Pyridine Core Research Articles

Atom-Economical Palladium Carbon-Catalyzed de Novo Synthesis of Trisubstituted Nicotinonitriles

A de novo palladium carbon-catalyzed synthesis of trisubstituted nicotinonitriles from easily synthesized homopropagylic or homoallylic aromatic alcohols in the presence of nitriles has been explored. The mechanism proceeds with an interesting generation of a Pd(II)-C palladacycle followed by an oxidative aromatization to generate the pyridine core. The pyridine core is generated with a noteworthy C-C bond cleavage in the case of the substituted nitriles. The moderate yields and easy separation of the products lend a unique importance to this one-pot methodology.

Design, synthesis, and biological activity of 5′-phenyl-1,2,5,6-tetrahydro-3,3′-bipyridine analogues as potential antagonists of nicotinic acetylcholine receptors

Starting from a known non-specific agonist (1) of nicotinic acetylcholine receptors (nAChRs), rationally guided structural-based design resulted in the discovery of a small series of 5′-phenyl-1,2,5,6-tetrahydro-3,3′-bipyridines (3a–3e) incorporating a phenyl ring off the pyridine core of 1. The compounds were synthesized via successive Suzuki couplings on a suitably functionalized pyridine starting monomer 4 to append phenyl and pyridyl substituents off the 3- and 5-positions, respectively, and then subsequent modifications were made on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist, which is highly selective for α3β4 nAChR (Ki=123nM) over the α4β2 and α7 receptors.

Synthesis and in vitro evaluation of dihydro-6H-chromeno[4,3-b]isoxazolo[4,5-e]pyridine derivatives as potent antidiabetic agents

A simple, straightforward, and highly efficient one-pot three-component synthesis of a pharmaceutically interesting kind of functionalized dihydro-6H-chromeno[4,3-b]isoxazolo[4,5-e]pyridine heterocycles has been developed based on an environmentally benign method. All synthesized compounds were evaluated for their antidiabetic activity against type 2 diabetes mellitus. The results indicated that most of the synthesized compounds exhibited moderate to good antidiabetic activity. Synthesized compound 4i demonstrated the highest inhibition of α-amylase activity (IC50 = 56.043 µg/mL). This finding suggests an approach to develop effective antidiabetic agents by incorporating pyridine core structure.

Regioselective TfOH-mediated hydroamidation of ynamides with nitriles

A new TfOH-mediated reaction of ynamides with nitriles as nucleophiles has been developed. The reaction works efficiently under mild reaction conditions to afford a new class of α-acylaminoenamides readily via the intermediacy of keteniminium ion. The reaction displays generality and a broad substrates scope. Additionally, the α-acylaminoenamides could be transformed to highly substituted pyridine, 4-aminopyrimidine or isoquinoline cores.

Ethyl 2-(6-bromo-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)acetate

The title imidazo [4,5-b] pyridine derivative, C16H14BrN3O2, crystallizes with two independent molecules (1 and 2) in the asymmetric unit. In molecule 1, the pendant phenyl ring is inclined to the imidazo[4,5-b]pyridine core by 43.10 (4)° while in molecule 2 the corresponding angle is 49.43 (4)°. The two molecules differ primarily in the conformations of the ester substituents. In the crystal, molecules are linkedviaC—H...N and C—H...O hydrogen bonds, forming sheets parallel to theabplane.

Synthesis of bioactive and fluorescent pyridine-triazole-coumarin peptidomimetics through sequential click-multicomponent reactions

An easy synthetic protocol for the peptide randomization of 3,5-dicyano pyridine derivatives by linking the pyridine core with a coumarin chromophore spaced by a linker triazole via copper (I) catalyzed [3+2] azide-alkyne cycloaddition (CuAAC) is described. The new peptidomimetics thus obtained are extended rule of 5 (eRo5) molecules suitable for the development of therapeutic agents for undruggable targets. The structural and photophysical properties of the molecules are also promising for the development of potential bio imaging agents based on these molecules.

Synthesis and Biological Evaluation of New Triazolo- and Imidazolopyridine RORγt Inverse Agonists.

