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Taking the previously reported compound BH-7d as the lead, we designed and synthesized a series of piperidinyl-substituted [1,2,4]triazolo[1,5-a]pyrimidines, and their anti-HIV activities as well as cytotoxicities were evaluated. Several compounds exhibited moderate anti-HIV (IIIB) potency, among which 2b was the most active one (EC50 = 4.29 μM). Structure-activity relationships derived from the antiretroviral results were analyzed. Additionally, most compounds demonstrated reduced cytotoxicity (CC50 > 200 μM) compared with those of BH-7d and etravirine. Molecular docking study further revealed the binding conformation of 2b in the binding pocket of HIV-1 reverse transcriptase. ispartof: CHEMICAL BIOLOGY & DRUG DESIGN vol:97 issue:1 pages:67-76 ispartof: location:England status: published

The condensation reaction of 2-mercapto-3-methoxybenzaldehyde with 3-aminopyridine afforded an unexpectedN-alkylated [1,5]dithiocine instead of theN-salicylideneaniline. The proposed mechanism for this condensation involves a strong intramolecular hydrogen bond between the thiol and the amine groups, leading to a second condensation. The corresponding product,i.e.4,10-dimethoxy-13-(pyridin-3-yl)-6H,12H-6,12-epiminodibenzo[b,f][1,5]dithiocine methanol 0.463-solvate, C21H18N2O2S2·0.463CH3OH, was characterized by single-crystal X-ray diffraction analysis. The supramolecular structure shows π–π stacking and S...S interactions in the crystal packing. Within the asymmetric unit, two geometries of the N atom are observed. Although a planar geometry should be expected, a pyramidal one is observed due to the crystal packing. The presence of the two geometries was further supported by density functional theory (DFT) calculations that show an electronic energy difference of less than 2 kJ mol−1between the two conformers.

A further investigation aiming to generate new potential antitumor agents led us to synthesize a new series of twenty-two compounds characterized by the presence of the 7-(3′,4′,5′-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine pharmacophore modified at its 2-position. Among the synthesized compounds, three were significantly more active than the others. These bore the substituents p-toluidino (3d), p-ethylanilino (3h) and 3′,4′-dimethylanilino (3f), and these compounds had IC50 values of 30–43, 160–240 and 67–160 nM, respectively, on HeLa, A549 and HT-29 cancer cells. The p-toluidino derivative 3d was the most potent inhibitor of tubulin polymerization (IC50: 0.45 µM) and strongly inhibited the binding of colchicine to tubulin (72% inhibition), with antiproliferative activity superior to CA-4 against A549 and HeLa cancer cell lines. In vitro investigation showed that compound 3d was able to block treated cells in the G2/M phase of the cell cycle and to induce apoptosis following the intrinsic pathway, further confirmed by mitochondrial depolarization and caspase-9 activation. In vivo experiments conducted on the zebrafish model showed good activity of 3d in reducing the mass of a HeLa cell xenograft. These effects occurred at nontoxic concentrations to the animal, indicating that 3d merits further developmental studies.

Strategies commonly used for the synthesis of functionalised bicyclo[1.1.1]pentanes (BCP) rely on the reaction of [1.1.1]propellane with anionic or radical intermediates. In contrast, electrophilic activation has remained a considerable challenge due to the facile decomposition of BCP cations, which has severely limited the applications of this strategy. Herein, we report the electrophilic activation of [1.1.1]propellane in a halogen bond complex, which enables its reaction with electron-neutral nucleophiles such as anilines and azoles to give nitrogen-substituted BCPs that are prominent motifs in drug discovery. A detailed computational analysis indicates that the key halogen bonding interaction promotes nucleophilic attack without sacrificing cage stabilisation. Overall, our work rehabilitates electrophilic activation of [1.1.1]propellane as a valuable strategy for accessing functionalised BCPs.

Two different series of fifty-two compounds, based on 3′,4′,5′-trimethoxyaniline (7a–ad) and variably substituted anilines (8a–v) at the 7-position of the 2-substituted-[1,2,4]triazolo [1,5-a]pyrimidine nucleus, had moderate to potent antiproliferative activity against A549, MDA-MB-231, HeLa, HT-29 and Jurkat cancer cell lines. All derivatives with a common 3-phenylpropylamino moiety at the 2-position of the triazolopyrimidine scaffold and different halogen-substituted anilines at its 7-position, corresponding to 4′-fluoroaniline (8q), 4′-fluoro-3′-chloroaniline (8r), 4′-chloroaniline (8s) and 4′-bromoaniline (8u), displayed the greatest antiproliferative activity with mean IC50′s of 83, 101, 91 and 83 nM, respectively. These four compounds inhibited tubulin polymerization about 2-fold more potently than combretastatin A-4 (CA-4), and their activities as inhibitors of [3H]colchicine binding to tubulin were similar to that of CA-4. These data underlined that the 3′,4′,5′-trimethoxyanilino moiety at the 7-position of the [1,2,4]triazolo [1,5-a]pyrimidine system, which characterized compounds 7a–ad, was not essential for maintaining potent antiproliferative and antitubulin activities. Compounds 8q and 8r had high selectivity against cancer cells, and their interaction with tubulin led to the accumulation of HeLa cells in the G2/M phase of the cell cycle and to apoptotic cell death through the mitochondrial pathway. Finally, compound 8q significantly inhibited HeLa cell growth in zebrafish embryos.

Reaction of methyl 2-aryl-5-(chlorosulfonyl)-1,3-oxazole-4-carboxylates with 1H-pyrazol-5-amines and 1H-1,2,4-triazol-5-amines proceeds with the participation of endocyclic aminoazole nitrogen atoms to yield products containing a primary amino group. Being treated by sodium hydride these products undergo a further transformation into the tricyclic compounds. It has been shown that the cyclocondensation pathway includes the Smiles rearrangement with extrusion of SO2 followed by the elimination of MeOH. This reaction sequence is a convenient approach to the synthesis of new annulated [1,3]oxazolo[5,4-d]pyrimidine derivatives.

