Novos derivados do sistema heterocíclico 1H-pirazolo[3,4-b]piridina: síntese e assinalamentos de hidrogênios e carbonos por RMN 1D e 2D

The synthesis and NMR analysis of seven new 4-(aryl)amino-5-carboethoxy-1,3-dimethyl-1H-pyrazolo[3,4- b]pyridines (7-13) are described. The synthetic approach used involved the preparation of intermediates 5-aminopyrazol (4), the enamine derivative (5) and the 4-chloro-1H-pyrazolo[3,4-b]pyridine (6). Compounds (7-13) were obtained by treatment of 6 with the desired aniline. The structures of new heterocyclic compounds and their precursors intermediates were assigned on the basis of spectral analysis including 1D and 2D NMR experiments [¹H; 13C{¹H} and DEPT; ¹H x ¹H - COSY; ¹H x13C - COSY, nJ CH, n = 1, 2 or 3 (HETECOR and COLOC)].

Síntese e atividade fitotóxica de 2-fenil-6,7-exo-isopropilidenodioxi-8-oxabiciclo [3.2.1]oct-2-eno

The [3+4] cycloaddition between furan and the oxyallyl cation generated from 1-bromo-1-phenylpropan-2-one (4), resulted in the formation of 2-phenyl-8-oxabicyclo[3.2.1]oct-6-en-3-one (5) in 30% yield. This compound was further converted into 2-phenyl-6,7-exo-isopropylidenedioxi-8-oxabicyclo[3.2.1]oct-2-ene (13) in 35.4% yield. The selective effect of compound (13) and its isomer 3-phenyl-6,7-exo-isopropylidenedioxi-8-oxabicyclo[3.2.1]oct -2-ene (1a) on the radicle growth of Sorghum bicolor L. (sorghum) and Cucumis sativus L. (cucumber) were evaluated. For both plants, compound 13 showed to be more potent than its isomer 1a.

Mechanism of 3,4-dihydroxybenzaldehyde electropolymerization at carbon paste electrodes: catalytic detection of NADH

Cyclic voltammetry was used to study 3,4-dihydroxybenzaldehyde (3,4-DHB) electropolymerization processes on carbon paste electrodes. The characteristics of the electropolymerized films were highly dependent on pH, anodic switching potential, scan rate, 3,4-DHB concentrations and number of cycles. Film stability was determined in citrate/phosphate buffer solutions at the same pH used during the electropolymerization process. The best conditions to prepare carbon paste modified electrodes were pH 7.8; 0.0 <= Eapl <= 0.25 V; 10 mV s-1; 0.25 mmol L-1 3,4-DHB and 10 scans. These carbon paste modified electrodes were used for NADH catalytic detection at 0.23 V in the range 0.015 <= [NADH] <= 0.21 mmol L-1. Experimental data were used to propose a mechanism for the 3,4--DHB electropolymerization processes, which involves initial phenoxyl radical formation.

Síntese de novos herbicidas derivados do 1,2alfa,4alfa,5-tetrametil-8-oxabiciclo[3.2.1]oct-6-en-3-ona

In this paper we report the synthesis of biologically active compounds through a [3+4] cycloaddition reaction to produce the main frame structure, followed by several conventional transformations. The 1,2alpha,4alpha,5-tetramethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one (11) obtained from a [3+4] cycloaddition reaction was converted into 1,2alpha,4alpha,5-tetramethyl-6,7-exo-isopropylidenedioxi-8 -oxabicyclo[3.2.1]octan-3-one (13) in 46% yield. This was further converted into the alcohols 1,2alpha,4alpha,5-tetramethyl-6,7-exo-isopropylidenedioxi-8-oxabicyclo[3.2.1]octan-3 alpha-ol (14), 1,2alpha,4alpha,5-tetramethyl-6,7-exo-isopropylidenedioxi-8 -oxabicyclo[3.2.1]octan-3beta-ol (15), 1,2alpha,4alpha,5-tetramethyl-3-butyl-6,7-exo-isopropylidenedioxi-8-oxabicyclo[3.2.1]octan-3 alpha-ol (17), 1,2alpha,4alpha,5-tetramethyl-3-hexyl-6,7-exo-isopropylidenedioxi-8-oxabicyclo[3.2.1]octan-3 alpha-ol (18) and 1,2alpha,4alpha,5-tetramethyl-3-decyl-6,7-exo-isopropylidenedioxi-8-oxabicyclo[3.2.1]octan-3 alpha-ol (19). Dehydration of 17, 18 and 19 with thionyl chloride in pyridine resulted in the alkenes 20, 21 and 22 in ca. 82% - 89% yields from starting alcohols. The herbicidal activity of the compounds synthesized was evaluated at a concentration of 100 µg g-1. The most active compound was 21 causing 42,7% inhibition against Cucumis sativus L.

