Synthesis and Pharmacological Activity of N-[β-(<Emphasis Type="Italic">para</Emphasis>-substituted benzoyl)ethyl]isoleucine and -Methionine

A series of N-[β-(p-substituted benzoyl)ethyl]-isoleucine and -methionine derivatives have been synthesized via the alkylation of amino acids with p-substituted β-diethylaminopropiophenone hydrochlorides. Some of the synthesized compounds possess significant antiinflammatory activity. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 7, pp. 26 – 27, July, 2005.     

Synthesis and anti-inflammatory,analgesic, and antipyretic activities of N-[β-(<Emphasis Type="Italic">p</Emphasis>-substituted benzoyl)ethyl]amino acids

Alkylation of a number of α-amino acids, as well as β-phenyl-β-alanine and γ-aminobutyric acid, with the hydrochlorides of p-substituted β-diethylaminopropiophenones resulted in the synthesis of N-[β-(p-substituted benzoyl)ethyl]cysteine, threonine, methionine, isoleucine, asparagine, and glutamine, along with β-phenyl-β-alanine, and γ-aminobutyric acid. The anti-inflammatory activities of the resulting compounds were studied; several of them had moderate anti-inflammatory activity. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 43, No. 1, pp. 14–16, January, 2009.     

Local anesthetic activity of new amidoxime derivatives

Three series of amidoxime derivatives including nitrous derivatives of α-chloro-α-isonitrosoacetone and hydrochlorides of O-aroyl-β-aminopropioamidoximes and 3-[β-(piperidin-1-yl)]ethyl-5-aryl-1,2,4-oxadiazoles were tested for conduction, infiltration, and terminal anesthesia. There are four interesting “hit” compounds, i.e., the hydrochloride of O-m-chlorophenyl-β-(benzimidazol-1-yl)propioamidoxime (VII), the hydrochloride of O-p-nitrophenyl-β-(benzimidazol-1-yl)propioamidoxime (VIII), 3-[β-(piperidin-1-yl)]ethyl-5-p-tolyl-1,2,4-oxadiazole (IX), and 3-[β-(piperidin-1-yl)]ethyl-5-m-chlorophenyl-1,2,4-oxadiazole (X), which exhibit higher activity than the reference drugs (trimecaine, lidocaine, novocaine, kazcaine). As a whole, all tested compounds were active in conduction and infiltration anesthesia (at the level of the reference drugs) and did not show activity in terminal anesthesia. Compounds VII – X are of interest for further testing under condition and infiltration anesthesia conditions.     

Synthesis and antitumor properties of new spiro(benzo[h]quinazoline-7,1′-cyclohexane) derivatives

4-Amino-3-cyano-1,2-dihydrospiro(naphathaline-2,1′-cyclohexane) (aminonitrile) was converted by interaction with p-tolyl acid chloranhydride into 4-(4-methylbenzoyl)amino-3-cyano-1,2-dihydrospiro(naphthaline-2,1′-cyclohexane) (II), which was subjected to cyclization to form 2-(p-tolyl)-4-oxo-3,4,5,6-tetrahydrospiro(benzo[h]quinazoline-5,1′-cyclohexane) (III). This aminonitrile was converted, using a known method, to 4-ethoxymethyleneimino-3-cyano-1,2-dihydrospiro(naphthaline-2,1′-cyclohexane) (IV). Compound IV was condensed with hydrazides of aromatic, alkylaromatic, and alkoxyaromatic acids in dimethylformamide, producing 5-substituted 7,8-dihydrospiro(benzo[h]triazolo[2,3-c]quinazolines) (Va-v) at high yield. The antitumor properties of the resulting compounds were studied using two models of grafted mouse tumors-Ehrlich ascites carcinoma (EAC) and sarcoma 180. Anumber of the newly synthesized compounds had, along with moderate acute toxicity, marked antitumor activity in experimental conditions. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 2, pp. 6–9, February, 2008.     