A vertex subset [Formula: see text] of a graph [Formula: see text] is a [Formula: see text]-dominating set if each vertex of [Formula: see text] is adjacent to either one or two vertices in [Formula: see text]. The minimum cardinality of a [Formula: see text]-dominating set of [Formula: see text], denoted by [Formula: see text], is called the [Formula: see text]-domination number of [Formula: see text]. In this paper, the [Formula: see text]-domination and the [Formula: see text]-total domination numbers of the generalized Petersen graphs [Formula: see text] are determined.

Aim. The aim of the given study was to conduct primary antimicrobial screening of novel [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one derivatives.Methods. The set of 169 novel [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one derivatives has been tested for activity against 5 bacteria: Escherihia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Staphylococcus aureus, and 2 fungi: Candida albicans and Cryptococcus neoformans. Primary antimicrobial screening has been conducted by whole cell growth inhibition assays, using the provided samples at a single concentration. Samples were tested in water – 0.3 % DMSO solutions with final sample concentrations 32 µg/ml (70-80 µMol).Results. [1,2,4]Triazolo[4,3-a]quinazolin-5(4H)-ones 5{1}, 7{1}, 7{2}, 7{3} showed more than 80 % inhibition of Acinetobacter baumannii growth and compounds 7{4} showed more than 80 % inhibition of growth fungi Cryptococcus neoformans.Conclusions. For the first time conducted antimicrobial screening of novel [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones showed that compounds, which had no amide group exhibited no antimicrobial activity, but several [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one derivatives containing amide group attached by carbon or sulfur-carbon chain possess antimicrobial activity against Acinetobacter baumannii or fungi Cryptococcus neoformans

[1,2,4]Triazolo[1,5-c]pyrimidine is a promising platform to develop adenosine receptor antagonists. Here, we tried to investigate the effect of the substituent at the 8 position of [1,2,4]triazolo[1,5-c]pyrimidine derivatives on affinity and selectivity at the human A3 adenosine receptor subtype. In particular, we have introduced both esters and amides, principally with a benzylic nature. In addition, a small series of 5-substituted [1,2,4]triazolo[1,5-c]pyrimidines was designed in order to complete the structure-activity relationship analysis. Several of these new compounds showed affinity towards human A3 adenosine receptor in the low nanomolar range, with the most potent derivative of the series bringing a 4-ethylbenzylester at the 8 position (compound 18, hA3AR Ki = 1.21 nM). Docking studies performed on the synthesized compounds inside models of human A1, A2A and A3 adenosine receptors showed similar binding modes, comparable with the typical crystallographic binding mode of the inverse agonist ZM-241,385.

With test systems CellTiter-Glo was determined the cytotoxicity of series N7-aryl/benzyl-3-tioxo-2,3-dihydro-7Н-[1,2,4]triazolo-[4,3-а]pyrazin-8-ones, their 3-S- acetamides and 3-S-benzyl derivatives. The synthesis of the compounds performed based on the previously developed and published scheme. Structure and purity of the compounds proved with 1H-NMR and element analysis.Methods. The method is based on determining the number of viable cells in culture by intensity of luminescence mixture of cell suspension of prostate cancer Du145, solution of the substance and CellTiter-Glo reagent. Tubercidin and taxol were used as reference drugs. The parameter СK50, that has been set according to a study, describes the ability of analyzed substances induce cell death.Results. Cytotoxic concentration of synthesized 3-substituted N7-aryl/benzyl-2,3-dihydro-7Н-[1,2,4]triazolo-[4,3-а]pyrazine-8-ones not exceed the maximum concentration of compounds, which were tested, and was above 30 mkM. This demonstrates the complete absence of negative impact of these substances on cells of prostate cancer Du145.Conclusions. Found that these compounds do not exhibit toxic effects on living cells, making the actual possibility of developing new effective and safe drugs on their base. Also inappropriate to search anticancer drugs among of the N7-aryl/benzyl-2,3-dihydro-7Н-[1,2,4]triazolo-[4,3-а]pyrazine-8-one derivatives

Adenosine was defined as a neuromodulator which exerts its action by interaction with specific G-protein coupled receptor termed adenosine receptors. Adenosine receptors are expressed in several tissues and cells of our body and exist as four different subtypes of these receptors: A 1 , A 2A , A 2B and A 3 . In the last years significant efforts were made to obtain highly potent and selective ligands for the four adenosine receptors subtypes. Both agonists and antagonists were used as pharmacological tools to study therapeutic implications of enhancing or blocking the adenosine receptors activity, and some of these compounds have reached clinical phases. The pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines (PTPs) represent one of the several templates designed as adenosine receptor antagonists. A lot of synthetic work was made on this scaffold in order to obtain potent A 2A and A 3 antagonists. Here were reviewed the synthetic approaches followed by both academia and industry to introduce different substituents at different positions of the PTP nucleus, in particular at the 2, 5, 7, 8 and 9 positions. Nevertheless PTP derivatives are tricyclic compounds with a high molecular weight which exhibit limitations such as poor aqueous solubility and difficult synthetic preparation. With the aim to obtain derivatives with the same potency and selectivity of PTP but with better drug-like properties, researchers made structural simplification of this scaffold. Replacement of the pyrazole or triazole rings of PTP led to the [1,2,4]triazolo[1,5-c]pyrimidine and pyrazolo[3,4- d]pyrimidine derivatives, respectively. Synthetic strategies for these compounds were reported, combined with the SAR profile on the adenosine receptors.

Triazole derivatives constitute an important group of heterocyclic compounds have have been the subject of extensive study in the recent past. These compounds have shown a wide range of biological and pharmacological activities. In this work, new fused tricyclic 1-(3-nitrophenyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]-benzodiazepines have been synthesized by the thermal cyclization of N'-(2,3-dihydro-1H-1,5-benzodiazepin-4-yl)-3- nitrobenzohydrazides. After screening ethanol, toluene and 1-butanol as solvents, butanol-1 was found to be the best choice for the cyclization reaction in order to obtain the highest yields of tricyclic derivatives. The chemical structures of the synthesized compounds were elucidated by the analysis of their IR, 1H- and 13C-NMR spectral data. For tentative rationalization of the reaction processes, the global and local reactivity indices of certain compounds, taking part in the reaction pathway, were assessed by means of quantum mechanical calculations using the conceptual density functional theory (DFT) approach. This work could be useful for the synthesis of new heterocyclic compounds bearing a fused triazole ring.

