Neuroprotective Effects of N‐Alkyl‐1,2,4‐oxadiazolidine‐3,5‐diones and Their Corresponding Synthetic Intermediates N‐Alkylhydroxylamines and N‐1‐Alkyl‐3‐carbonyl‐1‐hydroxyureas against in vitro Cerebral Ischemia

Herein we report the synthesis and neuroprotective effects of new N‐alkyl‐1,2,4‐oxadiazolidine‐3,5‐diones and their corresponding synthetic intermediates, N‐alkylhydroxylamines and N‐1‐alkyl‐3‐carbonyl‐1‐hydroxyureas, in an in vitro model of ischemia. We found five analogues that protect HT22 cells from death in the concentration range of 1–5 μM . Because members of the MAP kinase family are known to be key players in nerve cell survival and death, we characterized the role of these kinases in the neuroprotective mechanisms of the newly synthesized analogues. The results indicate that these compounds provide neuroprotection through distinct mechanisms of action.     

Monomers and polymers of 4‐(N,N‐diallylamino)pyridine functions

4‐(N,N‐Diallylamino)pyridine (DAAP), N,N‐diallylaminobenzene (DAAB), N,N,N′,N′‐tetrallyl‐4,4′‐diaminobenzidine (AAB), N,N,N′,N′‐tetrallyl‐4,4′‐diaminodiphenyl sulfone (AABS), and N,N,N′,N′‐tetrallyl‐4,4′‐diaminodiphenyl ether (AABE) were prepared by sodium substitution and N‐allylation. Moreover, linear polyDAAP, poly(DAAP‐co‐DAAB), and network poly(DAAP‐co‐AAB), poly(DAAP‐co‐AABS), and poly(DAAP‐co‐AABE), all being polymers containing supernucleophilic groups, were synthesized in the cyclopolymerization. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 77: 363–367, 2000     

Polymerization of 4‐(4′‐N‐1,8‐naphthalimidophenyl)‐1,2,4‐triazolidine‐3,5‐dione with diisocyanates

4‐(4′‐Aminophenyl)‐1,2,4‐triazolidine‐3,5‐dione ( 1 ) was reacted with 1,8‐naphthalic anhydride ( 2 ) in a mixture of acetic acid and pyridine (3 : 2) under refluxing temperature and gave 4‐(4′‐N‐1,8‐naphthalimidophenyl)‐1,2,4‐triazolidine‐3,5‐dione ( NIPTD ) ( 3 ) in high yield and purity. The compound NIPTD was reacted with excess n‐propylisocyanate in N,N‐dimethylacetamide solution and gave 1‐(n‐propylamidocarbonyl)‐4‐[4′‐(1,8‐naphthalimidophenyl)]‐1,2,4‐triazolidine‐3,5‐dione ( 4 ) and 1,2‐bis(n‐propylamidocarbonyl)‐4‐[4′‐(1,8‐naphthalimidophenyl)]‐1,2,4‐ triazolidine‐3,5‐dione ( 5 ) as model compounds. Solution polycondensation reactions of monomer 3 with hexamethylene diisocyanate ( HMDI ), isophorone diisocyanate ( IPDI ), and tolylene‐2,4‐diisocyanate ( TDI ) were performed under microwave irradiation and conventional solution polymerization techniques in different solvents and in the presence of different catalysts, which led to the formation of novel aliphatic‐aromatic polyureas. The polycondensation proceeded rapidly, compared with conventional solution polycondensation, and was almost completed within 8 min. These novel polyureas have inherent viscosities in a range of 0.06–0.20 dL g^?1 in conc. H₂SO₄ or DMF at 25°C. Some structural characterization and physical properties of these novel polymers are reported. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 2861–2869, 2003     

Functionalization of the 3′‐Ends of DNA and RNA Strands with N‐ethyl‐N‐coupled Nucleosides: A Promising Approach To Avoid 3′‐Exonuclease‐Catalyzed Hydrolysis of Therapeutic Oligonucleotides

