Synthesis of N-substituted aminomethylene-benzofuran-2-ones

A series of substituted 3-R-aminomethylenebenzofuranones has been synthesized via the reactions of 3-[(dimethylamino)methylene-and 3-ethoxymethylene]benzofuran-2-(3H)-one with various amino derivatives. The synthesized compounds offer a promising basis in the search for biologically active substances. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 10, pp. 38–41, October, 2007.     

Synthesis and antiinflammatory activities of 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-ones

A series of 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-ones was synthesized and evaluated as candidate antiinflammatory/analgesic agents as well as dual inhibitors of prostaglandin and leukotriene synthesis. Some compounds that showed dual inhibitory activity were found to possess equipotent antiinflammatory activities to indomethacin, with reduced ulcerogenic effects. One of the compounds, N-methoxy-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-o ne, was found to have a wider safety margin than indomethacin or piroxicam, and was selected for detailed evaluation as a candidate drug for clinical application.     

Synthesis of alkyl-substituted arecoline derivatives as gamma-aminobutyric acid uptake inhibitors

A series of N-methyltetrahydropyridine-3-carboxylic acids and methyl esters have been synthesized and biologically evaluated. Arecoline (6) was lithiated with LDA in THF to give 7, which was treated with various alkyl halides to afford exclusively the alpha-substituted products 8a-g. Thermodynamic reaction of 7 with carbonyl compounds gave the corresponding 5-substituted arecoline derivatives 10a-q. When phenyldiazonium tetrafluoroborate was used as electrophile, 8h and 9 were obtained. The relative stereochemistry of 10j-o was established by 1H NMR spectroscopy. Compound 12 was obtained by condensation of the silylketene acetal 11 with N-acetylindoxyl. Dehydration of 10a-c yielded 14a-c, respectively. Deprotection of the esters 14a, 14c, and 15 followed by chromatography on an ion-exchange resin gave the amino acids 16a, 16c, and 16d. The alcohol 17 was obtained by LiAlH4 reduction of the corresponding ester 14c. The amino acid 16c displayed a marked inhibitory effect on the synaptosomal uptake of gamma-amino[3H]butyric acid ([3H]GABA). The type of inhibition was competitive with a Ki of 12.9 microM. Compound 16d also inhibited [3H]GABA uptake but was about 10 times weaker than 16c. None of the biologically tested compounds (8a-g, 9, 10a-q, 12, 14a-c, 16a-d, 17) showed any effect in binding studies using [3H]GABA as ligand.     

Synthesis of novel N-substituted imidazolecarboxylic acid hydrazides as monoamine oxidase inhibitors

Novel 2-alkylsulfanyl-1-benzyl-5-imidazolecarboxylic acid hydrazides (15a,b) were synthesized as analogues of isocarboxazide, which is a known nonselective irreversible monoamine oxidase inhibitor and tested for monoamine oxidase A and B inhibitory activity. Neither of the compounds showed any inhibition of MAO B activity up to a high concentration of 100 microM. An MAO A activity was only slowly inhibited at this high concentration after prolonged incubation with either compound. This suggests any observed inhibition is not very specific.     

Synthesis of new oxazolin-5-ones derivatives as antibacterial agents

1-Aryl-4-arylidene-2-oxazoline-5-ones (I) and the corresponding unsaturated amidoesters (II) and arylidene hypuric acid hydrazide (III) were obtained. The hydrazides and 1-aryl-1,3-dithiophenol-2-amidopropan-3-ones derivatives (IV) were also obtained. The derivatives were tested for their antibacterial, activities.     

Synthesis and biological activity of some new benzimidazolyl-azetidin-2-ones and -thiazolidin-4-ones

Arylidene-2-aminobenzimidazoles (1) were prepared by condensation of 2-aminobenzimidazole with aromatic aldehydes. Cyclocondensation of mercaptoacetic acid, chloracetylchloride and phthaloyl glycyl chloride on 1 giving the corresponding 4-thiazolidinones (2) and azetidinones (3 and 4) respectively, in good yields. The biological activities of the prepared compounds were screened against several strains of bacteria.     

