Pyridine Core Research Articles

Vinylene-linked pyridine-pyrrole donor–acceptor conjugated polymers

Vinylene-linked donor–acceptor–donor semiconducting polymers have been prepared by electropolymerization of the new monomers 2,6-bis[( E)-2-(1-methylpyrrol-2-yl)vinyl]pyridine and 2,5-bis[( E)-2-(1-methylpyrrol-2-yl)vinyl]pyridine. The monomers, consisting of two pyrrole donor units and a central pyridine acceptor ring spaced by vinylene links, differ by the substitution pattern around the central pyridine core (2,6 vs. 2,5-substitution). The electropolymerization process is more efficient on the 2,5-derivative. The new polymers show reversible electrochemistry dominated by a strong charge trapping effect. Poly(2,5-bis[( E)-2-(1-methylpyrrol-2-yl)vinyl]pyridine) energy levels closely match those of design rules for optimized polymers in combination with fullerene derivatives in bulk heterojunction solar cells.

Copper(i)-mediated preparation of new pyrano[3′,4′:4,5]imidazo[1,2-a]pyridin-1-one compounds under mild palladium-free conditions

A general and efficient Cu(I)-mediated cross-coupling and heterocyclization reaction of 3-iodoimidazo[1,2-a]pyridine-2-carboxylic acid, and terminal alkynes was developed under very mild conditions. This method allows the introduction in one pot of a third ring fused in positions 2 and 3 of the imidazo[1,2-a]pyridine core with reasonable yields and total regioselectivity. This procedure does not require the use of any expensive supplementary additives, and is palladium-free.

Highly Versatile Synthetic Approach to Oligopyridines and Derivatives by Kröhnke-type Ring-closure Reactions

The synthesis of a large variety of different conjugated oligopyridines and derivatives with electron poor and/or rich peripheral substituents and with pyridine and other (hetero)aromatic cores by the highly versatile Krohnke-type synthesis is described. Simple electronic and steric considerations of the participating unsaturated ketones (chalcones) allow a rough estimation of the synthetic accessibility of the desired compounds.

3-(Dichloroacetyl)chromone; A New Building Block for the Synthesis of Formylated Purine Isosteres: Design and Synthesis of Fused α-(Formyl)pyridines

The first synthesis of 3-(dichloroacetyl)chromone from 3-(dimethylamino)-1-(2-hydroxyphenyl)propen-1-one and dichlo- roacetyl chloride is described. The reaction of electron-rich amino- heterocycles with 3-(dichloroacetyl)chromone provides a set of diverse fused pyridines bearing the CHCl2-substituent at the a-posi- tion of the pyridine core. Subsequent hydrolysis leads to the forma- tion of annulated a-(formyl)pyridines.

3-Methoxalylchromone - A Versatile Reagent for the Regioselective Synthesis of 1-Desazapurine

The reaction of 5-amino-1H-imidazoles with 3-methox- alylchromone provided a set of imidazo(4,5-b)pyridines (1-des- azapurines) bearing the CO2Me substituent at the a-position of the pyridine core. The corresponding acids were synthesized by subse- quent hydrolysis of the ester function. Being typical purine isos- teres, 1-desazapurines are considered to be potent pharmacophores, and are widely used in drug design and medicinal chemistry.

Design and synthesis of 3-pyridylacetamide derivatives as dipeptidyl peptidase IV (DPP-4) inhibitors targeting a bidentate interaction with Arg125

We have previously discovered nicotinic acid derivative 1 as a structurally novel dipeptidyl peptidase IV (DPP-4) inhibitor. In this study, we obtained the X-ray co-crystal structure between nicotinic acid derivative 1 and DPP-4. From these X-ray co-crystallography results, to achieve more potent inhibitory activity, we targeted Arg125 as a potential amino acid residue because it was located near the pyridine core, and some known DPP-4 inhibitors were reported to interact with this residue. We hypothesized that the guanidino group of Arg125 could interact with two hydrogen-bond acceptors in a bidentate manner. Therefore, we designed a series of 3-pyridylacetamide derivatives possessing an additional hydrogen-bond acceptor that could have the desired bidentate interaction with Arg125. We discovered the dihydrochloride of 1-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-(2-methylpropyl)pyridin-3-yl]acetyl}-l-prolinamide (13j) to be a potent and selective DPP-4 inhibitor that could interact with the guanidino group of Arg125 in a unique bidentate manner.

