimidine derivatives4, 5 &6 and a tetrazolo[1,5-a] pyrimidine derivative7. Reaction of2 with the chalcone analogue 2-thenylidene-2′-acetothienone, gave the pyrazoline derivative8.     

A new furofuran lignan from <Emphasis Type="Italic">Isodon japonicus</Emphasis>

A new sesamin type furofuran lignan, (−)-sesamin-2,2′-diol (1), along with two known flavonoids (2 and 3) and three phenolic compounds (4–6) were isolated from the aerial parts of Isodon japonicus. The structures of these compounds were determined by analysis of spectroscopic data (1D-, 2D-NMR, HRMS and CD) and by comparison of the data with those of related metabolites.     

Synthesis of new hydantoin-3-ethanethiol derivatives

5-sec-Butylthiomethyl-5-alkyl (methyl or phenyl) hydantoins (3−x) were prepared by the reaction of sec-butylthiomethyl alkyl (methyl or phenyl) ketone (1–2), potassium cyanide and ammonium carbonate. 3-(2-Bromoethyl) hydantoins (5–6) were the reaction products of 5-sec-butylthiomethyl-5-alkyl (methyl or phenyl) hydantoin and 1,2-dibromoethane in the presence of potassium hydroxide. Alkylation of5 and6 with an excess of alkyl (methyl or ethyl) iodide in THF with sodium hydride as base gave three 1-alkyl (methyl or ethyl)-3-(2-bromoethyl) hydantoins (7–9). Treatment of the 2-bromoethyl group with potassium thioacetate and triethylamine gave three 1-alkyl (methyl or ethyl)-3-(2-acetylthioethyl) hydantoins (10–12). Hydrolysis of the 2-acetylthioethyl group with sodium hydroxide in methanol afforded the three 1-alkyl (methyl or ethyl)-3-(2-mercaptoethyl) hydantoins.     

Synthesis, radiolabeling and stability of new nitrophenol complexes of Technetium-99m as possible hypoxia imaging radiopharmaceuticals

The synthesis of seven ^99mTc-labeled nitrophenol radiosensitizers (N₂OS chelates) was undertaken for evaluating their in vitro biostabilty as possible hypoxia tumor imaging agents. The title compounds (2–7) were successively synthesized, characterized, and finally radiolabeled (^99mTc-NaTcO₄, stannous chloride, pH 10) to obtain the new complexes (8a–8f) for evaluation. The purity and stability of complexes (in human and rat serum) were evaluated by chromatographic methods (radio-TLC, ITLC, HPLC). The most stable complex (over 6 h) was ^99mTc-labeled 3-[3′-N-(2″-hydroxy-5″-nitrobenzylamino)-2′-propanol]-1-(4′-methyl)thiourea (8e). Biodistribution studies of 8e in mammary tumor-bearing rats are in progress. Published in Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 9, pp. 50–53, September, 2006.     

Synthesis of several new isoxazole,imidazo[1,2-a]pyridine,imidazo[1,2-a]pyrimidine,benzoxadiazine and benzothiazine derivatives from hydroximoyl halides

Furoylhydroximoyl chloride3 reacted with 2-aminopyridine, 2-aminopyrimidine,O-aminophenol,O-phenylenediamine and aminothiophenol to afford imidazo[1,2-a]pyridine6, imidazo[1,2-a]pyrimidine8, benzoxadiazine10, nitrosobenzopyrazine13a and nitrosobenzothiazine13b, respectively. Isoxazoline18 and pyrrolidino[3,4-d]isoxazolin-4,6-dione derivatives19a and19b obtained by the reaction of3 with acrylonitrile and N-arylmaleimide. Hydroximoyl chloride3 reacted with thiophenol and sodium benzenesulfinate to yield furylglyoxaloxime16a and16b, respectively. Hydroximoyl chloride3 reacted also with some active methylene compound to give isoxazole derivatives20–23, respectively.     

