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A series of imidazo[1,5-a]quinoxaline amides, carbamates, and ureas which have high affinity for the gamma-aminobutyric acid A/benzodiazepine receptor complex was developed. Compounds within this class have varying efficacies ranging from antagonists to full agonists. However, most analogs were found to be partial agonists as indicated by [35S]TBPS and Cl- current ratios. Many of these compounds were also effective in antagonizing metrazole-induced seizures in accordance with anticonvulsant and possible anxiolytic activity. Selected quinoxalines displayed limited benzodiazepine-type side effects such as ethanol potentiation and physical dependence in animal models. Dimethylamino urea 41 emerged as the most interesting analog, having a partial agonist profile in vitro while possessing useful activity in animal models of anxiety such as the Vogel and Geller assays. In accordance with its partial agonist profile, 41 was devoid of typical benzodiazepine side effects.

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A metal-free approach to meta-substituted phenols from cyclohex-2-enone via catalytic oxidative aromatization has been developed. The transformations are initiated with a catalytic amount of molecular iodine as the direct oxidant, while dimethyl sulfoxide is employed as the terminal oxidant. This practical approach is capable of avoiding the use of metal promoters and costly reagents, the lengthy synthesis, and overoxidation of products, and thus facilitates the efficient construction of meta-substituted phenol derivatives from inexpensive commercial chemicals under mild conditions. The synthetic utility of this approach is evident in the de novo syntheses of two bioactive molecules with good total yields, in which easily available chemicals were employed, protective groups were not utilized, and no unwanted carbon atoms were removed in each step. (Figure presented.).

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A new series of 4-acetyl-1-substituted-3,4-dihydroquinoxalin-2(1H)-ones (3?14) were designed and synthesized in order to evaluate their alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor antagonism as a proposed mode of their anticonvulsant activity. The structure of the synthesized compounds was confirmed by elemental analysis and spectral data (infrared, 1H nuclear magnetic resonance (NMR), 13CNMR, and mass). The molecular design was performed for all synthesized compounds to predict their binding affinity towards AMPA-receptor in order to rationalize their anticonvulsant activity in a qualitative way and explain the possible interactions that might take place between the tested derivatives and AMPA receptor in comparing to compounds III and YM872 in order to obtain the anticonvulsant effect. The data obtained from the molecular modeling was strongly correlated with that obtained from the biological screening which revealed that; compounds 14b, 14a, and 13b showed the highest binding affinities toward AMPA-receptor and also showed the highest anticonvulsant activities against pentylenetetrazole-induced seizures in experimental mice. The relative potencies of these compounds were 1.89, 1.83, and 1.51 respectively, in comparing to diazepam.

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A ruthenium(II)-catalyzed deoxygenative transfer hydrogenation of amides to amines using HCO2H/NEt3 as the reducing agent is reported for the first time. The catalyst system consisting of [Ru(2-methylallyl)2(COD)], 1,1,1-tris(diphenylphosphinomethyl) ethane (triphos) and Bis(trifluoromethane sulfonimide) (HNTf2) performed well for deoxygenative reduction of various secondary and tertiary amides into the corresponding amines in high yields with excellent selectivities, and exhibits high tolerance toward functional groups including those that are reduction-sensitive. The choice of hydrogen source and acid co-catalyst is critical for catalysis. Mechanistic studies suggest that the reductive amination of the in situ generated alcohol and amine via borrowing hydrogen is the dominant pathway. (Figure presented.).

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The present study was undertaken to evaluate whether a novel series of 2,6-diaza-5-oxobicyclo[5.4.0]undeca-1(7),8,10-triene derivatives exhibited antagonistic activity for vasopressin V1 and V2 receptors. Most of these compounds were synthesized and showed a high affinity potential for V2 receptor and low to moderate affinity potential for V1 receptor. The most potent and V2-selective compound, N-[4-[2,6-diaza-6-[2-(4- methylpiperazinyl)-2-oxoethyl]-5-oxobicyclo [5.4.0] undeca-1 (7),8,10-trien- 2-yl]-carbonyl]phenyl] [2-(4-methylphenyl)phenyl]formamide (11b), exhibited IC50’s of 2.9 nM for the V2 receptor and 200 nM for the V1 receptor, respectively. When administered orally to rat, 11b showed an approximately 18-fold increased urine volume in comparison with control rat.

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A facile and versatile procedure for the synthesis of 5-hetaryl-3-(2-hydroxybenzoyl)-1H-pyrroles and 4-(2-hydroxybenzoyl)-1H-pyrrole-2-carboxylic acid derivatives was established on the basis of TMSCl promoted recyclization of 3-formylchromone with various hetarylmethylamines and glycine derivatives.

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Iron(III) tetraphenylporphyrin chloride, Fe(TPP)Cl, efficiently catalyzed the insertion of carbenes derived from methyl 2-phenyldiazoacetates into O-H bonds of aliphatic and aromatic alcohols, with yields generally above 80%. Although the analogous N-H insertions are rapid at room temperature, the O-H insertion reactions are slower and required heating in refluxing methylene chloride for about 8 hours using 1.0 mol.% catalyst. Fe(TPP)Cl was also found to be effective for tandem N-H insertion/cyclization reactions when 1,2-diamines and 1,2-alcoholamines were treated with diazo reagents to give piperazinones and morpholinones and related analogs such as quinoxalinones and benzoxazin-2-ones. This approach provides a new one-pot route for synthesizing these classes of heterocyclic compounds.

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The present invention provides novel ureas containing N-aryl or N-heteroaryl substituted heterocycles and analogues thereof, which are selective inhibitors of the human P2Y1 receptor. The invention also provides for various pharmaceutical compositions of the same and methods for treating diseases responsive to modulation of P2Y 1 receptor activity.

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Background: Fibroblast growth factor (FGF) receptors (FGFRs) play a key role in tumor growth and angiogenesis. The present report describes our search for an extracellularly binding FGFR inhibitor using a combined molecular modeling and de novo design strategy. Methods: Based upon crystal structures of the receptor with its native ligand and knowledge of inhibiting peptides, we have developed a computational protocol that predicts the putative binding of a molecule to the extracellular domains of the receptor. This protocol, or scoring function, was used in combination with the de novo synthesis program ‘SYNOPSIS’ to generate high scoring and synthetically accessible compounds. Results: Eight compounds belonging to 3 separate chemical classes were synthesized. One of these compounds, alofanib (RPT835), was found to be an effective inhibitor of the FGF/FGFR2 pathway. The preclinical in vitro data support an allosteric inhibition mechanism of RPT835. RPT835 potently inhibited growth of KATO III gastric cancer cells expressing FGFR2, with GI50 value of 10 nmol/L. Conclusion: These results provide strong rationale for the evaluation of compound in advanced cancers.

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In an effort to identify HDAC isoform selective inhibitors, we designed and synthesized novel, chiral 3,4-dihydroquinoxalin-2(1H)-one and piperazine-2,5-dione aryl hydroxamates showing selectivity (up to 40-fold) for human HDAC6 over other class I/IIa HDACs. The observed selectivity and potency (IC50 values 10-200 nM against HDAC6) is markedly dependent on the absolute configuration of the chiral moiety, and suggests new possibilities for use of chiral compounds in selective HDAC isoform inhibition.

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