High-content screening of feeder-free human embryonic stem cells to identify pro-survival small molecules

The propensity of human embryonic stem cells to die upon enzymatic disaggregation or low-density plating is an obstacle to their isolation and routine use in drug discovery and basic research. Equally, the very low rate of establishment of implanted cells hinders cell therapy. In the present study we have developed a high-content assay for human embryonic stem cell survival and used this to screen a range of libraries of 'lead-like' small molecules and known bioactives. From this we identified 18 confirmed hits with four structural classes being represented by multiple compounds: a series of 5-(acyl/alkyl-amino)indazoles, compounds with a 4-(acylamino)pyridine core, simple N⁶,N⁶-dialkyladenines and compounds with a 5-(acylamino)indolinone core. In vitro kinase profiling indicated that the ROCK (Rho-associated kinase)/PRK2 (protein kinase C-related kinase 2) protein kinases are of pivotal importance for cell survival and identified previously unreported compound classes that inhibited this important biological activity. An evaluation using an extensive panel of protein kinases showed that six of our hit compounds exhibited better selectivity for ROCK inhibition than the routinely used commercially available ROCK inhibitor Y-27632. In this screen we also identified the K(+)-ATP channel opener pinacidil and show that it probably promotes cell survival, by 'off-target' inhibition of ROCK/PRK2. We have therefore identified novel pro-survival compounds of greater specificity, equivalent potency and reduced toxicity relative to the routinely employed ROCK inhibitor Y-27632.

Total Syntheses of the Thiopeptides Amythiamicin C and D

The thiopeptides amythiamicin C and D were synthesized by employing amide bond formation, a Stille cross-coupling reaction, and two Negishi cross-coupling reactions as key transformations. The central 2,3,6-trisubstituted pyridine ring of the target compounds was introduced as a 2,6-dibromo-3-iodopyridine, which was selectively metalated at the 3-position and connected to the complete Southern fragment of the amythiamicins by a Negishi cross-coupling. For the synthesis of amythiamicin C, this step was followed by a Negishi cross-coupling at C-6 of the pyridine core. Subsequent attachment of the Eastern fragment was achieved by amide bond formation and macrolactam ring closure by a Stille cross-coupling at C-2. The Eastern bithiazole fragment of the amythiamins was constructed also by regioselective metalation and cross-coupling reactions. The pivotal step involved the diastereoselective addition of 4-bromothiazole-2-magnesium bromide to a chiral sulfinyl imine. For the synthesis of amythiamicin D, the order of cross-coupling at C-6, amide bond formation, and cross-coupling at C-2 was changed. The amide bond formation to the Eastern fragment was performed first and it was subsequently attempted to close the macrolactam by an intramolecular regioselective Stille cross-coupling at C-2. Despite the low regioselectivity of this reaction it paved the way to the immediate completion of the amythiamicin D synthesis when followed by a Negishi cross-coupling at C-6 with 2-zincated methyl thiazole-5-carboxylate.