Mir iskusstva 3-4 (1899)

Venäjällä syntyi 1800-luvun lopulla taiteilijaryhmiä, joista ehkä tunnetuin on Mir iskusstva eli Taiteen maailma. Ryhmä järjesti omia näyttelyitä, koska sen nuoret jäsenet olivat vielä sen verran tuntemattomia, että heitä ei kelpuutettu isoihin näyttelyihin. Vuosisadan taitteessa erilaisille ryhmille oli luonnollista julkaista omaa lehteä. Mir iskusstva –ryhmän keulahahmoihin kuulunut A. Benua kirjoitti: 'kirjoitan, siis olen'. Ryhmän idea oli 'taide ei ole ylellisyyttä, se on kansan aikaansaannosta ja sille luotua'. Päätoimittaja Sergej Djagilevin ajatuksena oli tehdä venäläistä maalaustaidetta tunnetuksi Pariisissa. Ryhmällä olikin suuri välittävä merkitys: se vei tietoa venäläisestä taiteesta Eurooppaan ja toi eurooppalaisen taiteen osaksi venäläistä taide-elämää. Myös suomalaisen taiteen kannalta tällä ryhmällä oli merkitystä. Heidän lehdessään esiteltiin Suomen taiteen suuret nimet: Akseli Gallen-Kallela, Albert Edelfelt, Pekka Halonen, Väinö Blomstedt, Eero Järnefelt, Magnus Enckell, Ville Wallgren. Vuonna 1898 Djagilev esitteli laajasti suomalaista taidetta perustamansa lehden ensimmäisessä numerossa. Nuoret pietarilaistaiteilijat olivat ihastuksissaan erityisesti Gallen-Kallelan edustamasta romantiikasta. Suomen taide ja arkkitehtuuri olivat myöhemminkin hyvin esillä lehdessä. Vuonna 1904, joka oli lehden viimeinen ilmestymisvuosi, esiteltiin suomalaisten taiteilijoiden vuoden 1903 näyttelyä.

3,4-Methylenedioxymethamphetamine enhances kainic acid convulsive susceptibility

Abstract Kainic acid (KA) causes seizures and neuronal loss in the hippocampus. The present study investigated whether a recreational schedule of 3,4-methylenedioxymethamphetamine (MDMA) favours the development of a seizure state in a model of KA-induced epilepsy and potentiates the toxicity profile of KA (20 or 30 mg/kg). Adolescent male C57BL/6 mice received saline or MDMA t.i.d. (s.c. every 3 h), on 1 day a week, for 4 consecutive weeks. Twenty-four hours after the last MDMA exposure, the animals were injected with saline or KA (20 or 30 mg/kg). After this injection, we evaluated seizures, hippocampal neuronal cell death, microgliosis, astrogliosis, and calcium binding proteins. MDMA pretreatment, by itself, did not induce neuronal damage but increased seizure susceptibility in all KA treatments and potentiated the presence of Fluoro-Jade-positive cells in CA1. Furthermore, MDMA, like KA, significantly decreased parvalbumin levels in CA1 and dentate gyrus, where it potentiated the effects of KA. The amphetamine derivative also promoted a transient decrease in calbindin and calretinin levels, indicative of an abnormal neuronal discharge. In addition, treatment of cortical neurons with MDMA (1050 μM) for 6 or 48 h significantly increased basal Ca2 +, reduced basal Na+ levels and potentiated kainate response. These results indicate that MDMA potentiates KA-induced neurodegeneration and also increases KA seizure susceptibility. The mechanism proposed includes changes in Calcium Binding Proteins expression, probably due to the disruption of intracellular ionic homeostasis, or/and an indirect effect through glutamate release.

