Heteroaromatic Fragments Research Articles

Pyridine Carboxamides Based on Sulfobetaines: Design, Reactivity, and Biological Activity.

The synthesis of the products of the 1,3-propanesultone ring opening during its interaction with amides of pyridinecarboxylic acids has been carried out. The dependence of the yield of the reaction products on the position (ortho-, meta-, para-) of the substituent in the heteroaromatic fragment and temperature condition was revealed. In contrast to the meta- and para-substituted substrates, the reaction involving ortho-derivatives at the boiling point of methanol unexpectedly led to the formation of a salt. On the basis of spectroscopic, X-Ray, and quantum-chemical calculation data, a model of the transition-state, as well as a mechanism for this alkylation reaction of pyridine carboxamides with sultone were proposed in order to explain the higher yields obtained with the nicotinamide and its N-methyl analog compared to ortho or meta parents. Based on the analysis of ESP maps, the positions of the binding sites of reagents with a potential complexing agent in space were determined. The in silico evaluation of possible biological activity showed that the synthetized compounds revealed some promising pharmacological effects and low acute toxicity.

Simple heteroaryl modifications in the 4,5-diarylisoxazol-3-carboxylic acid scaffold favorably modulates the activity as dual mPGES-1/5-LO inhibitors with in vivo efficacy

Microsomal prostaglandin E2 synthase-1 (mPGES-1), 5-lipoxygenase (5-LO) and 5- lipoxygenase-activating protein (FLAP) are key for biosynthesis of proinflammatory lipid mediators and pharmacologically relevant drug targets. In the present study, we made an attempt to explore the role of small heteroaromatic fragments on the 4,5-diarylisoxazol-3-carboxylic acid scaffold, which are selected to interact with focused regions in the active sites of mPGES-1, 5-LO and FLAP. We report that the simple structural variations on the benzyloxyaryl side-arm of the scaffold significantly influence the selectivity against mPGES-1, 5-LO and FLAP, enabling to produce multi-target inhibitors of these protein targets, exemplified by compound 18 (IC50 mPGES-1 = 0.16 µM; IC50 5-LO = 0.39 µM) with in vivo efficacy in animal model of inflammation. The computationally modeled binding structures of these new inhibitors for three targets provide clues for rational design of modified structures as multi-target inhibitors. In conclusion, the simple synthetic procedure, and the possibility of enhancing the potency of this class of inhibitors through structural modifications pave the way for further development of new multi-target inhibitors against mPGES-1, 5-LO and FLAP, with potential application as anti-inflammatory agents.

NMR study of dyadic and triadic splitting in copoly(arylene)phthalides based on diphenyl oxide and diphenyl sulfide.

All 13 C NMR signals of the poly(arylene) polymers, O-1, S-7, OS-4, OOS-3, OOOS-2, SSO-5, and SSSO-6 (where O is a diphenyleneoxiphthalide unit and S is a diphenylenethiophthalide unit) in dyads and triads were assigned unequivocally with two-dimensional NMR techniques (ge-2D [1 H-1 H] COSY, ge-2D [1 H-13 C] HSQC, and ge-2D [1 H-13 C] HMBC), and for each atom, the increments of the shifts are determined. For structurally similar carbon atoms of the phthalide cycle and heteroaromatic fragments of the skeletal chain, additive signal splitting schemes in phthalide centered dyads and in diphenylene oxide and in diphenylene sulfide centered triads are considered, based on taking into account the contributions to their shielding of adjacent and distant substituents. It was shown that the nature of the splitting of the signals of each of the 20 carbon atoms in 3,3-bisphenylphthalide fragments is determined by the type of carbon atom (tertiary or quaternary, even or odd), the type of heteroatoms in adjacent heteroaromatic fragments, their distance from the identified carbon nucleus, and their polyad symmetry. The results obtained in this article will greatly facilitate our further studies and, in particular, will allow us to study the microstructure of statistical copolymers based on the asymmetric OS monomer at the dyad and triad levels.

Late-Stage Functionalization by Chan-Lam Amination: Rapid Access to Potent and Selective Integrin Inhibitors.