Complexes of Click‐Derived Bistriazolylpyridines: Remarkable Electronic Influence of Remote Substituents on Thermodynamic Stability as well as Electronic and Magnetic Properties

2,6-Bis(1,2,3-triazol-4-yl)pyridine (btp) ligands with substitution patterns ranging from strongly electron-donating to strongly electron-accepting groups, readily prepared by means of Cu-catalyzed 1,3-dipolar cycloaddition (the "click" reaction), were investigated with regard to their complexation behavior, and the properties of the resulting transition-metal compounds were compared. Metal-btp complexes of 1:1 stoichiometry, that is, [Ru(btp)Cl(2)(dmso)] and [Zn(btp)Br(2)], could be isolated and were crystallographically characterized: they display octahedral and trigonal-bipyramidal coordination geometries, respectively, and exhibit high aggregation tendencies due to efficient pi-pi stacking leading to low solubilities. Metal-btp complexes of 1:2 stoichiometry, that is, [Fe(btp)(2)](2+) and [Ru(btp)(2)](2+), could also be synthesized and their metal centers show the expected octahedral coordination spheres. The iron compounds exhibit quite a complex magnetic behavior in the solid state including spin crossover near room temperature, and hysteresis and locking into high-spin states on tempering at 400 K, depending on the substituents on the btp ligands. Cyclic voltammetry studies of [Ru(btp)(2)](2+) reveal strong modulation of the oxidation potentials by more than 0.6 V and a clear linear correlation to the Hammett constant (sigma(para)) of the substituent at the pyridine core. Isothermal titration calorimetry was used to measure the thermodynamics of the Fe(II)-btp complexation process and enabled accurate determination of the complexation enthalpies, which display a linear relationship with the sigma(para) values for the terminal phenyl substituents. Detailed NMR spectroscopic studies finally revealed that in the case of Fe(II) complexation, dynamics are rapid for all investigated btp derivatives in acetonitrile, while replacing Fe(II) by Ru(II) or changing the solvent to dichloromethane effectively slows down ligand exchange. The results nicely demonstrate the utility of substituent parameters, originally developed for linear free-energy relationships to explain reactivity in organic reactions, in coordination chemistry, and to illustrate the potential to custom-design btp ligands and complexes thereof with predictable properties. The fast equilibration of the [Fe(btp)(2)](2+) complexes together with their tunable stability and interesting magnetic properties should enable the design of dynamic metallosupramolecular materials with advantageous properties.

Genetic interception and structural characterization of thiopeptide cyclization precursors from Bacillus cereus.

The pyridine core of the thiocillins has long been postulated to arise from a late-stage tail-to-tail condensation of two dehydroalanines. Genetic disruption of tclM, a proposed "Diels-Alderase", allowed isolation of acyclic precursors to this pyridine ring. The isolated products possess the full cohort of post-translational modifications that are normally displayed by the thiocillins, including dehydrobutyrines, thiazoles, C-terminal decarboxylation, and the two previously unconfirmed dehydroalanines. Additionally, leader peptides have undergone extensive N-terminal degradation and the remaining leader peptide residues have been N-succinylated. These results identify TclM and its homologues in other thiazolyl peptide producing strains as the enzymes responsible for the trans-annular heteroannulation at core of this class of molecules.

A Novel Phenylimidazo[1,2-α]pyridine Core Skeleton and Pharmacophore Model as Hypoxia-Inducible Factor Inhibitors

A Novel Phenylimidazo[1,2-α]pyridine Core Skeleton and Pharmacophore Model as Hypoxia-Inducible Factor Inhibitors

Manipulation of Thiocillin Variants by Prepeptide Gene Replacement: Structure, Conformation, and Activity of Heterocycle Substitution Mutants

Bacillus cereus ATCC 14579 converts the C-terminal 14 residues of a 52-mer prepeptide into a related set of eight variants of the thiocillin subclass of thiazolyl peptide antibiotics by a cascade of post-translational modifications that alter 13 of those 14 residues. We have introduced prepeptide gene variants into a knockout strain to conduct an alanine scan of all 14 progenitor residues, as well as a serine scan of the six cysteine residues that are converted to thiazoles in the mature natural product. No mature scaffolds were detected for the S1A and S10A mutants, consistent with their roles as the source of the pyridine core. In both the alanine and serine scans, only one substitution mutant failed to produce a mature scaffold: cysteine 11. Cysteine to serine mutants gave mixture of dehydrations, aromatizations, and unaltered alcohol side chains depending on position. Overall, substitutions that altered the trithiazolylpyridine core or reduced the conformational rigidity of the 26-membered macrocyclic loop led to loss of antibiotic activity. In total, 21 peptide mutants were cultured, from which production of 107 compounds was observed and 94 compounds, representing 17 structural mutants, were assayed for antibiotic activity. High-resolution NMR solution structures were determined for one mutant and one wild-type compound. These structures demonstrate that the tight conformational rigidity of the natural product is severely disrupted by loss of even a single heterocycle, perhaps accounting for the attendant loss of activity in such mutants.