The development of nucleic acid derivatives to generate novel medical treatments has become increasingly popular, but the high vulnerability of oligonucleotides to nucleases limits their practical use. We explored the possibility of increasing the stability against 3′‐exonucleases by replacing the two 3′‐terminal nucleotides by N‐ethyl‐N‐coupled nucleosides. Molecular dynamics simulations of 3′‐N‐ethyl‐N‐modified DNA:Klenow fragment complexes suggested that this kind of alteration has negative effects on the correct positioning of the adjacent scissile phosphodiester bond at the active site of the enzyme, and accordingly was expected to protect the oligonucleotide from degradation. We verified that these modifications conferred complete resistance to 3′‐exonucleases. Furthermore, cellular RNAi experiments with 3′‐N‐ethyl‐N‐modified siRNAs showed that these modifications were compatible with the RNAi machinery. Overall, our experimental and theoretical studies strongly suggest that these modified oligonucleotides could be valuable for therapeutic applications.     

Copolymerization of N‐(4‐carboxyphenyl) itaconimide or N‐(4‐carboxyphenyl) itaconamic acid with methyl methacrylate

This paper describes the synthesis and characterization of N‐(4‐carboxyphenyl) itaconamic acid (CPA) and N‐(4‐carboxyphenyl) itaconimide (CPI) obtained by reacting itaconic anhydride with p‐aminobenzoic acid. Structural and thermal characterization of CPA and CPI was done using ¹H‐NMR, FTIR, and differential scanning calorimetry (DSC). Copolymerization of CPA or CPI with methyl methacrylate (MMA) in solution was carried out at 60 °C using azobisisobutyronitrile as an initiator and dimethyl acetamide or THF as solvent. Feed compositions having varying mole fractions of CPA or CPI ranging from 0.05–0.20 or 0.1–0.5 were taken to prepare copolymers. Copolymerizations were terminated at low percentage conversion. Structural characterization of copolymers was done by ¹H‐NMR and elemental analysis. Copolymer composition was determined using percentage nitrogen content. The reactivity ratios were r₁ (MMA) = 0.68 ± 0.06 and r₂ (CPI) = 0.46 ± 0.06. The intrinsic viscosity [η] was determined using an Ubbelohde suspension level viscometer. [η] decreased with increasing mole fraction of N‐(p‐carboxyphenyl) itaconimide or N‐(p‐carboxyphenyl) itaconamic acid in copolymers. Glass transition temperature and thermal stability of the copolymers were determined using DSC and thermogravimetric analysis, respectively. The glass transition temperature (T_g) as determined from DSC scans increased with increasing amounts of CPA or CPI in copolymers. A significant improvement in the char yield was observed upon copolymerization. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 98: 1909–1915, 2005     

Preparation of 1,4,5‐Trisubstituted 5‐Acyl‐1,2,3‐triazoles by Selective Acylation between Copper(I)‐Carbon(sp) and Copper(I)‐Carbon(sp2) Bonds with Acyl Chlorides

A one‐pot, three‐component method for preparation of 1,4,5‐trisubstituted 5‐acyl‐1,2,3‐triazoles has been developed based on a highly selective acylation of the copper(I)‐carbon(sp²) bond with acyl chlorides in the presence of the copper(I)‐carbon(sp) bond. The procedure is characterized by high efficiency and simple conditions.

     

N‐Benzyl‐4‐((heteroaryl)methyl)benzamides: A New Class of Direct NADH‐Dependent 2‐trans Enoyl–Acyl Carrier Protein Reductase (InhA) Inhibitors with Antitubercular Activity

Isoniazid (INH) remains one of the cornerstones of antitubercular chemotherapy for drug‐sensitive strains of M. tuberculosis bacteria. However, the increasing prevalence of multidrug‐resistant (MDR) and extensively drug‐resistant (XDR) strains containing mutations in the KatG enzyme, which is responsible for the activation of INH into its antitubercular form, have rendered this drug of little or no use in many cases of drug‐resistant tuberculosis. Presented herein is a novel family of antitubercular direct NADH‐dependent 2‐trans enoyl–acyl carrier protein reductase (InhA) inhibitors based on an N‐benzyl‐4‐((heteroaryl)methyl)benzamide template; unlike INH, these do not require prior activation by KatG. Given their direct InhA target engagement, these compounds should be able to circumvent KatG‐related resistance in the clinic. The lead molecules were shown to be potent inhibitors of InhA and showed activity against M. tuberculosis bacteria. This new family of inhibitors was found to be chemically tractable, as exemplified by the facile synthesis of analogues and the establishment of structure–activity relationships. Furthermore, a co‐crystal structure of the initial hit with the enzyme is disclosed, providing valuable information toward the design of new InhA inhibitors for the treatment of MDR/XDR tuberculosis.     