A variety of novel [1,2,4]triazolo[1,5-c]pyrimidine-13-ones (4a-f) and (5b-d) could be obtained via reaction of 9-amino-7-(4’-chlorophenyl)-8,9-dihydro-8-imino-6H,7H-[1]benzopyrano[3`,4`:5,6]pyrano[2,3-d]pyrimidine-6-one (3) with a variety of reagents. Pyrano[2,3-d]pyrimidine-6-ones 5a, 8a-c and pyrimido[1,6-b][1,2,4]-triazine-3,14-dione (6) were also prepared. The antimicrobial activity of some of the synthesized compounds was tested.

In the last 20 years intense medicinal chemical efforts led to the synthesis of a variety of adenosine receptor (AR) agonists and antagonists for the pharmacological characterization of this family of G protein-coupled receptors.1 Several classes of heterocyclic derivatives have been reported as AR antagonists with high levels of both affinity and selectivity. Recently, the synthesis of more simplified heterocyclic derivatives has been strongly investigated in order to obtain derivatives with a better pharmacokinetic profile. In particular bicyclic systems such as adenine, triazolo-pyrazine, triazolo-pyrimidines and triazolo-triazine could be considered some of the most promising targets.2 One of the most appealing bicyclic core is the triazolo-triazine nucleus, which led in the past to the discovery of potent and selective A2A AR antagonists, such as ZM241385.3 In the past, our group performed a study on this nucleus trying to optimize substitution at the C5 and N7 positions with the aim of improving affinity and selectivity versus the hA2BAR and hA3AR subtypes. In particular, inclusion at the N7 position of arylcarbamoyl (for A3) or arylacetyl (for A2B) moieties, which gave good results in the pyrazolotriazolopyrimidine family, has been investigated.4 Unfortunately, none of these substitutions led to the desired selectivity. Regarding the A3 subtype, lack of affinity was probably observed because only lipophilic moieties were present at the 5 position (phenoxy, dimethylamino, thiomethyl) avoiding the formation of hydrogen bonds with residues inside the binding pocket of the A3 adenosine receptor. Our aim, in this work, was to synthesise new [1,2,4]triazolo[1,5-a][1,3,5]triazines introducing substituents at the 5 position able to form hydrogen bonds, such as monosubstituted amines, in order to verify if it is capable of enhance affinity and selectivity towards the A3 AR. The analogues were docked in a homology model of the hA3 AR, and the per residue electrostatic and hydrophobic contributions to the binding were assessed and stabilizing factors were proposed in order to support the experimental binding data.References (1) Moro, S, et al. Med. Res. Rev. 2006, 26, 131-159. (2) Muller, C, et al. Biochim. Biophys. Acta 2010, 1808, 1290-1308. (3) Poucher, SM, et al. Br. J. Pharmacol. 1995, 115, 1096–1102. (4) Pastorin, G, et al. Bioorg. Med. Chem. 2010, 18, 2524-2536.

[1,2,4]Triazolo[1,5-c]pyrimidine derivatives are reported in literature as A2A adenosine receptor (AR) antagonists useful for the treatment of Parkinson’s disease (PD), senile dementia and depression (1).1 We decided to explore the [1,2,4]triazolo[1,5-c]pyrimidine scaffold in order to obtain antagonists selective towards hA3 AR. Inactivation of the A3 AR is being studied in glaucoma but also in inflammatory diseases such as asthma.2 In a previous work, we have found that, in order to obtain good hA3 AR antagonists, the better substitutions at the 5 and 8 positions are a little alkylamino (methyl or ethylamino) and an ethylester moieties, respectively. Here we report a novel series of [1,2,4]triazolo[1,5-c]pyrimidines where we have introduced different alkyl, cycloalkyl, aryl and heteroaryl moieties at the 2 position (2). Surprisingly, the introduction of substituted-phenyl rings led to subnanomolar affinities at the hA3 AR. The best compound of this series is represented by the ethyl 2-(4-methoxyphenyl)-5-(methylamino)-[1,2,4]triazolo[1,5-c]pyrimidine-8-carboxylate (3) which shows a Ki of 0.47 nM towards hA3 AR and a 4200- and 8400-fold selectivity over hA1 and hA2A ARs, respectively.1. Shimada, J.; Imma, H.; Osakada, N.; Shiozaki, S.; Kanda, T.; Kuwana, Y. [1,2,4]Triazolo[1,5-c]pyrimidine derivatives. 2003, US6545000. 2. Cheong, S.L; Federico, S.; Venkatesan, G.; Mandel, A.L.; Shao, Y.M.; Moro, S.; Spalluto, G.; Pastorin, G. The A3 adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry and in silico approaches. Med. Res. Rev. 2013, 33, 235-335.

A series of 40 derivatives of the [1,2]oxazolo[5,4-e]indazoles ring system have been prepared with good yields using a versatile and convenient route. Annelation of the [1,2]oxazole ring on the indazole-4-one system was achieved by reaction of the corresponding enaminoketones with hydroxylamine hydrochloride. Derivatives of the title ring system were tested by the National Cancer Institute of Bethesda and one of them (13t) showed growth-inhibitor activity against all the 54 human tumour cell lines generally at low micromolar concentrations.