Synthesis, conformation analysis, and anxiolytic activity of retropeptide analogs of 4-cholecystokinin

Potential dipeptide anxiolytics with the general formula Ph(CH₂)₅ CO-X-L-Trp-NH₂(X = Gly, β-Ala, GABA, L-Pro) have been synthesized on the basis of the 4-cholecystokinin structure. These compounds exhibit anxiolytic activity in the elevated plus-maze test in rats at doses of 0.01–0.5 mg/kg (i.p.). The activity among these derivatives increases in the following order: GABA → β-Ala → Gly → Pro. Conformation analysis of dipeptides in solution by ¹H NMR method with the use of the nuclear Overhauser effect and peptide vicinal ³J(H-NC^α-H) coupling constants has been carried out. It is established that the percentage of βI-turn conformation stabilized by hydrogen bonds with the participation of C-end amide group proton also increases in the order β-Ala → Gly → Pro derivatives. It is concluded that the βI-turn conformation is probably the biologically active one in the synthesized substituted dipeptides. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 7, pp. 21–26, July, 2006.     

P2Y Receptor Mediated Modulation of Insulin Release by a Novel Generation of 2-Substituted-5′-O-(1-Boranotriphosphate)-Adenosine Analogues

Purpose A series of C2-substituted ATP analogues was previously shown to have potent insulin-secreting properties, yet with poor tissue-selectivity for the pancreatic β-cell. The present study was designed to evaluate the binding profile on β-cell membranes and the effects on insulin release and pancreatic vascular resistance of a second generation of P2Y₁ receptor agonists, based on C2-substitution of the adenosine 5′-O-(1-boranotriphosphate) scaffold.Materials and Methods Functional experiments were performed in the rat isolated pancreas model; binding studies with ATP-α-[³⁵S] were performed in membrane homogenates from the rat insulinoma INS-1 cell line. The diastereoisomers of the compounds are designated by A and B.Results Under 8.3 mmol l⁻¹ glucose, 2-methylthio-ATP-α-B, A isomer, induced a biphasic and concentration dependent insulin response; its maximal efficacy reaches ninefold the baseline secretion and its EC₅₀ is 28.1 nmol l⁻¹. No significant effect of this isomer was observed on vascular resistance, whereas the B isomer, which was a less potent insulin secretagogue, consistently induced a transient vasoconstriction. Interestingly, the insulin response induced by 2-methylthio-ATP-α-B, A isomer, was clearly glucose-dependent. This drug competes with ATP-α-[³⁵S] binding in a complex two sites interaction model, with a K _0.5 value of 17.7 nmol l⁻¹. 2-Chloro-ATP-α-B had a similar insulin-secreting profile as 2-methylthio-ATP-α-B, with a lower tissue-selectivity. The non-substituted ATP-α-B analog, A isomer, was less potent than the C2-substituted derivatives (A isomers) and had a vasorelaxant effect.Conclusions We conclude that 2-methylthio-ATP-α-B, A isomer, is a potent and tissue-selective P2Y receptor agonist with high efficacy. Its insulin-releasing action is glucose-dependent, which gives interest to this compound as a drug candidate for treating type 2 diabetes.     

Interrelation of the antioxidant activity and synergistic action of sterically hindered derivatives of β-(4-hydroxy-3,5-di-<Emphasis Type="Italic">tert</Emphasis>-butylphenyl)propionic acid in compositions with α-tocopherol

We have studied the inhibitory action of sterically hindered phenolic antioxidant (AO) derivatives of β-(4-hydroxy-3,5-di-tert-butylphenyl)propionic acid, which are modified by ethanolamine residues substituted at the nitrogen atom with N-alkyl radicals R having variable chain length (from 1 to 16 carbon atoms). The AO activity has been studied in the reaction of initiated oxidation of homogenous methyl oleate (MO) solution in chlorobenzene. It is shown that AOs act according to two mechanisms. First, they react with peroxide radicals at a reaction rate constant of k ₇ = (0.59 − 1.06) × 10⁴ (M × sec)⁻¹ and, second, they destroy reactive oxygen species with the formation of molecular products. The AO properties of β-(4-hydroxy-3,5-di-tert-butylphenyl)propionic acid derivatives depend substantially on their chemical structure and oxidation conditions. In lipid solution, these AOs effectively slow down MO oxidation. Asynergism in the joint inhibitory action of α-tocopherol and AO derivatives of β-(4-hydroxy-3,5-di-tert-butylphenyl)propionic acid has been observed. Independent methods (UV spectroscopy and high-performance liquid chromatography) were employed to study the kinetics of α-tocopherol consumption (used separately and in a binary mixture with synthetic AOs) in the course of MO oxidation. In the synergistic composition, the rate of α-tocopherol consumption is significantly decreased. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 4, pp. 22–29, April, 2007.     