Synthesis and Structure–Activity Relationship Studies of 2‐(1,3,4‐Oxadiazole‐2(3H)‐thione)‐3‐amino‐5‐arylthieno[2,3‐b]pyridines as Inhibitors of DRAK2

In recent years, DAPK‐related apoptosis‐inducing protein kinase 2 (DRAK2) has emerged as a promising target for the treatment of a variety of autoimmune diseases and for the prevention of graft rejection after organ transplantation. However, medicinal chemistry optimization campaigns for the discovery of novel small‐molecule inhibitors of DRAK2 have not yet been published. Screening of a proprietary compound library led to the discovery of a benzothiophene analogue that displays an affinity constant (K_d) value of 0.25 μM . Variation of the core scaffold and of the substitution pattern afforded a series of 5‐arylthieno[2,3‐b]pyridines with strong binding affinity (K_d=0.008 μM for the most potent representative). These compounds also show promising activity in a functional biochemical DRAK2 enzyme assay, with an IC₅₀ value of 0.029 μM for the most potent congener. Selectivity profiling of the most potent compounds revealed that they lack selectivity within the DAPK family of kinases. However, one of the less potent analogues is a selective ligand for DRAK2 and can be used as starting point for the synthesis of selective and potent DRAK2 inhibitors.     

Novel Monocyclam Derivatives as HIV Entry Inhibitors: Design,Synthesis, Anti‐HIV Evaluation,and Their Interaction with the CXCR4 Co‐receptor

The CXCR4 receptor has been shown to interact with the human immunodeficiency virus (HIV) envelope glycoprotein gp120, leading to fusion of viral and cell membranes. Therefore, ligands that can attach to this receptor represent an important class of therapeutic agents against HIV, thus inhibiting the first step in the cycle of viral infection: the virus–cell entry/fusion. Herein we describe the in silico design, synthesis, and biological evaluation of novel monocyclam derivatives as HIV entry inhibitors. In vitro activity testing of these compounds in cell cultures against HIV strains revealed EC₅₀ values in the low micromolar range without cytotoxicity at the concentrations tested. Docking and molecular dynamics simulations were performed to predict the binding interactions between CXCR4 and the novel monocyclam derivatives. A binding mode of these compounds is proposed which is consistent with the main existing site‐directed mutagenesis data on the CXCR4 co‐receptor. Moreover, molecular modeling comparisons were performed between these novel monocyclams, previously reported non‐cyclam compounds from which the monocyclams are derived, and the well‐known AMD3100 bicyclam CXCR4 inhibitors. Our results suggest that these three structurally diverse CXCR4 inhibitors bind to overlapping but not identical amino acid residues in the transmembrane regions of the receptor.     

The Discovery and Development of the N‐Substituted trans‐3,4‐Dimethyl‐4‐(3′‐hydroxyphenyl)piperidine Class of Pure Opioid Receptor Antagonists

N‐Substituted trans‐3,4‐dimethyl‐4‐(3‐hydroxyphenyl)piperidines are a class of pure opioid receptor antagonists with a novel pharmacophore. This opioid receptor antagonist pharmacophore was used as a lead structure to design and develop several interesting and useful opioid receptor antagonists. In this review we describe: 1) early SAR studies that led to the discovery of LY255582 and analogues that are nonselective opioid receptor antagonists developed for the treatment of obesity; 2) the discovery and commercialization of LY246736 (alvimopan; ENTEREG®), a peripherally selective opioid receptor antagonist that accelerates the time to upper and lower GI recovery following surgeries that include partial bowel resection with primary anastomosis; and 3) the discovery and development of the potent and selective κ opioid receptor antagonist JDTic and analogues as potential pharmacotherapies for treating depression, anxiety, and substance abuse (nicotine, alcohol, and cocaine). In addition, the use of JDTic for obtaining the X‐ray structure of the human κ opioid receptor is discussed.     

