Green Synthesis of Aromatic Nitrogen-Containing Heterocycles by Catalytic and Non-Traditional Activation Methods.

Recent advances in the environmentally benign synthesis of aromatic N-heterocycles are reviewed, focusing primarily on the application of catalytic methods and non-traditional activation. This account features two main parts: the preparation of single ring N-heterocycles, and their condensed analogs. Both groups include compounds with one, two and more N-atoms. Due to the large number of protocols, this account focuses on providing representative examples to feature the available methods.

Structural Features of Small Molecule Antioxidants and Strategic Modifications to Improve Potential Bioactivity.

This review surveys the major structural features in various groups of small molecules that are considered to be antioxidants, including natural and synthetic compounds alike. Recent advances in the strategic modification of known small molecule antioxidants are also described. The highlight is placed on changing major physicochemical parameters, including log p, bond dissociation energy, ionization potential, and others which result in improved antioxidant activity.

Preparation of Deuterium Labeled Compounds by Pd/C-Al-D2O Facilitated Selective H-D Exchange Reactions.

The chemo/regioselective H-D exchange of amino acids and synthetic building blocks by an environmentally benign Pd/C-Al-D2O catalytic system is described. Due to the importance of isotope labeled compounds in medicinal chemistry and structural biology, notably their use as improved drug candidates and biological probes, the efficient and selective deuteration methods are of great interest. The approach is based on selective H-D exchange reactions where the deuterium source is simple D2O. D2 gas is generated in situ from the reaction of aluminum and D2O, while the commercially available palladium catalyst assists the H-D exchange reaction. The high selectivity and efficiency, as well as the simplicity and safe nature of the procedure make this method an environmentally benign alternative to current alternatives.

Recent Advances in the Synthesis of Isoquinoline-Fused Benzimidazoles.

This review includes recent developments in the synthesis of benzo[4,5]imidazo[2,1-a]isoquinolines with particular attention given to categorizing protocols based on the structural features of the ring architecture and crystallographically characterized reaction products.

[Assessment of Cyclofusion Capabilities of Normal Subjects with 3D Dynamic Random-Dot Stereograms]. / Messung der Zyklofusionskompetenz bei Normalprobanden mittels dynamischer 3-D-"Random-Dot"-Stereogramme.

BACKGROUND: Evaluation of a new method for cyclofusion measurement. PATIENTS AND METHODS: The maximal incyclofusion and excyclofusion tolerated of 20 normal subjects (15 females, mean age 36 ± 9.9 years) were measured by computer-generated dynamic random-dot stereograms (DRDS). Subjects had to detect the orientation of only binocularly visible Landolt C stimuli randomly presented with a 3-D monitor. Both eyes were separately stimulated with shutter glasses. The DRDS-pattern projected to the left and right eye were rotated in the opposite direction in 0.5° steps. In 10 subjects, cyclofusion measurements were repeated. RESULTS: Incylofusional amplitudes were between 2.5° and 6°, excyclofusional amplitudes measured between 3° and 5.5°. Mean incyclofusion was 3.71° (SD 0.82) and mean excyclofusion measured 4.24° (SD 0.73). Repeated measurements of incyclofusion and excyclofusion in the same subject demonstrated a difference of about 0.5° (0.55° for incyclofusion, 0.45° for excyclofusion). CONCLUSIONS: The DRDS Landolt C method provided a reliable assessment with good reproducibility of cyclofusion in healthy subjects with only binocularly perceivable objects. Our cyclofusional capabilities were slightly higher than those received with dissociating 2D measurements.

Synthesis and application of ß-carbolines as novel multi-functional anti-Alzheimer's disease agents.

The design, synthesis and assessment of ß-carboline core-based compounds as potential multifunctional agents against several processes that are believed to play a significant role in Alzheimer's disease (AD) pathology, are described. The activity of the compounds was determined in Aß self-assembly (fibril and oligomer formation) and cholinesterase (AChE, BuChE) activity inhibition, and their antioxidant properties were also assessed. To obtain insight into the mode of action of the compounds, HR-MS studies were carried out on the inhibitor-Aß complex formation and molecular docking was performed on inhibitor-BuChE interactions. While several compounds exhibited strong activities in individual assays, compound 14 emerged as a promising multi-target lead for the further structure-activity relationship studies.

Sulfonamides as multifunctional agents for Alzheimer's disease.

Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized with the aim of producing multifunctional agents against several processes involved in the pathology of Alzheimer's disease (AD). The potency of the compounds were assessed in the inhibition of Aß self-assembly (fibril and oligomer formation), in modulating cholinesterase (AChE, BuChE) activity, and scavenging free radicals. Several compounds exhibited promising Aß self-assembly and cholinesterase inhibition and in parallel, showed good free radical scavenging properties. The investigation of the scaffold described in this study resulted in the identification of three compounds (14, 19 and 26) as promising leads for the further design of multifunctional drug candidates for AD.

Early-onset binocularity in preterm infants reveals experience-dependent visual development in humans.

Although there is a great deal of knowledge regarding the phylo- and ontogenetic plasticity of the neocortex, the precise nature of environmental impact on the newborn human brain is still one of the most controversial issues of neuroscience. The leading model-system of experience-dependent brain development is binocular vision, also called stereopsis. Here, we show that extra postnatal visual experience in preterm human neonates leads to a change in the developmental timing of binocular vision. The onset age of binocular function, as measured by the visual evoked response to dynamic random dot correlograms (DRDC-VEP), appears to be at around the same time after birth in preterm (4.07 mo) and full-term (3.78 mo) infants. To assess the integrity of the visual pathway in the studied infants, we also measured the latency of the visual-evoked response to pattern reversal stimuli (PR-VEP). PR-VEP latency is not affected by premature birth, demonstrating that the maturation of the visual pathway follows a preprogrammed developmental course. Despite the immaturity of the visual pathway, clearly demonstrated by the PR-VEP latencies, our DRCD-VEP data show that the visual cortex is remarkably ready to accept environmental stimulation right after birth. This early plasticity makes full use of the available extra stimulation time in preterm human infants and results in an early onset of cortical binocularity. According to our data, the developmental processes preceding the onset of binocular function are not preprogrammed, and the mechanisms turning on stereopsis are extremely experience-dependent in humans.

Exploring the noninnocent character of electron rich π-extended 8-oxyquinolate ligands in ruthenium(II) bipyridyl complexes.

A series of ruthenium polypyridyl complexes are presented incorporating π-extended electron rich derivatives of the 8-oxyquinolate (OQN) ligand. The π-donating property of the OQN ligand introduces covalent character to the Ru(dπ)-OQN(π) bonding scheme enhancing its light harvesting properties and diversifying its redox properties, relative to the classic ruthenium(II) trisbipyridyl complex [Ru(bpy)3](2+). Synthesis and characterization is presented for the complexes [Ru(bpy)2(R-OQN)](PF6), where bpy = 2,2'-bipyridine and R = 5-phenyl, 5,7-diphenyl, 2,4-diphenyl, 5,7-bis(4-methoxyphenyl), 5,7-bis(4-(diphenylamino)phenyl). A comprehensive bonding analysis is presented for the [Ru(bpy)2(OQN)](+) system illustrating the origin of its unique spectroscopic and redox properties relative to [Ru(bpy)3](2+). This model is then extended to enable a consistent interpretation of spectra and redox properties for the π-extended [Ru(bpy)2(R-OQN)](PF6) series. Electronic structures have been probed experimentally by a combination of electrochemical and spectroscopic techniques (UV-vis-NIR absorption, emission, EPR spectroscopy) where (metal-ligand)-to-ligand (MLLCT) charge-transfer properties are described by time dependent-density functional theory (TD-DFT) analysis, at the B3LYP/6-31g(d,p) level of approximation. Substantial mixing, due to bonding and antibonding combinations of Ru(dπ) and OQN(π) orbitals, is observed at the HOMO and HOMO-3 levels for the ruthenium-oxyanion bond in [Ru(bpy)2(OQN)](+), which is responsible for the low-energy MLLCT based electronic transition and destabilization of the HOMO level viz. cyclic voltammetry. This noninnocent π-bonding phenomenon is consistent throughout the series which allows for controlled tuning of complex redox potentials while maintaining panchromatic absorption properties across the visible spectrum. Extensive charge delocalization is observed for the one-electron oxidized species using a combination of UV-vis-NIR, EPR spectroelectrochemistry, and Mulliken spin-density analysis, giving strong evidence for hole-delocalization across the delocalized Ru(dπ)-OQN(π) system, in particular for the electron rich 5,7-bis(4-methoxyphenyl) and 5,7-bis(4-(diphenylamino)phenyl) systems.

Chemo-and regioselective aqueous phase, co-acid free nitration of aromatics using traditional and nontraditional activation methods.