Modulation of immunoreactive protein kinase C-α and β isoforms and G proteins by acute and chronic treatments with morphine and other opiate drugs in rat brain

The abundance of protein kinase C-α and β isoforms (PKC-αβ), PKC-α messenger (m) RNA and guanine nucleotide-binding G protein subunits (Gα_i1/2, Gα_o and Gβ) were quantitated in the rat cerebral cortex after acute and chronic treatments with various opiate drugs. Acute (100mg/kg for 2h) and chronic (10 to 100mg/kg for 5 days) treatment with morphine decreased similarly the immunoreactivity of PKC-αβ (28% and 32%, respectively). Acute (2h) and chronic treatment (5 days) with other μ-agonists heroin (30mg/kg and 10 to 30mg/kg) and methadone (30mg/kg and 5 to 30mg/kg) also induced similar decreases of PKC-αβ (acute: 25% and 23%; chronic: 28% and 18%). After the chronic treatments, spontaneous (48h) or naloxone (2mg/kg)-precipitated opiate withdrawal (2h) resulted in up-regulation of PKC-αβ above control levels (30-38%), and in the case of morphine withdrawal in a concomitant marked increase in the expression of PKC-α mRNA levels (2.3-fold). Acute (2h) treatments with pentazocine (80mg/kg, mixed κ/δ-agonist and μ-antagonist), spiradoline (30mg/kg, selective κ-agonist) and [D-Pen², D-Pen⁵] enkephalin (14nmol i.c.v., selective δ-agonist) induced significant decreases of PKC-αβ (19–33%). Chronic (5 days) treatment with pentazocine (10 to 80mg/kg), but not spiradoline (2 to 30mg/kg), also induced a similar decrease of PKC-αβ (35%). In pentazocine- or spiradoline-dependent rats, naloxone (2mg/kg) did not induce up-regulation of brain PKC-αβ. Acute (10mg/kg for 2h) and chronic (2×10mg/kg for 5 and 14 days) treatment with naloxone did not alter PKC-αβ immunoreactivity. Chronic, but not acute, treatment with μ-agonists (morphine, heroin and methadone) increased the immunoreactivities of Gα_i1/2 (33-37%), Gα_o (25-41%) and Gβ (10-33%) protein subunits. In heroin- and methadone-dependent rats naloxone (2mg/kg)-precipitated withdrawal (2h) did not modify the up-regulation of these G proteins induced by chronic μ-opiate treatment. In marked contrast to μ-agonists, chronic treatment with high doses of pentazocine and spiradoline or acute treatment with [D-Pen², D-Pen⁵] enkephalin did not result in up-regulation of these G protein subunits. After chronic treatment with μ-agonists, significant negative correlations were found when the percentage changes in immunoreactivity of PKC-αβ were related to the percentage changes in immunoreactivity of Gα_i1/2 (r =-0.53, n = 29) and Gβ (r =-0.41, n = 24) in the same brains. PKC-αβ abundance did not correlate significantly with the density of Gα_o (r =-0.21, n = 28). Together the results indicate that the brain PKC-αβ system may play a major regulatory role in opiate tolerance and dependence. Moreover, the possible in vivo cross-communication between this regulatory enzyme and specific inhibitory G proteins may also be of relevance in the cellular and molecular processes of opiate addiction. Received: 15 July 1996 / Accepted: 22 November 1996     

A rubrofusarin gentiobioside isomer from roastedCassia tora

From the roasted seeds ofCassia tora L., a new naphthopyrone glycoside was isolated and characterized as 10-[(β-D-glucopyranosyl-(1→6)-O-β-D-glucopyranosyl)oxyl-5-hydroxy-8-methoxy-2-methyl-4H-naphtho [1,2-b]pyran-4-one(isorubrofusarin gentiobioside). Along with isorubrofusarin gentiobioside, alaternin and adenosine were isolated and identified.     