Tez (Yüksek Lisans) -- İstanbul Teknik Üniversitesi, Fen Bilimleri Enstitüsü, 2013, Thesis (M.Sc.) -- İstanbul Technical University, Institute of Science and Technology, 2013, Anaç ve ekibinin yaptıkları çalışmalarda, α, β-doymamış karbonil bileşikleri ile diazo bileşiklerinin katalitik ortamdaki reaksiyonlarını incelemiştir. Bu reaksiyonlarda sıklıkla dihidrofuran türevlerine rastlanmıştır. Bu ürün oluşumu [1,5]- elektrosiklik halka kapanması reaksiyonu üzerinden gerçekleşmektedir. Bu reaksiyonların gerçekleşebilmesi için α, β-doymamış karbonil bileşiklerinin, β-pozisyonlarında, uygun geometriye sahip bir hidrojen taşımaları ve ayrıca bu bileşiklerin, s-cis konformasyonunda olmaları gerektiği sonucuna varılmıştır. Konjugasyonun daha da uzatıldığı çıkış bileşiklerinin analog reaksiyonlarında [1,5]- elektrosiklik halka kapanması reaksiyonunun yanısıra [1,7]- elektrosiklik halka kapanması reaksiyonunun da oluştuğu gözlenmiştir. Ekibin önceki çalışmalarına paralel olarak bu tez çalışmasında, α, β,γ,δ-doymamış diketon, diester ve keto-esterler bileşiklerinin bakır(II) asetilasetonat veya Rh(II) asetat katalizörleri varlığında, çeşitli diazo bileşikleriyle reaksiyonları incelenmiştir. Bu amaç doğrultusunda öncelikle, sadece karbonil gruplarında farklılık gösteren ve δ-konumunda furan grubu içeren üç adet farklı α, β,γ,δ-doymamıs dikarbonil bilesiği sentezlenmistir. Bu bileşikler: (E)-dimetil 2-(3-(furan-2-il)alliliden)malonat, (E)-3-(3-(furan-2-il)alliliden)pentan-2,4-dion ve (2E/Z,4E)-etil 2-asetil-5-(furan-2-il)penta-2,4-dienoat’dır. Daha sonra, sentezlenen bu bileşiklerin çeşitli diazo bileşikleri ile katalitik ortamdaki reaksiyonları incelenmiştir. İlk olarak: sentezlenmiş analog yapılardaki üç adet konjuge karbonil bileşiğinin ayrı ayrı dimetil diazomalonat (akseptör-akseptör özellikli karbenoid verir) ile bakır(II) asetilasetonat katalizörlüğünde reaksiyonları gerçekleştirilmiştir. (E)-Dimetil 2-(3-(furan-2-il)alliliden)malonat ile gerçekleştirilen reaksiyonda -ekibin daha önceki çalışmalarından farklı olarak- furan üzerinde oluşan siklopropanın halka açılma ürünü olan (3E/Z,6E)-tetrametil 5-oksonon-1,3,6,8-tetraen-1,1,9,9-tetrakarboksilat bileşiği elde edilmiştir. Reaksiyon Rh(II) asetat katalizörü ile tekrarlandığında yine aynı ürünün oluştuğu görülmüştür. (E)-3-(3-(furan-2-il)alliliden)pentan-2,4-dion bileşiğinin dimetil diazomalonat ile bakır(II) asetilasetonat katalizörlüğünde reaksiyonu incelendiğinde ise karbonil ilid üzerinden [1,5]-elektrosiklik halka kapanma ürünü ((E)-dimetil 4-asetil-3-(2-(furan-2-il)vinil)-5-metilfuran-2,2(3H)-dikarboksilat) tek ürün olarak elde edilmiştir. Dimetil diazomalonatın (2E/Z,4E)-etil 2-asetil-5-(furan-2-il)penta-2,4-dienoat bileşiği ile analog reaksiyonunda karbonil ilid üzerinden [1,7]-elektrosiklik halka kapanma ürünü olan 6-etil 2,2-dimetil 3-(furan-2-il)-7-metiloksepin-2,2,6(3H)-trikarboksilatın tek ürün olduğu görülmüştür. (E)-Dimetil 2-(3-(furan-2-il)alliliden)malonat bileşiğinin dimetil diazomalonat ile [1,5]/[1,7]-elektrosiklik halka kapanma reaksiyonlarını vermeyip sadece poli-fonksiyonlu polien vermesi dikkat çekicidir. Bu nedenle araştırmanın yönü bu diesterli konjuge çıkış bileşiğinin dimetil diazomalonattan (akseptör-akseptör özellikli karbeboid verir) daha farklı karakterlerdeki diazo bileşikleriyle olan reaksiyonlarına yönlendirilmiştir. Bu amaçla etil diazoasetat (akseptör), 1-diazo-1-fenilpropan-2-on (donör-akseptör), (E)-metil 2-diazo-4-fenilbut-3-enoat (donör-akseptör) ile reaksiyonlar gerçekleştirilmiştir. Etil diazoasetat ile Rh(II) asetat katalizörleri varlığında gerçekleştirilen reaksiyonda da sadece furan üzerinde oluşan siklopropanın halka açılmasıyla oluşan (3E,6E,8E)-9-etil 1,1-dimetil 5-oksonon-1,3,6,8-tetraen-1,1,9-trikarboksilat ele geçmektedir. Aynı reaksiyon bakır(II) asetilasetonat katalizörlüğünde gerçekleştirildiğinde de aynı ürünün oluştuğu görülmüştür. Donör-akseptör özellikli 1-diazo-1-fenilpropan-2-on ile Rh(II) asetat katalizörleri varlığında gerçekleştirilen reaksiyonda karbonil ilidin [1,5]-elektrosiklik halka kapanma ürünü olan (E)-metil 5-asetil-4-(2-(furan-2-il)vinil)-2-metoksi-5-fenil-4,5-dihidrofuran-3-karboksilat bileşiği elde edilmiştir. Diğer bir donör-akseptör özellikli (E)-metil 2-diazo-4-fenilbut-3-enoat bileşiği ile Rh(II) asetat katalizörlüğündeki reaksiyonda ise çıkış bileşiği ile reaksiyon gözlenmemiştir. Bunun yerine diazo bileşiğinin kendi içinde halkalaştığı tespit edilmiştir., Metal carbenoids are readily generated by metal-catalyzed decomposition of diazoacetates and occupy an established position as versatile synthetic intermediates in organic chemistry. In comparison to free carbenes, metal carbenoids are endowed with increased stability, and are capable of highly selective reactions. They are highly electrophilic but their reactivity profile is very dependent on the structure of the carbenoid and the metal. Most of the early literature on metal-catalyzed carbenoid reactions used copper complexes as the catalysts and ethyl diazoacetate as the carbenoid source. In recent years dirhodium tetracarboxylates have become the catalysts of choice and a much wider range of carbenoid precursors has been developed. Anaç and co-workers have investigated reactions of α, β-unsaturated carbonyl compounds and diazo carbonyl compounds in catalytic medium. In these reactions, dihydrofuran derivatives have been obtained. This product formation is occurred by [1,5]-electrocyclic ring closing reactions. For these reactions are to occur, it is reported that the α, β-unsaturated carbonyl compounds must have hydrogen atom at their β-position with suitable geometry and also, they should favor s-cis conformation. In their continuing report, Anaç’s group determined that sytryldicarbonyls having at least one keto function yielded also dihydrobenzoxepine derivatives by a 1,7-electrocyclization reaction in larger/equal amounts with respect to dihydrofuran derivatives by a 1,5-electrocylization. In this study, benzylidene acetylacetone was treated with dimethyl diazomalonate in the presence of Cu(acac)2 to yield the dihydrofuran and dihydrobenzoxepine in a 1:1.5 ratio. Z- and E-ethyl acetobenzylidene