Electrophilic aromatic nitrations are used for the preparation of a variety of synthetic products including dyes, agrochemicals, high energy materials, fine chemicals and pharmaceuticals. Traditional nitration methods use highly acidic and corrosive mixed acid systems which present a number of drawbacks. Aside from being hazardous and waste-producing, these methods also often result in poor yields, mostly due to low regioselectivity, and limited functional group tolerance. As a consequence, there is a need for effective and environmentally benign methods for electrophilic aromatic nitrations. In this work, the major aim was to develop reaction protocols that are more environmentally benign while also considering safety issues. The reactions were carried out in dilute aqueous nitric acid, and a broad range of experimental variables, such as acid concentration, temperature, time, and activation method, were investigated. Mesitylene and m-xylene were used as test substrates for the optimization. While the optimized reactions generally occurred at room temperature without any activation under additional solvent-free conditions, slight adjustments in acid concentration, stoichiometric equivalents, and volume were necessary for certain substrates, in addition to the activation. The substrate scope of the process was also investigated using both activated and deactivated aromatics. The concentration of the acid was lowered when possible to improve upon the safety of the process and avoid over-nitration. With some substrates we compared traditional and nontraditional activation methods such as ultrasonic irradiation, microwave and high pressure, respectively, to achieve satisfactory yields and improve upon the greenness of the reaction while maintaining short reaction times.

Diaryl hydrazones as multifunctional inhibitors of amyloid self-assembly.

The design and application of an effective, new class of multifunctional small molecule inhibitors of amyloid self-assembly are described. Several compounds based on the diaryl hydrazone scaffold were designed. Forty-four substituted derivatives of this core structure were synthesized using a variety of benzaldehydes and phenylhydrazines and characterized. The inhibitor candidates were evaluated in multiple assays, including the inhibition of amyloid ß (Aß) fibrillogenesis and oligomer formation and the reverse processes, the disassembly of preformed fibrils and oligomers. Because the structure of the hydrazone-based inhibitors mimics the redox features of the antioxidant resveratrol, the radical scavenging effect of the compounds was evaluated by colorimetric assays against 2,2-diphenyl-1-picrylhydrazyl and superoxide radicals. The hydrazone scaffold was active in all of the different assays. The structure-activity relationship revealed that the substituents on the aromatic rings had a considerable effect on the overall activity of the compounds. The inhibitors showed strong activity in fibrillogenesis inhibition and disassembly, and even greater potency in the inhibition of oligomer formation and oligomer disassembly. Supporting the quantitative fluorometric and colorimetric assays, size exclusion chromatographic studies indicated that the best compounds practically eliminated or substantially inhibited the formation of soluble, aggregated Aß species, as well. Atomic force microscopy was also applied to monitor the morphology of Aß deposits. The compounds also possessed the predicted antioxidant properties; approximately 30% of the synthesized compounds showed a radical scavenging effect equal to or better than that of resveratrol or ascorbic acid.

Design, synthesis and biological activity of multifunctional α,ß-unsaturated carbonyl scaffolds for Alzheimer's disease.

A series of compounds containing an α,ß-unsaturated carbonyl moiety, such as chalcones and coumarins were designed, synthesized and tested in a variety of assays to assess their potential as anti-Alzheimer's disease (AD) agents. The investigations included the inhibition of cholinesterases (AChE, BuChE), the inhibition of amyloid beta (Aß) self-assembly and the disassembly of preformed Aß oligomers. Several compounds showed excellent potential as multifunctional compounds for AD. Docking studies for 16 that performed well in all the assays gave a clear interpretation of various interactions in the gorge of AChE. Based on the results, the long-chain coumarin scaffold appears to be a promising structural template for further AD drug development.

Selective reduction of condensed N-heterocycles using water as a solvent and a hydrogen source.

The reduction of unprotected indoles and quinolines is described using water as a hydrogen source. The method is based on the application of a RANEY® type Ni-Al alloy in an aqueous medium. During the reaction the Al content of the alloy, used as reductants, reacts with water in situ providing hydrogen and a RANEY® Ni catalyst, thus the alloy serves as a hydrogen generator as well as a hydrogenation catalyst. The simplicity and efficacy of the method are illustrated by the selective reduction of a variety of substituted indoles and quinolines to indolines and tetrahydroquinolines, respectively.

Selective reduction of ketones using water as a hydrogen source under high hydrostatic pressure.