Syntheses of potentially active 1-substituted imidazo-[1,2-c]pyrimidine derivatives

A series of 1-substituted 7-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5-ones has been obtained by treatment of 2-hydroxy-4-mercapto-6-methyl-5-pyrimidinecarboxylic acid ( 1 ) with aminoalcohols followed by chlorination, cyclization and alkylation. Some of the obtained imidazo[1,2-c]pyrimidine derivatives were CNS active and showed antiinflammatory activity.     

Inhibition of ATP-induced cAMP formation by 5’-p-fluorosulfonylbenzoyladenosine in NG108-15 cells

ATP is known to increase intracellular cAMP levels in NG108-15 cells via a novel purinoceptor and this response is inhibited by the P₁ purinoceptor antagonist methylxanthine. In the present study, we examined the effects of 5’-p-fluorosulfonylbenzoyladenosine (FSBA), an affinity ligand for ATP-binding proteins, on cAMP formation mediated by activation of adenylate cyclase (AC)-linked purinoceptors in NG108-15 cells. cAMP levels were determined by RIA using an anti-succinyl-cAMP antiserum. FSBA (100 μM) increased intracellular cAMP about 2.6-fold. However, FSBA-induced cAMP formation was abolished by pretreatment with adenosine deaminase, suggesting that adenosine, a breakdown product of FSBA, is involved in FSBA-induced cAMP formation. In contrast, pretreatment of cells with FSBA in the presence of adenosine deaminase inhibited cAMP formation induced by ATP and β,γ-methylene-ATP (β,γ-MeATP), without affecting the prostaglandin E₁ (PGE₁)-induced response. The inhibitory effect of FSBA on ATP-induced cAMP formation was concentration-dependent with a concentration required for half-maximal inhibition (IC₅₀) of around 3 μM. The inhibitory effect of FSBA was not affected by pertussis toxin (PTX)-treatment. Pretreatment with FSBA (10 μM) depressed the maximal response to β,γ-MeATP by 60%, but did not affect the response to 5’-N-ethylcarboxamidoadenosine. The inhibitory effect of FSBA (100 μM) increased time-dependently during pretreatment and partly resisted wash-out. The inhibition by FSBA was protected by simultaneous addition of β,γ-MeATP during the FSBA pretreatment, indicating that both FSBA and the ATP analogue interacted with the same receptor site. The pretreatment with FSBA did not affect the increase in [Ca²⁺]_i induced by ATP, UTP or benzoylbenzoic ATP. These results suggest that FSBA inhibits cAMP accumulation induced in NG108-15 cells by ATP or related agonists by selective modification of an AC-linked purinoceptor. Received: 28 July 1997 / Accepted: 14 April 1998     

Synthesis and biological activity of novel 1H-1,4-diazepines containing benzene sulfonyl piperazine moiety

The synthesis of biologically active 1H-1,4-diazepines 6a–e in good yield, from the heterocyclization reaction of [N ⁴-(4-acetylamino) benzene sulfonyl) piperazinyl-N ¹-propyl]-1,3-dialkyl/aryl propane-1,3-dione 5a–e and ethylenediamine (EDA) in the presence of silica sulphuric acid (SSA) is described. The novel β-diketones/β-ketoesters 5a–e were synthesized by the condensation reaction of [N ⁴-(4-acetylamino) benzene sulfonyl) piperazinyl-N ¹-1-bromopropane with various β-diketones/β-ketoesters 4a–e. All structures of the newly synthesized compounds were elucidated by elemental analysis and spectral studies. The compounds 6a–e have been screened for antimicrobial, antifungal and anthelmintic activity.     