New isoflavones from Belamcandae Rhizoma

Four new isoflavones (iristectrigenin A-7-glucoside (2), 8-hydroxytectrigenin (5), 8-hydroxyiristectrigenin A (6), and 8-hydroxyirigenin (7–1) have been isolated from Belamcandae Rhizoma (the rhizome of Belamcanda chinensis), along with nine known compounds: tectridin (1), tectrigenin-4′-glucoside (3), astragalin (4), irilin D (7–2), isotectrigenin (8), tectrigenin (9), iristectrigenin B (10), hispiludin (11–1), and irigenin (11–2). The structures of 2, 5, 6 and 7–1 were determined by spectroscopic methods, including high-resolution mass spectrometry (HR-MS), proton nuclear magnetic resonance (¹H-NMR), carbon-13 NMR (¹³C-NMR), and various two-dimensional (2D)-NMR techniques.     

Effects of Δ<Superscript>9</Superscript>-THC and WIN-55,212-2 on place preference in the water maze in rats

Abstract Rationale. Cannabinoids such as Δ⁹-tetrahydrocannabinol (Δ⁹-THC) or WIN-55,212–2 (WIN-2) have psychoactive effects on cognition. As a result, the reinforcing properties of Δ⁹-THC or WIN-2 may confound learning and memory tests with false negative results. It therefore seems advisable to assess the reinforcing properties of the drugs in the same behavioural model used for learning experiments. Objective. We therefore developed conditioned place preference protocols in the open-field water maze and tested both Δ⁹-THC (2 mg/kg) and WIN-2 (1 mg/kg and 3 mg/kg). Given that previous reports on cannabinoids have revealed conflicting data and that this was a novel behavioural test, we also tested the benzodiazepine receptor agonist diazepam (2.5 mg/kg). Some methodical refinements were appropriate in order to determine the behavioural strategy implemented by the animals. Methods. All animals were injected intraperitoneally 30 min prior to training/testing. In experiment 1, male hooded Lister rats injected with drug were repeatedly placed on the drug-related platform and subsequently tested for place preference. In experiment 2, rats were trained to swim to the drug platform on drug days and to the vehicle platform on vehicle days. A series of probe trials was introduced to delineate what had been learned. Experiment 3 studied the effect of WIN-2 on spatial learning in the water maze. Results. Neither WIN-2 nor Δ⁹-THC induced place preference in the water maze. When trained in the swim procedure, however, WIN-2 was neutral, but Δ⁹-THC resulted in place aversion. Conversely, diazepam consistently produced place preference in both procedures. WIN-2 (3 mg/kg), however, produced a small learning deficit in the spatial water maze task. Conclusion. It appears that the reinforcing properties of Δ⁹-THC and WIN-2 in the doses used here are different, despite them both being agonists at cannabinoid receptors within the central nervous system. The fact that Δ⁹-THC may be aversively related to a particular context has implications for previous work reporting deficits in spatial learning. Electronic Publication     

Synthesis and reactions of some pyridazine derivatives

3,4-Diphenyl-5-cyanopyridazin-6-one 3 was prepared from the reaction of cyano-acetamide2 with benzilhydrazone in dry pyridine. A series of its derivatives was prepared. Tolyl and benzene sulphonyl derivatives6a and6b are also prepared. 3,4-Diphenyl-5-cyano-pyridazin-6-thione5 was obtained from3 by the action of P₂S₅ while 3,4-diphenyl-5-cyano-6-chloropyridazine4 was obtained from3 by the action of POCl₃. The reaction of4 with hydrazine hydrate directly afforded the pyrazolopyridazine derivative7. Compound4 also reacted with phenylhydrazine, aniline, thiophenol and anthranilic acid to yield pyridazine derivatives8, 9, 10 and11, respectively. On treatment of compound11 with acetic anhydride it cyclised to afford pyridazino pyrimidine derivatives12.