Retinoic-acid-related orphan receptor γt (RORγt) is a key transcription factor implicated in the production of pro-inflammatory Th17 cytokines, which drive a number of autoimmune diseases. Despite diverse chemical series having been reported, combining high potency with a good physicochemical profile has been a very challenging task in the RORγt inhibitor field. Based on available chemical structures and incorporating in-house knowledge, a new series of triazolo- and imidazopyridine RORγt inverse agonists was designed. In addition, replacement of the terminal cyclopentylamide metabolic soft spot by five-membered heterocycles was investigated. From our efforts, we identified an optimal 6,7,8-substituted imidazo[1,2-a]pyridine core system and a 5-tert-butyl-1,2,4-oxadiazole as cyclopentylamide replacement leading to compounds 10 ((S)-N-(8-((4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)methyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-methylpyrimidine-5-carboxamide) and 33 ((S)-N-(8-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)-3-methylpiperazin-1-yl)methyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-methylpyrimidine-5-carboxamide). Both derivatives showed good pharmacological potencies in biochemical and cell-based assays combined with excellent physicochemical properties, including low to medium plasma protein binding across species. Finally, 10 and 33 were shown to be active in a rodent pharmacokinetic/pharmacodynamic (PK/PD) model after oral gavage at 15 mg kg-1 , lowering IL-17 cytokine production in ex vivo antigen recall assays.

Diamidophosphite–oxazolines with a pyridine core in Pd-catalyzed asymmetric reactions

We have designed and synthesized a small library of readily available P,N,N-diamidophosphite–oxazoline ligands containing 1,3,2-diazaphospholidine rings and a pyridine moiety. The use of these ligands provides up to 96% ee in Pd-catalyzed asymmetric allylations of (E)-1,3-diphenylallyl acetate; up to 80% ee in the Pd-catalyzed asymmetric alkylation of cinnamyl acetate with ethyl 2-oxocyclohexane-1-carboxylate and up to 94% ee in the Pd-catalyzed desymmetrization of N,N′-ditosyl-meso-cyclopent-4-ene-1,3-diol biscarbamate. The influence of the structural modules, such as the nature of the phosphorus containing ring or pyridine substituent as well as of the addition of zinc(II) 5,10,15,20-tetraphenylporphyrin on the catalytic activity and enantioselectivity is discussed.

One-pot synthesis of 2-ferrocenyl-substituted pyridines

A facile, one-pot method for the synthesis of 2-ferrocenylpyridines is described. When reacted with propargylamine, α,β-alkynic ketones produced N-propargylic β-enaminones in situ, which, in the presence of copper(I) chloride, underwent electrophilic cyclization to afford 2-ferrocenylpyridine derivatives in good to high yields. This cyclization was found to be general for a variety of α,β-alkynic ketones and tolerated the presence of aryl groups with electron-withdrawing and electron-donating substituents. The enrichment of the pyridine core with a ferrocenyl moiety, in addition to benzoyl groups, may offer potential for the synthesis of molecules of pharmacological interest.

Magnetic Supported Copper Nanoparticles: An Efficient Heterogeneous Catalyst for the Synthesis of 1,2‐Diketones by Cross‐Coupling Reaction of Imidazo[1,2‐a]pyridines with Methyl Ketones

A convenient and new copper nanoparticles‐catalyzed cross‐coupling reaction of imidazo[1,2‐a]pyridines with methyl ketones has been developed to synthesize 1,2‐diketones that have an imidazo[1,2‐a]pyridine core. Highly active magnetic copper nanoparticles [i.e., Cu4O3@Fe3O4_C(II)] were prepared and characterized by standard materials characterization techniques, which included transmission electron microscopy, scanning electron microscopy, X‐ray photoelectron spectroscopy (XPS) and X‐ray diffraction. These methods were also used to acquire information about the size, oxidation state, and crystallinity of the nanoparticle catalyst. With this method, a variety of pharmaceutically important 1,2‐dicarbonyl imidazo[1,2‐a]pyridines were readily synthesized in moderate to good yields. The catalyst was easily separated from the reaction mixture by using an external magnetic field and could be recycled 6 times with only a negligible change in the catalytic performance.

