An in-depth exploration of six decades of the Kröhnke pyridine synthesis - a review.

The Kröhnke Pyridine Synthesis has been discovered about six decades ago (1961), by Fritz Kröhnke and Wilfried Zecher at the University of Giessen. The original method involved the reaction of α-pyridinium methyl ketone salts with α,ß-unsaturated carbonyl compounds in the presence of a nitrogen source, frequently ammonium acetate. Since its discovery, the Kröhnke methodology has been demonstrated to be suitable for the preparation of mono-, di-, tri- and tetra-pyridines, with important applications in several research fields. Over the years, a number of modifications to the original approach have been developed and reported, enabling for the broad applicability of these methods even in modern days, also for the synthesis of non-pyridine compounds. In this critical and tutorial review, we will thoroughly explore and discuss the potential of the original method, the refinements that have been made over the years, as well as some applications arising from each type of pyridine and/or non-pyridine compounds produced by Kröhnke's approach.

The proof of concept of 2-{3-[N-(1-benzylpiperidin-4-yl)propyl]amino}-6-[N-methyl-N-(prop-2-yn-1-yl)amino]-4-phenylpyridine-3,5-dicarbonitrile for the therapy of neuropathic pain.

In the search for new small molecules for the therapy of neuropathic pain, we found that 2-{3-[N-(1-benzylpiperidin-4-yl)propyl]amino}-6-[N-methyl-N-(prop-2-yn-1-yl)amino]-4-phenylpyridine-3,5-dicarbonitrile (12) induced a robust antiallodynic effect in capsaicin-induced mechanical allodynia, a behavioural model of central sensitization, through σ1R antagonism. Furthermore, administration of compound 12 to neuropathic animals, fully reversed mechanical allodynia, increasing its mechanical threshold to levels that were not significantly different from those found in paclitaxel-vehicle treated mice or from basal levels before neuropathy was induced. Ligand 12 is thus a promising hit-compound for the therapy of neuropathic pain.

Discovery of indoleninyl-pyrazolo[3,4-b]pyridines as potent chemotherapeutic agents against colorectal cancer cells.

A new series of indolenines decorated with pyrazolo[3,4-b]pyridines were designed and synthesized in up to 96% yield from the acid-catalyzed cyclocondensation of 1,3-dialdehydes with 3-aminopyrazoles. X-ray crystallography on a representative derivative, 5n, revealed two close to planar conformations whereby the N-atom of the pyridyl residue was syn or anti to the pyrrole-N atom in the two independent molecules of the asymmetric unit. The computational and DNA binding data suggest that 5n is a strong DNA intercalator with the results in agreement with its potent cytotoxicity against two colorectal cancer cell lines (HCT 116 and HT-29). In contrast to doxorubicin, compounds 5k-o have higher druggability (compliance to more criteria stated in Lipinski's rule of five and Veber's rule), higher bioavailability, and better medicinal chemistry properties, indicative of their potential application as chemotherapeutical agents.

Copper (II) complex supported on magnetic nanoparticles as a novel nanocatalyst for the synthesis of imidazo[1,2-a]pyridines.

Research on the synthesis of imidazo[1,2-a]pyridines has gained great importance among synthetic chemists because there have been numerous reports of their biological and medicinal activities. In this respect, we fabricated CuCl2 immobilized on Fe3O4 nanoparticles modified with 1,10-phenanthroline-5,6-diol [Fe3O4@Diol/Phen-CuCl2] and investigated its catalytic activity for the preparation of imidazo[1,2-a]pyridine derivatives through one-pot three-component reaction of 2-aminopyridines, aldehydes and terminal alkynes under ecofriendly conditions. FT-IR spectroscopy, EDX, SEM, TEM, XRD, TGA, VSM and ICP-OES techniques employed in order to identify the structure of the as-constructed Fe3O4@Diol/Phen-CuCl2 nanocatalyst. This catalytic system has a series of advantages such as the synthesis of imidazo[1,2-a]pyridine products with high yields in suitable time, performing the reactions in an environmentally friendly solvent (PEG), easy preparation of the catalyst with a simple method, and the recyclability of the Fe3O4@Diol/Phen-CuCl2 nanocatalyst.

Conformation-Associated C···dz2-PtII Tetrel Bonding: The Case of Cyclometallated Platinum(II) Complex with 4-Cyanopyridyl Urea Ligand.