Neuroleptics as antagonists of gamma-aminobutyric acid

Experiments on the neurons of isolated spinal cord of rats aged 9-14 days have revealed that like picrotoxin, the neuroleptics reduce the GABA-induced depolarization of primary afferents, hyperpolarization of the motoneurons and inhibition of the function of the interneurons which exercise the inhibitory control of motoneuronal activity. The highest GABA-lytic activity was displayed by the butirophenon derivatives (droperidol and haloperidol). Triphthazin slightly yields to these drugs as regards the activity. Aminazin and levomepromazin have a moderate GABA-lytic activity, whereas thioridazin and ftorphenazin have none. A possible role of the GABA-lytic activity of the neuroleptics in their antipsychotic action is discussed.     

The antihypoxic activity of endogenous cyclic derivatives of gamma-aminobutyric acid

Pirrolidone-2, gamma-butyrolacton, succinic anhydride were found to possess pronounced antihypoxic activity that manifested itself in their ability to decrease the level of lactic acid accumulated during hypoxia. Pirrolidone-2 and succinic anhydride increase succinic dehydrogenase activity in vitro. At intraperitoneal administration the above mentioned compounds lead to lactate dehydrogenase activity inhibition under normal conditions while during circulatory hypoxia they stimulate lactate dehydrogenase reaction promoting the maintenance of energy balance of the cerebral tissue at the appropriate level.     

Synthesis and study of some new N-substituted imide derivatives as potential anticancer agents

A new series of N-substituted imide derivatives have been synthesized by treating phthalic anhydride, naphthalic anhydride and their substituted derivatives with 2-hydrazino-1-imidazoline hydrobromide, various para-substituted aryl amines, aminoglutethimide and 2,4-dinitrophenyl hydrazine. Compounds 9, 10, 12, 18, 19, 23, 24 and 34-36 have been selected and screened for antineoplastic activity by National Cancer Institute, Bethesda, USA. Some newer aminoglutethimide derivatives 37-39 have also been prepared in order to study the effect of N-substitution on its pharmacological profile for the treatment of carcinoma. These compounds (37-39) have exhibited weak inhibition of human placental aromatase as compared to aminoglutethimide.     

Isothiouronium compounds as gamma-aminobutyric acid agonists.

Analogues of gamma-aminobutyric acid (GABA) incorporating an isothiouronium salt as a replacement for a protonated amino functional group have been investigated for activity on: GABA receptors in the guinea-pig ileum; [3H]-GABA and [3H]-diazepam binding to rat brain membranes; and GABA uptake and transamination. For the homologous series of omega-isothiouronium alkanoic acids, maximum GABA-mimetic activity was found at 3-[(aminoiminomethyl)thio]propanoic acid. Introduction of unsaturation into this compound gave two isomeric conformationally restricted analogues. The trans isomer was inactive at GABA receptors while the cis compound ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid (ZAPA)) was more potent than muscimol and GABA as a GABA agonist with respect to low affinity GABA receptor sites. Both isomers were moderately potent at inhibiting the uptake of [3H]-GABA into rat brain slices. Comparison of possible conformations of the two unsaturated isomers by interactive computer graphics modelling and comparison with muscimol has led to a plausible active conformation of ZAPA, which may be a selective and potent agonist for low affinity GABA binding sites.     

N-substituted 3-acetyltetramic acid derivatives as antibacterial agents

In order to expand the structure-activity relationship of tetramic acid molecules with structural similarity to the antibiotic reutericyclin, 22 compounds were synthesized and tested against a panel of clinically relevant bacteria. Key structural changes on the tetramic acid core affected antibacterial activity. Various compounds in the N-alkyl 3-acetyltetramic acid series exhibited good activity against Gram-positive bacterial pathogens including Bacillus anthracis, Propionibacterium acnes, Enterococcus faecalis, and both Methicillin-sensitive and -resistant Staphylococcus aureus.