acetates were also reacted under the same conditions to compare the reactivities of conjugated ketone- and ester-ylides in order to obtain formal 1,7-/1,5- electrocyclization reactions in the same studies. In both attempts, the dihydrofuran from ester-ylide and dihydrobenzoxepine from keto-ylide were obtained approximately in the same ratios. They reported that the initially formed keto-/ester-ylides are highly polarized and do not need to undergo 1,5-/1,7-electrocyclization reactions directly, but may rather undergo a rotation around their C( α)-C( β) bonds in order to yield their regiospecific ring closures. According to this study, the ester-ylides did not prefer the formation of dihydrobenzoxepines, whereas the keto-ylides. The reaction of furans with acceptor substituted carbenoids usually leads to unravelling of the heterocycle, resulting in differentially functionalized dienes in good yield. Werker and co-workers determined that Rh2(OAc)4-catalyzed reaction between ethyl diazoacetate with furan revealed the formation of four products including cyclopropane, two isomeric dienes as well as alkylation product. Additionally, cyclopropane is unstable and rearranges to diene upon prolonged standing. The formation of dienes can be proposed from several intermediates. One possibility is that a zwitterionic intermediate forms by electrophilic addition of the carbenoid to the furan ring at the 2-position. In another report, Pirrung’s group demonstrated that furan reacts with 2-diazo-1,3-cyclohexanedione (acceptor–acceptor carbenoid) to generate tricycle in good yield. For this structure would need to be derived from a zwitterionic intermediate derived from attack of the carbenoid at the 3-position, which is electronically unfavored. Pirrung suggested that the regiochemistry is due to the stereoelectronics involved in ringopening of the furanocyclopropane. This reaction has been extended to a range of furan derivatives with variable success. Another report is about reaction of furans with donor–acceptor carbenoids. Davies and co-workers determined that the Rh2(S-DOSP)4-catalyzed reaction of aryldiazoacetates with furan gave predominantly biscyclopropane when aryldiazoacetates was used in a three-fold excess. Most interestingly, when the reaction is conducted with 2,5-dimethylfuran biscyclopropane is formed, which has the opposite sense of absolute configuration to biscyclopropane which mention previous sentence. According to Davies report the donor groups in the donor–acceptor substituted carbenoids seem to make these carbenoids less prone to the formation of zwitterionic intermediates compared to the acceptor carbenoids. However, if electron-donating groups are incorporated into the furan, then zwitterionic transformations can become the dominant reaction pathway. This is clearly seen in the reaction with 2-methoxyfuran with aryldiazoacetate where the dienes become the exclusive products. This is an important consideration, as metal carbenoids that are very electrophilic will tend to react via zwitterionic intermediates while the donor–acceptor carbenoids, and to a lesser extent the acceptor carbenoids, will tend to react in a concerted manner. Very electron-rich heterocycles would also be expected to favor the formation of zwitterionic intermediates. In this thesis, we studied the reactions of three α, β,γ,δ-unsaturated diketone, diester and ketone-ester compounds and four diazo compounds in the presence of copper(II) acethylacetonate [Cu(acac)2] or Rh(II) acetate catalysts. The starting three α, β,γ,δ-unsaturated dicarbonyl compounds, containing the same furan group at their β-positions but having different carbonyl functions were synthesized. These compounds are (E)-dimethyl 2-(3-(furan-2 il)allylidene) malonate, (E)-3-(3-(furan-2-yl)allylidene)pentane-2,4-dione and (2E/Z,4E)-ethyl 2-acetyl-5-(furan-2-yl)penta-2,4-dienoate. Then the reactions of these synthesized three conjugated carbonyls with dimethyl diazomalonate in the presence of copper(II) acetylacetonate/benzene were studied. The reaction of (E)-3-(3-(furan-2-yl)allylidene)pentane-2,4-dione yielded [1,5]-electrocyclic ring closing compound ((E)-dimethyl-acetyl-3-(2-(furan-2-yl)vinyl)-5-methylfuran-2,2(3H)-dicarboxylate) as a sole product. When similar reaction was carried out with (2E/Z,4E)-etyl 2-acetile-5-(furan-2-yl)penta-2,4-dienoate compound, [1,7]-electrocyclic ring closing compound (6-ethyl 2,2-dimethyl 3-(furan-2-yl)-7-methyloxepine-2,2,6(3H)-tricarboxilate) was obtained as a sole product. But in the reaction of (E)-dimethyl 2-(3-(furan-2-yl)allylidene)malonate with dimethyl diazomalonate a ring-opening product of furan function ((3E/Z,6E)-tetramethyl 5-oksonone-1,3,6,8-tetraene-1,1,9,9-tetracarboxilate) was obtained as a sole product. When the reaction was repeated in the presence of Rh(II) acetate, the same product was obtained. In this case, our attention was directed to the the reaction of (E)-dimethyl 2-(3-(furan-2-yl)allylidene)malonate that didn’t yield [1,5]/[1,7]-electrocyclic closure products. So, dimethyl diazomalonate (acceptor-acceptor carbenoid) reactant was altered with ethyl diazoacetate (acceptor), 1-diazo-1-phenylpropane-2-one (donor-acceptor) and (E)-methyl 2-diazo-4-phenylbut-3-enoate) (donor-acceptor). The reaction of (E)-dimethyl 2-(3-(furan-2-yl)allylidene)malonate with ethyl diazoacetate, in the presence of Rh(II) acetate were performed and a ring-opening product ((3E,6E,8E)-9-ethyl 1,1-dimethyl 5-oxonone-1,3,6,8-tetraene-1,1,9-tricarboxilate) was obtained again as a sole product. The same result was endorsed in the presence of copper(II) acetylacetonate catalyst. But in the reactions of the two donor-acceptor diazo compounds (1-diazo-1-phenylpropane-2-one and (E)-methyl 2-diazo-4-phenylbut-3-enoate) poliene derivatives couldn’t be obtained. While the reaction of 1-diazo-1-phenylpropane-2-one in the presence of Rh(II) acetate yielded [1,5]-electrocyclic ring closing compound ((E)-Methyl 5-acetyl-4-(2-(furan-2-yl)vinyl)-2-methoxy-5-phenyl-4,5-dihydrofuran-3-carboxylate, (E)-methyl 2-diazo-4-phenylbut-3-enoate didn’t yield any reaction with other reactant., Yüksek Lisans, M.Sc.