A late-stage functionalization of the aromatic ring in amino acid derivatives is described. The key step is a copper-catalysed diversification of a boronate ester by amination (Chan-Lam reaction) that can be carried out on a complex β-aryl-β-amino acid scaffold. This not only considerably extends the substrate scope of amination partners, but also delivers an array of potent and selective integrin inhibitors as potential treatment agents of idiopathic pulmonary fibrosis (IPF). This versatile chemical strategy, which is amenable to high-throughput-array protocols, allows the installation of pharmaceutically valuable heteroaromatic fragments at a late stage by direct coupling to NH heterocycles, leading to compounds with drug-like attributes. It thus constitutes a useful addition to the medicinal chemist's repertoire.

A visible-light mediated three-component radical process using dithiocarbamate anion catalysis.

We report a photoinduced three-component radical process, which couples readily available alkyl chlorides, maleimides, and heteroaromatic fragments to rapidly generate complex chiral products with high diastereocontrol. This method generates radicals via an SN2-based photochemical catalytic mechanism, which is not reliant on the redox properties of the precursors. It therefore grants access to open-shell intermediates from substrates that would be incompatible with or inert to classical radical-generating strategies. The redox-neutral conditions of this process make it tolerant of redox-sensitive substrates and allow the installation of multiple biologically relevant heterocycles within the cascade products.

Synthesis and properties of bis((4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)alkanes

The aim of this work was the synthesis of bis((4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)alkanes using available reagents and study of their properties. Matherial and methods . 4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-thiol was used as an intermediate compound, obtained from methyl 2-(thiophen-2-yl)acetate. Its synthesis has been described in previous studies. During the bis((4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)alkane moiety formation stage, dibromoalkanes (dibromomethane, dibromopropane, dibromobuthane) were used as secondary reagents. The reaction was conducted in propan-2-ol. The presence of reaction products has been confirmed applying spectral methods. Synthesis of bis((4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)alkanes 0.01 M of the correspondent alkyl halide is added to the corresponding 3-(3-R-1,2,4-triazol-5-thiomethyl)-1,2,4-triazol-5-thione (0.01 M) in mixture of 0.01 mole NaОН and 30 mL of ethanol or propan-1-ol, and the mixture is boiled until the neutralization (during 3 hours reflux). The mixture is filtered, solvent is evaporated. White crystalline matter, practically insoluble in water, soluble in organic solvents. Compounds were purified by recrystallization from dimethylformamide-water mixture (1:1). Results. Distinction of compounds was confirmed by chromatography-mass-spectrometry. 1 H NMR spectra of the obtained compounds were characterized by number of signals. The protons of alkylsulfide fragment resonate in a weak field appearing as multiplets at 3.12–3.07 ppm and 2.25–2.10 ppm. The protons of methyl group, which bond the heteroaromatic fragments together, resonate as a singlet at 3.92–3.87 ppm. Aromatic protons of thiophene fragments appear as multiplets at 6.95–6.78 and 6.99–7.20 ppm. The protons of methyl fragment of N-alkyl substituent appear as a multiplet at 4.21–3.98 ppm, protons of methyl fragment resonate as a triplet at 1.52–1.57 ppm. IR spectra of the studied compounds showed presence of C-S fragment, which appears as a band of molecular stretching at 693 cm -1 . Stretching vibrations of С-H fragment of thiophene ring is observed at 715–693 cm -1 . The CH 2 fragment appears as strong stretching (at 2935–2905 cm-1 and 2865–2855 cm -1 ) and moderate bending vibrations (at 1493–1460 cm -1 ). Also recommended for “polymethylene fragment” are characteristic deformation vibrations at 730–720 cm -1 . Symmetrical and asymmetrical bending at 1385–1380 and 1470–1465 cm -1 characterize the presence of СН 3 group. Preliminary screening of acute toxicity and biological activity parameters has been carried out. Conclusions . Nine compounds were obtained; their structures were confirmed.The characteristics of the synthesized compounds were assessed with computer processing using PASS online tool. The most promising compounds were selected for in vitro research. It was clarified during the analysis of results that the obtained compounds may exhibit various types of biological activities. The most probable effect predicted for the nine studied compounds is antimicrobial activity.