3,4-Methylenedioxymethamphetamine enhances kainic acid convulsive susceptibility

Abstract Kainic acid (KA) causes seizures and neuronal loss in the hippocampus. The present study investigated whether a recreational schedule of 3,4-methylenedioxymethamphetamine (MDMA) favours the development of a seizure state in a model of KA-induced epilepsy and potentiates the toxicity profile of KA (20 or 30 mg/kg). Adolescent male C57BL/6 mice received saline or MDMA t.i.d. (s.c. every 3 h), on 1 day a week, for 4 consecutive weeks. Twenty-four hours after the last MDMA exposure, the animals were injected with saline or KA (20 or 30 mg/kg). After this injection, we evaluated seizures, hippocampal neuronal cell death, microgliosis, astrogliosis, and calcium binding proteins. MDMA pretreatment, by itself, did not induce neuronal damage but increased seizure susceptibility in all KA treatments and potentiated the presence of Fluoro-Jade-positive cells in CA1. Furthermore, MDMA, like KA, significantly decreased parvalbumin levels in CA1 and dentate gyrus, where it potentiated the effects of KA. The amphetamine derivative also promoted a transient decrease in calbindin and calretinin levels, indicative of an abnormal neuronal discharge. In addition, treatment of cortical neurons with MDMA (1050 μM) for 6 or 48 h significantly increased basal Ca2 +, reduced basal Na+ levels and potentiated kainate response. These results indicate that MDMA potentiates KA-induced neurodegeneration and also increases KA seizure susceptibility. The mechanism proposed includes changes in Calcium Binding Proteins expression, probably due to the disruption of intracellular ionic homeostasis, or/and an indirect effect through glutamate release.

Ácido canárico (3,4-seco derivado do lupano) em própolis do Ceará

Phytochemical investigation of a propolis sample from Alto Santo - Ceará, Brazil, allowed identification of triterpenes (lupeol, lupenone, germanicone, canaric acid) and flavonoids (quercetin, kaempferol and acacetin), which were identified by spectroscopic data (IR, MS, and NMR, including 2D techniques). This is the first report of canaric acid in propolis. Propolis extract and flavonoids showed antioxidant activity using a DPPH radical scavenging assay.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Kivikk'aho-lauluja nrot 1, 2, 6, 3, 4, 5

Digitoitu 13. 8. 2008.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Determinação de 3,4-metilenodioximetanfetamina (MDMA) em comprimidos de Ecstasy por cromatografia líquida de alta eficiência com detecção por fluorescência (CLAE-DF)

This paper describes the development and validation of simple and selective analytical method for determination of 3.4-methylenedioxymethamphetamine (MDMA) in Ecstasy tablets, using high performance liquid chromatography with fluorescence detection. Analysis was performed in a reversed phase column (LiChrospher 100 C18, 150 x 4.6 mm, 5 µm), isocratic elution with phosphate buffer 25 mmol/L pH 3.0 and acetonitrile (95:5, v/v). The method presents adequate linearity, selectivity, precision and accuracy. MDMA concentration in analyzed tablets showed a remarkable variability (from 8.5 to 59.5 mg/tablet) although the tablet weights were uniform, indicating poor manufacturing control thus imposing additional health risks to the users.

Antimycobacterial and cytotoxicity activities of free and liposome-encapsulated 3-(4'-bromo[1,1'-biphenyl-4-yl)-3-(4-bromo-phenyl)-N,N-dimethyl-2-propen-1-amine

The antimycobacterial activity of 3-(4'-bromo[1,1'-biphenyl-4-yl)-3-(4-bromo-phenyl)-N,N-dimethyl-2-propen-1-amine (BBAP), free or incorporated in preformed liposomes, on extracellular M. tuberculosis H37Rv was 8 and 25 μM (MIC), respectively. Extracellular antimycobacterial activity was not significantly improved by entrapment of BBAP in liposomes, but there was a 6.1-fold reduction of BBAP cytotoxicity on J774 macrophages. Liposomal BBAP or its free form showed IC50 values of 165 and 27 μM, resulting in a selectivity index (SI=IC50/MIC) of 3.4 and 6.6, respectively. Free BBAP in concentrations from 10 to 80 μM were quite effective in eliminating intracellular M. tuberculosis while liposomal formulation was less effective at these concentrations.