New Schiff Bases with Pyridine Core: Spectral, Thermal and Optical Characterizations

Problem statement: Numerous studies have been conducted on the Schiff base's alkyl and alkyloxy possessing aromatic core. However, the thermo tropic properties of Schiff base's ester (or alkanoyloxy) with pyridine core was rare studied. Approach: To study spectral, thermal and optical behaviors of Schiff base ester possessing heterocyclic (pyridine) terminal core. A series of 4-[(pyridin-3-ylmethylene) amino] phenylalkanoates were prepared and all the members are differed by the length of alkanoyloxy chain, Cn-1H2n-1COO, where n = 12, 14, 16 and 18. The thermal and optical characteristics were studied using differential scanning calorimetry and polarizing optical microscopy. Results: DSC studies showed that all of the title compounds exhibited direct isotropization and recrystallization during heating and cooling cycles, respectively. Under polarizing optical microscope, crystal phase texture was observed to change to dark region isotropic without displaying any liquid crystal phase. Conclusion: The presence of terminal pyridine core suppressed the formation of mesosphere in the compounds studied.

Antitumor activity and COMPARE analysis of bis-indole derivatives

This paper reports the synthesis of new derivatives (formed by two indole systems separated by a central moiety) analogous of potent antitumor agents previously described. The activity of the bis-indoles bearing a pyridine core confirms the good result described in the previous paper and compound 4c was chosen for the first in vivo experiment (Hollow Fiber Assay). COMPARE analysis and structure–activity relationships were also considered. Contrary to data reported by other Authors, no correlations were found between antitumor activity and NQO1 induction.

(E)-N-{[6-Chloro-4-(4-chlorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl]methylene}benzene-1,2-diamine: a three-dimensional framework structure built from only two hydrogen bonds

The molecules of the title compound, C(26)H(19)Cl(2)N(5), are conformationally chiral, with none of the aryl groups coplanar with the pyrazolo[3,4-b]pyridine core of the molecule. A single unique N-H...N hydrogen bond links the molecules into two symmetry-related sets of C(11) chains running parallel to the [011] and [011] directions, respectively, and these two sets of chains are linked into a continuous three-dimensional framework structure by a single unique C-H...N hydrogen bond which forms a chain parallel to the [100] direction.

Quick Access to Diverse Polymerizable Molecules (a Monomer Library) by Catalytic [2 + 2 + 2] Cycloaddition Reactions of Functionalized Alkynes

The [2 + 2 + 2] cycloaddition reactions of 1,6-diynes and alkynes with a functional group(s), such as epoxide, oxetane, ester, alcohol, phenol, amine, borate, styrene, and methacrylate, catalyzed by a dipimp/CoCl2·6H2O/Zn reagent [dipimp: 2-(2,6-diisopropylphenyl)-iminomethyl-pyridine] yielded a variety of polymerizable molecules (monomers) having a 2,3-dihydro-1H-indene core structure. Similarly, the [2 + 2 + 2] cycloaddition reactions of 1,6-diynes and nitriles with a functional group(s) catalyzed by a dppe/CoCl2·6H2O/Zn reagent [dppe: 1,2-bis(diphenylphosphino)ethane] gave a variety of polymerizable molecules (monomers) with a 6,7-dihydro-5H-cyclopenta[c]pyridine core structure. Among the resulting monomers, 5-phenyl-1,3-dihydrospiro[indene-2,3′-oxetane] prepared from 3,3-di(prop-2-ynyl)oxetane and phenylacetylene was representatively polymerized in the presence of BF3 catalyst. A cationic random copolymerization of one of 1,3-dihydrospiro[indene-2,3′-oxetane] derivatives with 3-ethyl-3-(phenoxymethyl)...