Metal‐Free Synthesis of Highly Substituted Pyridines by Formal [2+2+2] Cycloaddition under Mild Conditions

AbstractThe synthesis of pyridines through direct intermolecular cycloaddition of alkynes and nitriles is a contemporary challenge in organic synthesis. A Brønsted acid mediated formal [2+2+2] cycloaddition of heteroalkynes and nitriles was developed that proceeds under mild conditions. This constitutes a modular approach to highly substituted pyridine cores.

Metal-Free Synthesis of Highly Substituted Pyridines by Formal [2+2+2] Cycloaddition under Mild Conditions.

The synthesis of pyridines through direct intermolecular cycloaddition of alkynes and nitriles is a contemporary challenge in organic synthesis. A Brønsted acid mediated formal [2+2+2] cycloaddition of heteroalkynes and nitriles was developed that proceeds under mild conditions. This constitutes a modular approach to highly substituted pyridine cores.

ChemInform Abstract: Keeping it Small, Polar, and Non‐Flat: Diversely Functionalized Building Blocks Containing the Privileged 5,6,7,8‐Tetrahydro[1,2,4]triazolo[4,3‐a]‐ and [1,5‐a]pyridine Cores.

AbstractDifferent sets of functionalized building blocks, e.

Biocatalytic Transamination for the Asymmetric Synthesis of Pyridylalkylamines. Structural and Activity Features in the Reactivity of Transaminases

A set of transaminases has been investigated for the biocatalytic amination of 1-(4-chloropyridin-2-yl)alkan-1-ones. The influence of the chain length of the n-1-alkanone at the C-2 position of the pyridine has been studied in the reaction with different (R)- and (S)-selective transaminases. Thus, enantiopure amines were isolated with high purity starting from a wide selection of prochiral ketones. On the one hand, excellent yields (from 97 to >99% conversion, up to 93% isolated yield) and stereoselectivity values (>99% ee for both amine enantiomers) were found for n-1-alkanone linear short chain substituents such as ethanone or propanone. On the other hand, more hindered substrates were accepted only when using evolved enzymes such as an evolved variant of (R)-Arthrobacter (ArRmut11-TA). An initial common structural feature was the presence of a chlorine atom on the C-4 position of the pyridine core, which was found to increase the reactivity of the starting ketone, giving extra versatility for the intro...

Conformational and Molecular Structures of α,β-Unsaturated Acrylonitrile Derivatives: Photophysical Properties and Their Frontier Orbitals.

We report single crystal X-ray diffraction (hereafter, SCXRD) analyses of derivatives featuring the electron-donor N-ethylcarbazole or the (4-diphenylamino)phenyl moieties associated with a -CN group attached to a double bond. The compounds are (2Z)-3-(4-(diphenylamino)-phenyl)-2-(pyridin-3-yl)prop-2-enenitrile (I), (2Z)-3-(4-(diphenylamino)phenyl)-2-(pyridin-4-yl)-prop-2-enenitrile (II) and (2Z)-3-(9-ethyl-9H-carbazol-3-yl)-2-(pyridin-2-yl)enenitrile (III). SCXRD analyses reveal that I and III crystallize in the monoclinic space groups P2/c with Z’ = 2 and C2/c with Z’ = 1, respectively. Compound II crystallized in the orthorhombic space group Pbcn with Z’ = 1. The molecular packing analysis was conducted to examine the pyridine core effect, depending on the ortho, meta- and para-positions of the nitrogen atom, with respect to the optical properties and number of independent molecules (Z’). It is found that the double bond bearing a diphenylamino moiety introduced properties to exhibit a strong π-π-interaction in the solid state. The compounds were examined to evaluate the effects of solvent polarity, the role of the molecular structure, and the molecular interactions on their self-assembly behaviors. Compound I crystallized with a cell with two conformers, anti and syn, due to interaction with solvent. DFT calculations indicated the anti and syn structures of I are energetically stable (less than 1 eV). Also electrochemical and photophysical properties of the compounds were investigated, as well as the determination of optimization calculations in gas and different solvent (chloroform, cyclohexane, methanol, ethanol, tetrahydrofuran, dichloromethane and dimethyl sulfoxide) in the Gaussian09 program. The effect of solvent by PCM method was also investigated. The frontier HOMO and LUMO energies and gap energies are reported.