A selective reduction of a broad variety of ketones is described. The method is based on the combination of a Ni-Al alloy and high hydrostatic pressure (HHP, 2.8 kbar) in an aqueous medium. The reaction of the Ni-Al alloy with water provides in situ hydrogen generation and the high pressure ensures that the H(2) formed remains in the solution, thus the C=O reduction readily occurs. The application of the HHP resulted in selective formation of the desired products and the common problem of non-selective overhydrogenation could be avoided. In most cases the reductions resulted in high yields and excellent selectivities without the use of any base.

Synthesis of diversely 1,3,5-trisubstituted pyrazoles via 5-exo-dig cyclization.

5-Exo-dig cyclocondensation of alk-3-yn-1-ones with hydrazines, in the presence of montmorillonite K-10, provides an effective method with a high atom economy for the synthesis of diversely 1,3,5-trisubstituted pyrazoles. The microwave-accelerated reaction proceeds in the absence of solvent and leads to 5-benzyl substituted pyrazoles with good yields (72-91%). The regiochemistry of the process was confirmed by the X-ray crystallographic structure determination of 1-(2-fluorophenyl)-5-(4-methylbenzyl)-3-phenyl-1H-pyrazole.

Recent Advances in the Green Synthesis of Heterocycles: From Building Blocks to Biologically Active Compounds.

Recent advances in the environmentally benign synthesis of common heterocycles are described. This account features three main parts; the preparation of non-aromatic heterocycles, one-ring aromatic heterocycles and their condensed analogs. Due to the great variety of and high interest in these compounds, this work focuses on providing representative examples of the preparation of the target compounds.

Disassembly of preformed amyloid beta fibrils by small organofluorine molecules.

A potential therapeutic approach for Alzheimer's disease is to reduce the amount of toxic amyloid-beta oligomers and fibrillar amyloid plaques. In order to contribute to this approach the ability of small organofluorine compounds that were previously reported as successful inhibitors of fibrillogenesis to destabilize preformed fibrils of the amyloid-beta peptide was studied. These organofluorine molecules including chiral compounds were tested in vitro using standard methods based on Thioflavin-T (THT) fluorescence spectroscopy, atomic force microscopy (AFM) and Fourier-transform infrared spectroscopy (FTIR). It was observed that 5'-halogen substituted 3,3,3-trifluoromethyl-2-hydroxyl-(indol-3-yl)-propionic acid esters showed significant activity in the disassembly of the preformed fibrils. Since the same compounds were identified as strong fibrillogenesis inhibitors as well, this dual action makes them promising candidates for further drug development.

Heteropoly acid-catalyzed microwave-assisted three-component aza-Diels-Alder cyclizations: diastereoselective synthesis of potential drug candidates for Alzheimer's disease.

A highly diastereoselective microwave-assisted three component synthesis of azabicyclo[2.2.2]octan-5-ones by a silicotungstic acid-catalyzed aza-Diels-Alder cyclization is described. The one-pot process involves the formation of the in situ generated Schiff base and its immediate cyclization with cyclohex-2-enone. The short reaction times, good yields and excellent diastereoselectivity make this annulation a practical and environmentally attractive method for the synthesis of the target compounds. Preliminary assays were carried out to determine the activity of the products in AChE as well as in amyloid ß fibrillogenesis inhibition.

Enantioselective Friedel-Crafts reaction of indoles with trifluoroacetaldehyde catalyzed by Cinchona alkaloids.

The first direct asymmetric synthetic preparation of trifluoro-1-(indol-3-yl)ethanols (TFIEs) is described by an enantioselective organocatalytic method from indoles and inexpensive trifluoroacetaldehyde methyl hemiacetal. The reaction is catalyzed by hydroquinine to produce TFIEs in an almost quantitative yield and with enantioselectivities up to 75% at room temperature. The enantioselectivity is strongly dependent on the concentration of substrates and catalyst due to the competitive noncatalyzed reaction.

Organofluorine Hydrazone Derivatives as Multifunctional Anti-Alzheimer's Agents with CK2 Inhibitory and Antioxidant Features.

A set of novel hydrazone derivatives were synthesized and analyzed for their biological activities. The compounds were tested for their inhibitory effect on the phosphorylating activity of the protein kinase CK2, and their antioxidant activity was also determined in three commonly used assays. The hydrazones were evaluated for their radical scavenging against the DPPH, ABTS and peroxyl radicals. Several compounds have been identified as good antioxidants as well as potent protein kinase CK2 inhibitors. Most hydrazones containing a 4-N(CH3 )2 residue or perfluorinated phenyl rings showed high activity in the radical-scavenging assays and possess nanomolar IC50 values in the kinase assays.