Enantioselective Synthesis of cis‐4‐Formyl‐β‐lactams via Chiral N‐Heterocyclic Carbene‐Catalyzed Kinetic Resolution

An efficient synthesis of optically pure cis‐4‐formyl‐β‐lactams (up to 99% ee) by a chiral NHC‐catalyzed ring expansion reaction has been realized, featuring the ready availability of both the substrate and the catalyst, and the mild reaction conditions. The current method is also suitable for the synthesis of enantioenriched 4‐formyl‐β‐lactams and succinimides containing quaternary carbon centers.     

Untersuchung der CO2‐Absorptionskinetik in wässrigen Lösungen von N,N‐Diethylethanolanmin und N‐Ethylethanolamin

N‐Ethylethanolamine (EEA) and N,N‐diethylethanolamine (DEEA) represent promising alkanolamines for CO₂ removal from gaseous streams, as they can be prepared from renewable resources. In this work, the reaction rate constant for the reaction between CO₂ and EEA and the liquid‐side mass transfer coefficient were determined from the absorption rate measurements in a blend comprising DEEA, EEA and H₂O. A stirred‐cell reactor was applied for the absorption studies, whereas a zwitterion mechanism for EEA and a base‐catalyzed hydration mechanism for DEEA were used to describe the reaction kinetics.     

Synthesis,characterization and fluorescence performance of a waterborne polyurethane‐based fluorescent dye 4‐amino‐N‐cyclohexyl‐1,8‐naphthalimide,WPU‐ACN

A waterborne‐polyurethane‐based fluorescent dye 4‐amino‐N‐cyclohexyl‐1,8‐naphthalimide (WPU‐ACN) was synthesized by attaching 4‐amino‐N‐cyclohexyl‐1,8‐naphthalimide (ACN) into polyurethane chains according to a prepolymer?ionomer process. The structure of WPU‐ACN was confirmed by means of Fourier transform infrared spectroscopy and UV?visible absorption. The number‐average molecular weight, glass transition temperature and average emulsion particle size for WPU‐ACN were determined as 7.8 × 10⁵ g mol^?1, 60 °C and 60 nm, respectively. The improved thermal stability of WPU‐ACN could be attributed to the incorporation of naphthalimide units in the preformed urethane groups. The fluorescence intensity of WPU‐ACN was dramatically enhanced compared with that of ACN. It was found that the fluorescence intensity of WPU‐ACN increased with increasing temperature, and the fluorescence spectra of WPU‐ACN showed a positive solvatochromic effect. In addition, the fluorescence of WPU‐ACN emulsion was very stable not only for long‐term storage but also for fluorescence quenching. © 2013 Society of Chemical Industry     

Characterization of films from chitosan and quaternized poly(4‐vinyl‐N‐butyl) pyridine solutions

All Blend films were prepared from a mixture of 2 wt % chitosan in acetate solution and 4 wt % quaternized poly(4‐vinyl‐N‐butyl) pyridine (QPVP) in aqueous solution and dried at room temperature for 72 h to obtain the films. Their structure and properties were studied by infrared (IR), wide‐angle X‐ray diffraction (WXRD), scanning electron microscopy (SEM), thermogravimetric analysis (TG), and differential scanning calorimetry (DSC). Crystallinities of the blend films decreased with the increase of QPVP when weight of QPVP content was less than 15.0 wt %. The thermostability, tensile strength, and breaking elongation of the films in dry state were better than those of chitosan film. Tensile strength of the blend film dried at 40°C under vacuum for 24 h achieved 56.38 MPa when the weight ratio of chitosan to QPVP was 9 : 1. The structural analysis indicated that there was a strong interaction between chitosan and QPVP resulting from strong adhesion between both polymers. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 559–566, 2004     

Functionalization of Poly(propylene) Fabric with 4‐Vinylpyridine,N,N‐Dimethylacrylamide and Styrene by γ‐Radiation‐Induced Grafting in an Aqueous Environment