Water Complexes of Ionic Liquids: 1‐Butyl‐3‐methyl Imidazolium Chloride and Tetrafluoroborate Systems in KBr Matrix.

AbstractIn the present work the formation of water complexes with ionic liquids (ILs) –1‐butyl‐3‐methylimidazolium chloride [bmim][Cl] and 1‐butyl‐3‐methylimidazolium tetrafluoroborate [bmim][BF4] in KBr matrix at ambient temperature by IR technique was studied. There was shown that between the components of the system the hydrogen bond, in which the heteroaromatic fragment and anion (Cl− or BF4−) can participate, arises. The ab initio calculation in terms of DFT predicts a possibility of an interaction between the hydrogen atoms of CH bond in heteroaromatic ring and CH3‐group with oxygen atom as well as between anion (Cl− or BF4−) with hydrogen atom of water molecule.

Amorphous Hole-Transporting Material based on 2,2'-Bis-substituted 1,1'-Biphenyl Scaffold for Application in Perovskite Solar Cells.

Perovskite solar cells are considered a promising technology for solar-energy conversion, with power conversion efficiencies currently exceeding 20 %. In most of the reported devices, Spiro-OMeTAD is used for positive-charge extraction and transport layer. Although a number of alternative hole-transporting materials with different aromatic or heteroaromatic fragments have already been synthesized, a cheap and well-performing hole-transporting material is still in high demand. In this work, a two-step synthesis of a carbazole-based hole-transporting material is presented. Synthesized compounds exhibited amorphous nature, good solubility and thermal stability. The perovskite solar cells employing the newly synthesized material generated a power conversion efficiency of 16.5 % which is slightly lower than that obtained with Spiro-OMeTAD (17.5 %). The low-cost synthesis and high performance makes our hole-transport material promising for applications in perovskite-based optoelectronic devices.

Effect of bulky substituents on the photochromic properties of indoline spiropyrans containing an annelated aromatic or heteroaromatic fragment

Novel indoline spiropyrans containing bulky neopentyl substituents at the nitrogen atom of the indoline fragment were prepared. The structure of the obtained compounds was established by a set of physicochemical methods of analysis. Comparison was made for the spectral absorption and kinetic parameters of the obtained compounds and their analogs containing methyl and benzyl substituents instead of neopentyl ones.

Multiple Ligands Targeting Cholinesterases and β‐Amyloid: Synthesis, Biological Evaluation of Heterodimeric Compounds with Benzylamine Pharmacophore

Alzheimer's disease (AD) is a fatal and complex neurodegenerative disorder for which effective treatment remains the unmet challenge. Using donepezil as a starting point, we aimed to develop novel potential anti-AD agents with a multidirectional biological profile. We designed the target compounds as dual binding site acetylcholinesterase inhibitors, where the N-benzylamine pharmacophore is responsible for interactions with the catalytic anionic site of the enzyme. The heteroaromatic fragment responsible for interactions with the peripheral anionic site was modified and three different heterocycles were introduced: isoindoline, isoindolin-1-one, and saccharine. Based on the results of the pharmacological evaluation, we identified compound 8b with a saccharine moiety as the most potent and selective human acetylcholinesterase inhibitor (IC50 = 33 nM) and beta amyloid aggregation inhibitor. It acts as a non-competitive acetylcholinesterase inhibitor and is able to cross the blood-brain barrier in vitro. We believe that compound 8b represents an important lead compound for further development as potential anti-AD agent.

Ferrocenyl (P,N)-diphosphines incorporating pyrrolyl, imidazolyl or benzazaphospholyl moieties: Synthesis, coordination to group 10 metals and performances in palladium-catalyzed arylation reactions

Three novel symmetrical ferrocenyl diphosphines with tertiary phosphorus atoms holding respectively nitrogen-containing heterocyclic derivatives of pyrrole, imidazole and benzazaphosphole were synthesized and characterized. Up to now, integration of heteroaromatic fragments, or more generally hetero-cycles, as substituents on the tertiary phosphines of symmetrical ferrocenyl diphosphines has been limited to the furyl motif. Their coordination to palladium and platinum group 10 transition metals was exemplified, and analyzed using single crystal X-ray diffraction. The performances obtained in palladium-catalyzed copper-free Sonogashira and Suzuki cross-coupling reactions using bromoarenes and chloroarenes are reported for the most efficient system. The unprecedented combination of a tert-butyl group and of an imidazolyl motif on the phosphorus atoms led to an air-stable ferrocenyl diphosphine, which allowed in combination with 0.1–0.2 mol% of palladium to generate catalytic systems able to couple some activated chloroarenes and most of the bromoarenes examined.