Asymmetrische reduktive Aminierung von Cycloalkanonen, 11. Mitt.1,2): Synthese optisch aktiver 2-substituierter Cycloheptanamine

Asymmetric Reductive Amination of Cycloalkanones, XI^1,2): Synthesis of Optically Active 2-Substituted Cycloheptanamines Asymmetric synthesis of 2-substituted cycloheptanamines from racemic cycloheptanones by means of reductive amination in a three-step procedure is described. Condensation of the ketones 1 with the optically active auxiliary R-(+)- or S-(-)-1-phenylethylamine leads to the imine mixtures 2 which are hydrogenated over Raney nickel to give the optically active, diastereomerically pure secondary amines 3 . Hydrogenolysis with Pd/C yields the optically active cis-2-substituted cycloheptanamines 4 .     

Synthesis and antiaggregant activity of 2-cycloalkylamino-5-thienyl- and -5-furyl-6<Emphasis Type="Italic">H</Emphasis>-1,3,4-thiadiazines

A series of new 5-(thienyl-2)-, 5-(furyl-2)-, and 5-(thienyl-3)-1,3,4-thiadiazine derivatives have been synthesized using methods based on the cyclocondensation of α-bromoacetylthiophenes or α-bromo-2-acetylfurans with 4-substituted thiosemicarbazides. The effects of the synthesized compounds on human platelet aggregation in vitro and on rabbit platelet aggregation ex vivo have been studied. The most active 5-(thienyl-2)-1,3,4-thiadiazines inhibit human platelet aggregation induced by ADP and arachidonic acid in a broad concentration range. These compounds have good potential as emergency drugs for the treatment and prophylaxis of infarction and stroke.     

Synthesis and antimicrobial and nitric oxide synthase inhibitory activities of novel isothiourea derivatives

The reaction of substituted benzylhalides, or of halomethyl derivatives of thiophene or furane, with thiourea or its derivatives yielded the respective isothioureas as hydrohalide salts. The products (a total of 17, including 16 novel compounds) were tested for activity against five Gram-positive and nine Gram-negative bacterial strains, six yeast species and two protozoan species. The most active against Gram-positive bacteria were S-(2,4-dinitrobenzyl)isothiourea hydrochloride (MIC range for four out of five strains tested: 12.5–25 μg/mL) and S-(2,3,4,5,6-pentabromobenzyl)isothiourea hydrobromide (MIC range: 12.5–50 μg/mL). The lowest MICs of novel isothioureas for yeast and Gram-negative bacteria ranged between 50 and 100 μg/mL. Nine novel isothioureas showed appreciable genotoxicity in the Bacillus subtilis ‘rec-assay’ test, the most potent being S-2-(5-nitrofuran-2-ylmethyl)isothiourea and S-(2-nitrobenzyl) isothiourea. At 10 μM concentration, S-(3,4-dichlorobenzyl)isothiourea hydrochloride and S-(2,3,4,5,6-pentabromobenzyl)isothiourea hydrobromide inhibited Ca²⁺/calmodulin-dependent (non-inducible) nitric oxide synthase activity in normal rat brain homogenates stronger (p < 0.05) than the reference drug 7-nitroindazole (by 78, 76 and 60%, respectively); ten other new isothiourea derivatives significantly inhibited the activity to a lower extent (by 28–60%). These results extend the list of promising isothioureas with substantial activity in vitro and suggest that an in-depth study of toxicity, antimicrobial properties in vivo and nitric oxide synthase isoform selectivity of selected novel compounds is warranted.     