Summary: VP and co‐monomers DMAAm and ST were successfully grafted onto a PP fabric in an emulsion copolymerization process initiated by γ‐radiation. The radiation dose, concentration of VP, the ratio of VP/DMAAm and VP/ST in the reaction solution, and the reaction temperature dependent graft copolymerization were investigated. The order of dependence of the initial rate of grafting on the radiation dose was found to be in the range of 1.2 to 0.93 for VP; 0.84 to 0.70 for VP/DMAAm and for VP/ST was in the range of 0.59 to 0.41. The activation energy of the graft copolymer reaction was determined to be 40.18 J · mol^?1 for 0.464 mol · L^?1 VP. In the case of co‐monomer mixtures (VP/DMAAm: 0.464/0.5) the energy of activation was noticeably higher at 49.71 J · mol^?1 while for VP/ST (0.464/0.436) the activation energy was same as that of VP. XRD results showed that overall crystallinity significantly decreased with the increase of graft weight with a noticeable change in the chemical structure of the PP, indicating that the graft copolymer reaction was taking place both in the amorphous and crystalline regions of PP. A similar characteristic behavior was also obtained by DSC, which revealed the presence of an endotherm process in the range of 25 to 130 °C depending on the degree of grafting, attributed to the grafted chains of the monomer/co‐monomers. In order to determine the graft copolymer reaction of VP, DMAAm and ST onto the backbone of PP, the reaction products were characterized by FTIR spectroscopy. A good correlation was found between changes of crystallinity and level of graft copolymerization as determined by WAXRD and DSC.

Typical XRD traces of as‐received PP fabric (PPF) and grafted with VP (PPF‐g‐VP).     

An Energetic N‐Oxide and N‐Amino Heterocycle and its Transformation to 1,2,3,4‐Tetrazine‐1‐oxide

This study reports the preparation of 1‐amino‐1,2,3‐triazole‐3‐oxide (DPX2) and its transformation to 1,2,3,4‐tetrazine‐1‐oxide. DPX‐2 provides insight into a novel N‐oxide/N‐amino high‐nitrogen system, being the first energetic material in this class. The ability of this material to undergo a nitrene insertion forming 1,2,3,4‐tetrazine‐1‐oxide was also studied, and evidence for this material, the first non‐benzoannulated 1,2,3,4‐tetrazine‐1‐oxide, is presented. The existence of both of these materials opens new strategies in energetic materials design. DPX2 was characterized chemically (Infrared, Raman, NMR, X‐ray) and as a high explosive in terms of energetic performances (detonation velocity, pressure, etc.) and sensitivities (impact, friction, electrostatic). DPX‐2 was found to possess good thermal stability and moderate sensitivities, indicating the viability of N‐amino N‐oxides as a strategy for the preparation of new energetic materials.     

Novel polyion complex films from chitosan and quarternized poly(4‐vinyl‐N‐carboxymethylpyridine) containing zwitterion structure units

Novel polyion complexes films of chitosan and quarternized poly(4‐vinyl‐N‐carboxymethylpyridine) containing zwitterion structure units were prepared by casting method. The aim of this work was to produce a hydrophilic film with the potential use as a hydrophilic membranes of the types used in membranes distillation and osmotic distillation for separating azeotropic, close‐boiling, and aqueous organic mixtures. Their structure and properties were studied by infrared, wide‐angle X‐ray diffraction, scanning electron microscopy, thermogravimetric analysis, tensile tester, and swelling measurements. The results indicated that polyion complexes occurred between chitosan and quarternized poly (4‐vinyl‐N‐carboxymethylpyridine) containing zwitterion structure units. The thermostability of these blends decreased with the increase of quarternized poly(4‐vinyl‐N‐carboxymethylpyridine) content. Initially, appreciable improvement in tensile strength and breaking elongation were achieved with increase of quarternized poly(4‐vinyl‐N‐carboxymethyl‐pyridine) content to 30%, the maximum value of 46.65 MPa tensile strength and 25.67% breaking elongation were achieved, respectively. The maximum degree of swelling was achieved when the weight ratio of chitosan versus poly(4‐vinyl‐N‐carboxymethylpyridine) was 50 : 50. Meanwhile, the relationship between their structure and properties was also discussed. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007