Brand new ring: A series of 27 derivatives of the new ring system [1,2]oxazolo[4,5-g]indole were conveniently prepared and tested at the NCI for antiproliferative studies. Several of them showed good inhibitory activity toward all tested cell lines, reaching GI50 values generally at the micromolar and sub-micromolar levels and in some cases at nanomolar concentrations. The mean GI50 values, calculated on the full panel, were in the range 0.25-7.08 μM.

[1,2,4]Triazolo[1,5-c]pyrimidine derivatives are reported in literature as A2A adenosine receptor (AR) antagonists useful for the treatment of Parkinson’s disease (PD), senile dementia and depression (1).[1] Several classes of heterocyclic derivatives have been reported as AR antagonists.[2] Among them, the Schering compound, preladenant (2), a pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (PTP) A2A antagonist (which is under phase III clinical trials for the treatment of PD), possesses the same lateral subtituent of compound 1.[2,3] In the [1,2,4]triazolo[1,5-c]pyrimidine compound (1) the pyrazole moiety of preladenant was substituted by a phenyl spacer, leading to a compound which displays the same affinity at the A2A AR. The [1,2,4]-triazolo[1,5-c]pyrimidine nucleus possesses a simpler structure and less nitrogen atoms than PTPs, thus it may be a scaffold with promising pharmacokinetics properties. So, starting from the similar behavior of [1,2,4]triazolo[1,5-c]pyrimidines and PTPs on ARs, and our experience on PTP as A3 AR antagonists, we decided to explore the [1,2,4]triazolo[1,5-c]pyrimidine scaffold as antagonists towards A3 AR. Initially, we introduced on the bicyclic scaffold the same substituents those give affinity and selectivity at the A3 AR in the PTP nucleus. On the basis of obtained results, the optimization of substitutions allow us, after 4 series (147compounds) of [1,2,4]triazolo[1,5-c]pyrimidine derivatives, to discover a potent and selective A3 AR antagonist, with a Ki of 0.47 nM. [1] Kyowa Hakko Kogyo Cp., Ltd., Tokyo (JP). Shimada, J.; Imma, H.; Osakada, N.; Shiozaki, S.; Kanda, T.; Kuwana, Y. [1,2,4]Triazolo[1,5-c]pyrimidine derivatives. 2003, US6545000. [2] Muller, C.E.; Jacobson, K.A. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim. Biophys. Acta. 2011, 1808, 1290–1308. [3] Neustadt, B.R.; Hao, J., Lindo, N.; Greenlee, W.J.; Stamford, A.W.; Tulshian, D.; Ongini, E.; Hunter, J.; Monopoli, A.; Bertorelli, R.; Foster, C.; Arik, L.; Lachowicz, J.; Nga, K.; Feng, K.I. Potent, selective, and orally active adenosine A2A receptor antagonists: arylpiperazine derivatives of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines. Bioorg. Med. Chem. Lett. 2007, 17, 1376–1380.

Adenosine receptors (ARs) are members of the superfamily of G protein-coupled receptors (GPCRs). There are four subtypes currently recognized: the A1AR, A2AAR, A2BAR and A3AR. The classical AR antagonist caffeine is the most consumed drug in the world. Its effects on the nervous system, such as enhancement of awareness and learning, have encouraged the investigation of selective AR antagonists for the treatment of various nervous system conditions. (1) Several classes of heterocyclic derivatives have been reported as AR antagonists with high levels of both affinity and selectivity. (2) The [1,2,4]-triazolo[1,5-c]pyrimidine nucleus possesses a low molecular weight and four nitrogen atoms, thus it may be a scaffold with promising pharmacokinetics properties. We have investigated substitutions at the 2, 5 and 8 positions, with the aim of obtaining potent antagonists selective only for one of the four adenosine receptor subtypes. A receptor-driven molecular modeling investigation has been carried out in order to support the experimental binding data and to justify the selectivity against the other receptor subtypes. (1) Moro, S.; Gao, Z.G.; Jacobson, K.A.; Spalluto, G. Med. Res. Rev. 2006, 26, 131-159. (2) Muller, C.E.; Jacobson, K.A. Biochim. Biophys. Acta. 2011, 1808, 1290–1308

The series new fused tricyclic [1,2,4]triazolo[4,3-a][1,5]benzodiazepines have been synthesized by condensation-cyclization reaction of 1,5-benzodiazepine hydrazine derivatives as starting materials and triethyl orthoformate or triethyl orthoacetate. After screening various solvents like ethanol, isopropanol, xylene, we have found that xylene was the best choice for this reaction, because the reaction proceeds well in high boiling solvent. The 1,5-benzodiazepine hydrazines with electron-releasing methyl group gave a products in a poorer yield after a longer period of time, whereas compounds with electron-withdrawing group afforded a better yield of corresponding triazoles. The structure of the cycloadducts has been assigned by means of IR, 1H and 13C NMR spectroscopic measurements.