Retinoid-related orphan receptor gamma t (RORγt) inhibitors from Vitae Pharmaceuticals (WO2015116904) and structure proposal for their Phase I candidate VTP-43742

ABSTRACTRetinoic acid receptor-related orphan nuclear receptor gamma t (RORγt or RORC2) is a key transcription factor for the differentiation of naïve proinflammatory CD4+ T cells and the production of T helper-17 (TH17) cells. Inhibiting RORγt activity is thought to be beneficial in targeting a variety of inflammatory and autoimmune disorders, however current candidates remain to be validated in the clinic. Recently Vitae Pharmaceuticals successfully finished its Phase 1 single ascending dose clinical study with their proprietary RORγt inverse agonist VTP-43742. On the basis of the reported promising results, Vitae Pharmaceuticals could currently be considered as having the leading clinical candidate in the RORγt inverse agonist category. This prompts the interest on the exact chemical structure of their clinical candidate. The first relevant patent application (WO2014179564) from Vitae Pharmaceuticals describes RORγt inverse agonists with a 5,6-dihydro-4H-pyrrolo[3,4-d]thiazole core, while in the second and latest patent application (WO2015116904) this element has changed towards a 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine core. By combining information from Vitae’s patent applications and trustworthy online information, the potential elucidation of the chemical structure of clinical candidate VTP-43742 is described.

Keeping it small, polar, and non-flat: diversely functionalized building blocks containing the privileged 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]- and [1,5-a]pyridine cores

Six sets of functionalized building blocks based on 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine as well as 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine cores have been prepared. These compounds are non-flat, bicyclic heterocycles that are likely to find utility as privileged motifs for lead-like compound design. One set of building blocks, (5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-6-ylmethyl)amines, proved useful as a scaffold for developing compounds that stimulate glucagon-like peptide-1 (GLP-1) secretion and are novel anti-diabetes drug leads.

In Vitro Biosynthesis of the Core Scaffold of the Thiopeptide Thiomuracin.

Thiopeptides are potent antibiotics that inhibit protein synthesis. They are made by a remarkable post-translational modification process that transforms a linear peptide into a polycyclic structure. We present here the in vitro biosynthesis of the core scaffold of thiomuracin catalyzed by six proteins. We show that cyclodehydration precedes dehydration, and that dehydration is catalyzed by two proteins in a tRNAGlu-dependent manner. The enzyme that generates the pyridine core from two dehydroalanines ejects the leader peptide as a C-terminal carboxamide. Mutagenesis studies of the enzyme TbtD identified important residues for a formal [4+2] cycloaddition process. The core structure of thiomuracin exhibits similar antimicrobial activity to other known congeners, illustrating that in vitro biosynthesis is a viable route to potent antibiotics that can be explored for the rapid and renewable generation of analogues.

Design and Development of Allyl Terminal Triaryl Pyridine Core Skeletal Modified Benzoxazines Based Polybenzoxazine-Silica (PBZ-SiO2) Hybrid Nanocomposites.

A series of skeletal modified novel allyl terminal benzoxazines (BZ-als) have been successfully designed and developed using triaryl pyridine core diamines via conventional one-pot Mannich reaction. The polybenzoxazine-silica (PBZ-SiO2) nanocomposites were prepared by thermal ring-opening polymerization of benzoxazines with different weight percentages of 3-methacryloxypropyltrimethoxysilane through in-situ sol-gel method. The formation of hybrid nanocomposites was confirmed by FT-IR. The substantial enhancement in the glass transition temperature was remarked for PBZ-SiO2 hybrids than their respective neat PBZ systems. The dielectric constant of the nanocomposites was found decreased with an increment in the silica content. The shift in the characteristic absorption/emissions corresponding to the neat PBZs toward lower wave-length ascertains the successful formation of PBZ-SiO2 nanocomposites. The discernible phase behaviour observed morphological studies reveals the molecular-level dispersion of silica particles over the organic networks.

ChemInform Abstract: Base‐Promoted N‐Pyridylation of Heteroarenes Using N‐Propargyl Enaminones as Equivalents of Pyridine Scaffolds.

AbstractN‐Propargyl enaminones, either in isolated form or generated in situ, are established as masked polysubstituted pyridine cores.