A study on the genotoxic activities of some new benzoxazoles

The Bacillus subtilis rec assay has been specially developed to detect DNA-damaging potential in chemicals, with the rationale based on the relative difference of survival of a DNA repair combination proficient strains and its deficient strain, which is interpreted as genotoxicity. The genotoxic activities of newly (1–6) and previously (7–18) synthesized various benzoxazoles and benzimidazoles were analyzed via the B. subtilis rec assay. Newly obtained benzoxazole and benzimidazole derivatives (1–6) were synthesized in the presence of polyphosphoric acid (PPA) and 6 N HCl, respectively to detect their DNA-damaging activities. Among the tested compounds, 6-methyl-2-(o-chlorophenyl)benzoxazole (9), 5-amino-2-(p-methylbenzyl)benzoxazole (4), 5-(p-fluorobenzamido)-2-phenylbenzoxazole (13), and 2-(p-methylaminophenyl)benzoxazole (18) showed genotoxic activities having Rec₅₀ values of 1.85, 1.74, 1.60, and 1.50 or S-probit values of 0.534, 0.482, 0.460, and 0.357, respectively. On the other hand, 2-(p-bromobenzyl)-5-methylbenzimidazole (6) and 2-benzyl-5-(p-fluorophenylacetamido)-benzoxazole (15) were exhibited a reverse effect that displayed a bacterial growth in the rec ^- strains while there was no any bacterial growth in rec ⁺ strains at the same concentration.     

A potential inhibitor of rat aortic vascular smooth muscle cell proliferation from the pollen of <Emphasis Type="Italic">Typha angustata</Emphasis>

By various chromatographic methods, three flavonoids, (2S)-naringenin (1), isorhamnetin 3-O-(2-O-α-l-rhamnopyranosyl) β-d-glucopyranoside (2), typhaneoside (3), and two sterol glycosides, β-sitosterol-3-O-(6-octadecanoyl) β-d-glucopyranoside (4) and β-sitosterol-3-O-(6-octadeca-9Z,12Z-dienoyl) β-d-glucopyranoside (5), were isolated from the pollen of Typha angustata. Their structures were determined on the basis of spectroscopic analyses. The flavonoids (1–3) were evaluated for their effects on the viability and proliferation of rat aortic smooth muscle cells. (2S)-naringenin (1) significantly inhibited cell proliferation in a dose-dependent manner without cytotoxic at concentrations of 30, and 50 μM; it reduced the number of cells following PDGF-BB treatment to 1.83 ± 0.30 × 10⁴ and 2.20 ± 0.60 × 10⁴ cells/well, respectively. These findings suggest that (2S)-naringenin has antiproliferative effects on aortic smooth muscle cells.     

Die Decker-Oxidation 2-substituierter N-Alkylpyridiniumverbindungen, 4. Mitt.: Eine neue Synthese 1,2-disubstituierter 6-Pyridone

A New Synthesis of 1,2-Disubstituted 6-Pyridones “Inverse” Decker-oxidation of the 2-substituted 1-methylpyridinium salts 1a – 1o in concentrated alkali yields the 2-substituted 1-methyl-6-pyridones 2a – 2o . A reaction mechanism is postulated, also explaining the formation of byproducts.     

Unabhängige Synthese der violetten Farbstoffe aus 1,2-Naphthochinon-4-sulfonsäure und primären aliphatischen Aminen sowie eines Nebenproduktes

Independent Synthesis of the Violet Dyes and of a By-product Formed in the Reaction of 1,2-Naphthoquinone-4-sulfonic Acid with Primary Aliphatic Amines 4-Dimethylamino-1,2-naphthoquinone ( 8 ) and 2-dimethylamino-1,4-naphthoquinone ( 10 ) are O-methylated by methyl fluorosulfonate to form the stable iminium salts 9 and 11 . In an analogous way the 2-alkylamino-l,4-naphthoquinones 13 were transformed into the iminium salts 14 . These salts condense with 3-amino-4-hydroxynaphthalene-I-sulfonic acid ( 15 ) to give the violet 3-[(3-alkylamino-4-oxo-l-naphthyliden)amino]-4-hydroxynaphthalene-l-sulfonic acids 2 . The iminium salt 14c reacts with benzylamine to yield the vinylogous amidinium salt 19 , which is oxidised by silver oxide in pyridine to give the N-benzylidene-2-phenyl-5-naphth[2,1-d]oxazolamine 20 . Reduction of 20 with LiAIH₄, leads to the formation of N-benzyl-2-phenyl-5-naphth[2,l-d]oxazolamine ( 7 )