U ovom diplomskom radu metodom difrakcije rentgenskih zraka na monokristalu određena je molekulska i kristalna struktura dinuklearnog oksovanadijevog(V) metokso-kompleksa s premosno vezanim molekulama derivata [1, 3, 4]tiadiazola. Intenziteti refleksa prikupljeni su pomoću automatskog detektora Oxford Diffraction Xcalibur 3 pri temperaturi od 110 K. Struktura je riješena direktnim metodama i utočnjena metodom najmanjih kvadrata do faktora nepouzdanosti R = 0, 0322. Istraživani kompleks kokristalizira s molekulama metanola u triklinskom sustavu u prostornoj grupi P-1 s parametrima jedinične ćelije: a = 11, 865(2)Å , b = 11, 951(2) Å , c = 14, 332(2)Å , α = 103, 07(2)°, β = 96, 86(2)°, γ = 119, 57(2)°. Dva vanadijeva atoma u molekuli kompleksa premoštena su okso skupinom i dvama [1, 3, 4]tiazolnim ligandima. Molekule kompleksa u kristalu slažu se tvoreći šupljine u koje se smještaju neuređene molekule metanola.

A series of novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives has been designed and synthesized in order to find novel anti-tumor compounds. The structures of all the compounds were confirmed by IR, 1H-NMR, MS and elemental analysis. Their anti-tumor activities against cancer cell lines (HT-1080 and Bel-7402) were tested by the MTT method in vitro. Among them, compound 19 displayed the best anti-tumor activity with IC50 values of 12.3 microM and 6.1 microM against Bel-7402 and HT-1080 cell lines respectively.

[1] (200 mg, 0.41 mmol) was refluxed in dimethylsulfoxide for 30 minutes. After cooling, the solvent was removed byevaporation under reduced pressure. The residue obtained was purified by chromatography on silica gel column (eluent: hexane/ethylacetate 90/10), then the isolated product was recrystallized from ethanol to give

The dioxepine part of the title heterocycle adopts a chair conformation. The position of O1 opposite to the lone pair at the N atom and the inequality of the bond angles O1-S1-N1>>O2-S1-N1 suggest an n-s* interaction of the lone-electron pair with the SVI[O, O', N, C]tetrahedral moiety.

Several derivatives of 4,5-disubstituted imidazole, 2,4,5-trisubstituted pyrimidine, 2-substituted purine, thiazolo[3,2-alpha]purine, [1,3]thiazino[3,2-alpha]purine, thiazolo[2,3-i]purine, [1,3]thiazino-[2,3-i]purine, and 6-substituted pyrazolo[3,4-d]pyrimidine were synthesized and tested as inhibitors of the xanthine oxidase enzyme. Of those, some 4-(acylamino)-5-carbamoylimidazoles and 2-thioalkyl-substituted purines exhibited very good inhibitory activity, being at least 500 times more effective than allopurinol. The ineffectiveness of 6-n-alkylpyrazolo[3,4-d]pyrimidines is imputable to the alkyl chain which could hinder the coordination with molybdenum according to the known mechanism for the binding of the inhibitor allopurinol; the effectiveness of imidazole derivatives, by contrast with the ineffectiveness of 4,5-diamino-2-(thioalkyl)-6-hydroxypyrimidines, indicates the relative importance of the five-membered ring in the interaction with the enzyme. Moreover, the marked effectiveness of the angularly-cyclized [1,3]thiazino[2,3-i]purinones, which constitute an interesting new class of inhibitors, together with the weak activity of linearly-cyclized derivatives, allowed us to characterize more precisely the lipophilic region of the enzyme facing the N(1)-C(2) positions of the substrate hypoxanthine.

A series of 1-sulfonyl-1a, 2, 6, 6a-tetrahydro-1H, 4H-[1, 3]-dioxepino[5, 6-b]azirines, has been synthesized and evaluated for its effects on blood glucose-decreasing activity. These derivates were prepared from 4, 7-dihydro-1, 3-dioxepins via vic(acylamino)halogenodioxepanes and dioxepanoazirines. Quantitative structure-property relationship and quantitative structure-activity relationship models, based on X-ray and molecular mechanic analyses, to our knowledge the first in the fieldof antihyperglycemics, were developed. They allow the prediction of properties (RP-HPLC attention times) and activities (hypoglycemic ratio) by the Connollys molecular surface areas. The lead compound in these models, sulfonyldioxepinoazirine 4i, expressed superior antihypergglycemic activity in comparison to metformin in alloxanized mice, irrespective of rout of application. It sgnificantly reduced blood glucose levels in glucose-primed mice, but did not cause a dose dependent decrease of blood glucose level in healty (nondiabetic, control) animals.

The synthesis of the ethinylaminophosphanes 1-5 from substituted alkinylmagnesium bromides and halogenoaminophosphanes is described. Reaction of 1 with various derivatives of urea yields the [1,3,4]thiazaphospholidines 6, 7, 11-13. 2 reacts with thiouracil to give compound 15, with 2-mercaptobenzimidazole to give compound 16 and 3 reacts with 2-mercaptobenzimidazole to give compound 17. The new [1,3,4]thiazaphospholidines can be transferred into the corresponding sulfides by heating with elemental sulfur or into their oxides by treatment with t-butyl-hydroperoxide. The spirocyclic compound 31 is the product from the reaction of 13 with o-chloranil. All new ethinylaminophosphanes, [1,3,4]thiazaphospholidines and their sulfides and oxides are characterized by nmr, mass and ir spectra. X-ray structure analyses of 15, 21 and 26 were performed.

Both dioxepine rings of the title compound, 1, 5-dihydro-3-(4, 7-dihydro-1, 3-dioxepin-2-yl)-9-hydroxy-8-methyl-3H-[1, 3]-dioxepino[5, 6-c]pyridinium maleate, adopt a twist-boat conformation. In the crystal structure the maleate anions are stacked exactly between the pyridine rings of the cations at an average distance of 3.5 A.

The alkali metal salts of 1,5-hexadien-3-ols undergo accelerated Cope rearrangements to the enolates of δ, ε-unsaturated carbonyl compounds. The generality of the rearrangement was investigated in numerous systems, particularly acyclic cases, and the effect of changes in substituents, counterions, solvents, and geometrical structures were noted and discussed. Applications of this methodology in synthesis included the synthesis of the insect pheromone frontalin, the preparation of selectively monoprotected 1,6-dicarbonyl compounds from 4-methoxy- and 4-phenylthio-1,5-hexadien-3-ols, and the construction of complex ring structures such as a D-homo-estratetraenone derivative. Thermochemical estimates of the energetics of anionpromoted alkoxide fragmentations were made, and in all cases heterolytic cleavage was favored over hemolytic cleavage by 8.5-53 kcal/mol. The implication of these and other thermochemical estimates is that the anionic oxy-Cope rearrangement occurs via a concerted mechanism rather than a dissociation-recombination process. The concepts of anion-induced bond weakening were successfully applied to an accelerated [1,3]-shift of a dithiane fragment in a cyclohexenyl system. Trapping experiments demonstrated that > 85% of the [1,3]-shift occurred within a solvent cage. Attempts at promoting an intramolecular ene reaction using the potassium salts of 2,7-octadien-1-o1 and 2,8-nonadien-1-o1 were unsuccessful. A general review of anion-promoted bond reorganizations and anion substituent effects is also presented.