Indole- and benzothiophene-based histamine H 3 antagonists

Previous research on histamine H 3 antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH 3 affinities. Select analogs were profiled in a rat pharmacokinetic model.

The synthetic challenge of diazonamide A, a macrocyclic indole bis-oxazole marine natural product

The complex structure of the marine metabolic diazonamide A comprises a dichlorinated indole bis-oxazole heteroaromatic fragment, and a [b]-fused dihydrobenzofuran-dihydroindole unit containing an animal carbon, all incorporated within a strained double macrocyclic array. This review details the synthetic studies on this fascinating natural product starting from early studies on the original structure (1991-2001), through the synthesis of the originally proposed structure and the subsequent structural revision, to the eventual successful syntheses of the natural product itself. Throughout we focus on the innovative ways in which synthetic chemists have approached the challenges posed by this natural product.

Synthesis and reactivity of 3-amino-9-methoxymethyl-7-methyl-3,4-dihydropyrido-[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-ones

The reaction of acyl derivatives of ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate with hydrazine hydrate gives a series of tricyclic 3-amino-3,4-dihydropyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-ones containing aliphatic, aromatic, or heteroaromatic fragments at C(2). The reactions of 3-aminopyridothieno[3,2-d]pyrimidin-4-ones with aldehydes, formamide, 2,5-dimethoxytetrahydrofuran, acetic anhydride, and Raney nickel were studied.

Synthesis, coordination properties, and analytical applications of mixed donor macrocycles containing the 1,10-phenanthroline sub-unit

The coordination properties towards different metal ions of a new class of mixed N/S-, and N/S/O-donor macrocycles containing the 1,10-phenanthroline sub-unit in the cyclic framework are reviewed. The conformational constraints imposed by the heteroaromatic fragment onto the aliphatic portion of the ring determine the coordination mode of these ligands which can stabilise low-valent Ni+, Pd+, Pt+, and Rh+ metal complexes. Structural and thermodynamic aspects of the coordination chemistry of these ligands are considered together with possible applications as building blocks in the synthesis of multi-centred systems, and as template in the construction of extended polyiodide networks. However, solution studies demonstrate the inability of these ligands to work as selective and specific fluorescent chemosensors for heavy transition and post-transition metal ions and the formation constants evaluated for the formation of 1:1 complexes with Pb2+, Cd2+, Hg2+, Cu2+, and Ag+ in acetonitrile are of the same order of magnitude. Nevertheless, some of these macrocyles are extremely effective to recognise Cu2+ or Ag+ over the other metal ions in transport processes, and have been successfully used as neutral ionophore in the construction of PVC-based ionselective electrodes and supported liquid membranes for analytical detection and separation, respectively, of these metal ions.

Distribution of vanadium and vanadyl porphyrins in petroleum distillates of different chemical types

1. 1. The greater part of atomic vanadium and vanadyl porphyrin molecules present in crude oils from all producing layers of the Samotlor deposit is concentrated in the petroleum resin, although the absolute concentration of V is maximum in asphaltene fractions. Vanadium atoms associate mainly with hetero-aromatic fragments of crude oil resin-asphalt substances. Up to 98% vanadium is contained in asphaltenes and almost all V atoms in petroleum fractions are contained in non-porphyric compounds. 2. 2. Using Samotlor crude oils a clear is observed with: a) a reduction in overall vanadium concentration in all fractions, b) in the content of vanadyl porphyrins in malthene fractions, c) according to the paraffinicity of crude oils, particularly in relation to intensification of catagenic transformations with increasing depth and age of the surrounding deposits.