A Direct, Copper-Catalyzed Functionalization of Pyridines with Alkynes

A one-pot, copper-catalyzed method to construct 2-alkynylpyridines is presented. This provides a route to access these products directly from terminal alkynes and the parent pyridine, and without prefunctionalization of the pyridine core. In addition, (Z)-alk-2-enylpyridines can be prepared via a related procedure. These reactions are used to synthesize a number of new alkynyl- and alkenyl-substituted pyridines in one pot.

3-Methoxalylchromone—a novel versatile reagent for the regioselective purine isostere synthesis

The first synthesis of 3-methoxalylchromone was described. The reaction of the latter with electron-rich aminoheterocycles afforded a set of heteroannelated pyridines bearing a CO(2)Me substituent located at the α-position of the pyridine core.

Three-Component Synthesis of Perfluoroalkyl- or Perfluoroaryl-Substituted 4-Hydroxypyridine Derivatives and Their Palladium-Catalyzed Coupling Reactions

A three-component reaction with lithiated alkoxyallenes, nitriles, and perfluorinated carboxylic acids as precursors led to a series of perfluoroalkyl- or perfluoroaryl-substituted 4-hydroxypyridine derivatives. These compounds were converted into 4-pyridyl nonaflates which can be employed as versatile building blocks for the synthesis of pi-conjugated compounds with use of palladium-catalyzed couplings. Suzuki reactions at C-4 and C-3 of the pyridine ring proceeded with moderate to high yields. In addition, Suzuki-Miyaura, Stille, or Buchwald-Hartwig coupling reactions have also been studied and afforded the corresponding highly substituted pyridine derivatives. Starting from an arylated propargylic ether the three-component reaction led to a pentasubstituted 4-hydroxypyridine derivative that could also be employed in palladium-catalyzed processes at C-4 and at C-3 of the pyridine core. With this simple approach the sterically highly crowded 3,4,5-triphenyl-substituted pyridine derivative 37a could be prepared and studied by an X-ray analysis. With acetonitrile as precursor a different reaction pathway was found when this component was used in excess resulting in a pyridine derivative with a new substitution pattern. In summary, the methods described here allow a flexible and fairly efficient entry to a variety of highly substituted pyridine derivatives bearing perfluorinated alkyl or aryl groups.

A versatile synthesis of benzothieno-annelated 1,2-dihydropyridine and 1,2,3,4-tetrahydropyridine derivatives: the effect of the structure of benzothieno-annelated pyridinium salts on their reduction by sodium borohydride

Benzothieno(2,3-c)pyridinium and benzothie- no(2,3-c)quinolinium salts were synthesized either by quaternization of benzothieno(2,3-c)pyridines, or recycli- zation of benzothieno(2,3-c)pyrylium salts with primary amines. One-pot synthesis of benzothieno(3,2-g)indolizi- nium salts from 1-(3-chloropropyl)-benzothieno(2,3-c) pyrylium included consequent recyclization of the pyryli- um core by ammonia into a pyridine intermediate and its further intramolecular quaternization reaction. Depending on the structure of benzothieno-annelated pyridinium salts, their reaction with sodium borohydride in methanol results in reduction of the pyridine core into tetrahydropyridine or dihydropyridine derivatives. Whereas reduction of benzo- thieno(2,3-c)pyridinium and benzothieno(3,2-g)indolizinium salts readily yields benzothieno-annelated tetrahydropyri- dines as a complex mixture of stereoisomers, reduction of benzothieno(2,3-c)quinolinium salts results in dihydropyr- idine derivatives. The structure of the latter, in particular, was confirmed by single-crystal X-ray diffraction analysis.