Cerebral function is associated with high metabolic activity that is supported by continuous supply of oxygen and glucose from the blood. Coupling between brain energy metabolism and neuronal activity has been studied extensively during the past decades. Notably, glucose metabolism was demonstrated to result from cellular cooperation between neurons and astrocytes. Although both cell types regulate synaptic transmission via the glutamate-glutamine cycle, the actual contribution of glial and neuronal oxidative metabolism is still unclear. Several research groups have tried to quantify cerebral energy metabolism in the living brain using methods, such as positron emission tomography, autoradiography and proton magnetic resonance spectroscopy (1H MRS). Yet, these methods lack chemical specificity and do not provide quantitative information specific to either cell types. The development of tracers detectable by MRS, such as 13C isotope, along with high magnetic field and dedicated hardware systems has improved sensitivity and has motivated the design of advanced metabolic modeling, in which cell types can be compartmentalized and which associated metabolic rates can be assessed independently of any prior estimations. The work of this thesis aimed at focally increasing neuronal activity and estimating the resulting changes in glial and neuronal oxidative metabolism using direct 13C MRS along with [1,6-13C]glucose infusion in vivo at 14.1 T. 4h-somatosensory stimulation paradigm was first developed in rats under alpha-chloralose. The protocol consisted on intermittently electrically stimulating both fore- and hindpaws, which resulted in a sustained and localized blood oxygenation level-dependent signal as assessed by functional magnetic resonance imaging. The relatively large activated area in the cortex allowed monitoring local 13C isotope incorporation over 4h into specific positions of glutamate, glutamine and aspartate. The analysis of the turnover curves with a two-compartment model of brain energy metabolism revealed an increase of both glial (VTCAg,+68 nmol/g/min,+22%) and neuronal (VTCAn,+62 nmol/g/min,+12%) oxidative metabolism associated with 95% increase (VNT,+67 nmol/g/min) in glutamate-glutamine cycle rate, which represents glutamatergic neurotransmission rate. The total increase in glucose oxidative metabolism was of 15% (CMRglc(ox), +67 nmol/g/min). In randomly delivering lines in 4 orientations and 2 directions, 4h-continuous stimulation of tree shrew primary visual cortex under light isoflurane anesthesia resulted in a decrease in both brain glucose concentration (-17%;-0.34 µmol/g) and phosphocreatine/creatine ratio (-9%;-0.07) after 16 minutes of stimulation onset, which recovered 21 minutes after stimulation offset. At the individual level, a nearly one-to-one relationships between VNT and CMRglc(ox) was observed. VTCAn and VTCAg were also coupled to VNT. At the group level, 20% increase in VNT (+0.038±0.042 µmol/g/min) resulted in 24% (+0.063±0.057 µmol/g/min) and 12% (+0.061±0.032 µmol/g/min) increase in VTCAg and VTCAn, respectively, resulting in 14% increase in CMRglc(ox) (+0.058±0.032 µmol/g/min). To conclude, this work demonstrates that a significant fraction of glucose is also oxidized in astrocytes and that both neuronal and astrocytic metabolism can be stimulated by and coupled to the glutamate-glutamine cycle rate.

Question:[1,2,4]Triazolo[1,5-c]pyrimidine (TP) derivatives are reported in literature as A2A adenosine receptor (AR) antagonists useful for the treatment of Parkinson’s disease, senile dementia and depression (1).1 The Schering compound, preladenant (2), a pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (PTP) A2A antagonist, possesses a lateral substituent similar to those of the TP compound 1.2,3 Although these two compounds are both potent A2A antagonist, the TP nucleus possesses a simpler structure and less nitrogen atoms than PTPs, thus it may be a scaffold with promising pharmacokinetics properties. So, starting from the structural similarity between TP and PTP A2A AR antagonists, and our experience on PTP nucleus as A3 AR antagonists, we decided to explore the TP scaffold in order to obtain potent antagonists towards A3 AR. Methods: All compounds were synthesized according to literature1 and have been evaluated for potency at all four human ARs. Results: Initially, we introduced at the 5 position of the TP scaffold the same substituents which gave affinity and selectivity at the A3 AR at the 5 position in the PTP nucleus. On the basis of obtained results, the optimization of substitutions at the 5, 8 and 2 positions, which led to 147 [1,2,4]triazolo[1,5-c]pyrimidine derivatives, allowed us to reach subnanomolar Ki values at the A3 AR and good levels of selectivity versus the other adenosine receptor subtypes. Conclusions: A novel promising class of potent and selective A3 adenosine receptor antagonist with a [1,2,4]triazolo[1,5-c]pyrimidine nucleus was discovered. References: [1] Kyowa Hakko Kogyo Cp., Ltd., Tokyo (JP). Shimada, J.; Imma, H.; Osakada, N.; Shiozaki, S.; Kanda, T.; Kuwana, Y. [1,2,4]Triazolo[1,5-c]pyrimidine derivatives. 2003, US6545000. [2] Muller, C.E.; Jacobson, K.A. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim. Biophys. Acta. 2011, 1808, 1290–1308. [3] Neustadt, B.R.; Hao, J., Lindo, N.; Greenlee, W.J.; Stamford, A.W.; Tulshian, D.; Ongini, E.; Hunter, J.; Monopoli, A.; Bertorelli, R.; Foster, C.; Arik, L.; Lachowicz, J.; Nga, K.; Feng, K.I. Potent, selective, and orally active adenosine A2A receptor antagonists: arylpiperazine derivatives of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines. Bioorg. Med. Chem. Lett. 2007, 17, 1376–1380.