The nucleophilic addition of 3-(4-cyanopyridin-2-yl)-1,1-dimethylurea (1) to cis-[Pt(CNXyl)2Cl2] (2) gave a new cyclometallated compound 3. It was characterized by NMR spectroscopy (1H, 13C, 195Pt) and high-resolution mass spectrometry, as well as crystallized to obtain two crystalline forms (3 and 3·2MeCN), whose structures were determined by X-ray diffraction. In the crystalline structure of 3, two conformers (3A and 3B) were identified, while the structure 3·2MeCN had only one conformer 3A. The conformers differed by orientation of the N,N-dimethylcarbamoyl moiety relative to the metallacycle plane. In both crystals 3 and 3·2MeCN, the molecules of the Pt(II) complex are associated into supramolecular dimers, either {3A}2 or {3B}2, via stacking interactions between the planes of two metal centers, which are additionally supported by hydrogen bonding. The theoretical consideration, utilizing a number of computational approaches, demonstrates that the C···dz2(Pt) interaction makes a significant contribution in the total stacking forces in the geometrically optimized dimer [3A]2 and reveals the dz2(Pt)→π*(PyCN) charge transfer (CT). The presence of such CT process allowed for marking the C···Pt contact as a new example of a rare studied phenomenon, namely, tetrel bonding, in which the metal site acts as a Lewis base (an acceptor of noncovalent interaction).

6-Amino-4-aryl-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamides: Synthesis, Biological Activity, Quantum Chemical Studies and In Silico Docking Studies.

New [1,2]dithiolo[3,4-b]pyridine-5-carboxamides were synthesized through the reaction of dithiomalondianilide (N,N'-diphenyldithiomalondiamide) with 3-aryl-2-cyanoacrylamides or via a three-component reaction involving aromatic aldehydes, cyanoacetamide and dithiomalondianilide in the presence of morpholine. The structure of 6-amino-4-(2,4-dichloro- phenyl)-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamide was confirmed using X-ray crystallography. To understand the reaction mechanism in detail, density functional theory (DFT) calculations were performed with a Grimme B97-3c composite computational scheme. The results revealed that the rate-limiting step is a cyclization process leading to the closure of the 1,4-dihydropyridine ring, with an activation barrier of 28.8 kcal/mol. Some of the dithiolo[3,4-b]pyridines exhibited moderate herbicide safening effects against 2,4-D. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) parameters were calculated and molecular docking studies were performed to identify potential protein targets.

Serendipitous Identification of Azine Anticancer Agents Using a Privileged Scaffold Morphing Strategy.

The use of privileged scaffolds as a starting point for the construction of libraries of bioactive compounds is a widely used strategy in drug discovery and development. Scaffold decoration, morphing and hopping are additional techniques that enable the modification of the chosen privileged framework and better explore the chemical space around it. In this study, two series of highly functionalized pyrimidine and pyridine derivatives were synthesized using a scaffold morphing approach consisting of triazine compounds obtained previously as antiviral agents. Newly synthesized azines were evaluated against lymphoma, hepatocarcinoma, and colon epithelial carcinoma cells, showing in five cases acceptable to good anticancer activity associated with low cytotoxicity on healthy fibroblasts. Finally, ADME in vitro studies were conducted on the best derivatives of the two series showing good passive permeability and resistance to metabolic degradation.

Imidazopyridine Family: Versatile and Promising Heterocyclic Skeletons for Different Applications.

In recent years, there has been increasing attention focused on various products belonging to the imidazopyridine family; this class of heterocyclic compounds shows unique chemical structure, versatile optical properties, and diverse biological attributes. The broad family of imidazopyridines encompasses different heterocycles, each with its own specific properties and distinct characteristics, making all of them promising for various application fields. In general, this useful category of aromatic heterocycles holds significant promise across various research domains, spanning from material science to pharmaceuticals. The various cores belonging to the imidazopyridine family exhibit unique properties, such as serving as emitters in imaging, ligands for transition metals, showing reversible electrochemical properties, and demonstrating biological activity. Recently, numerous noteworthy advancements have emerged in different technological fields, including optoelectronic devices, sensors, energy conversion, medical applications, and shining emitters for imaging and microscopy. This review intends to provide a state-of-the-art overview of this framework from 1955 to the present day, unveiling different aspects of various applications. This extensive literature survey may guide chemists and researchers in the quest for novel imidazopyridine compounds with enhanced properties and efficiency in different uses.

Meta-Selective Copper-Catalyzed C-H Arylation of Pyridines and Isoquinolines through Dearomatized Intermediates.

C(sp2)-H functionalization offers an efficient strategy for the synthesis of various elaborated N-containing heteroarenes. Along these lines, oxazino pyridines that can be readily prepared from pyridines, have been introduced as powerful substrates in radical- and ionic-mediated meta-C-H functionalization. However, the regioselective meta-C-H arylation of pyridines remains a great challenge. Herein, a copper-catalyzed meta-selective C-H arylation of pyridines and isoquinolines through bench-stable dearomatized intermediates is reported. Electrophilic aryl-Cu(III) species, generated from readily accessible aryl I(III) reagents, enable the efficient meta-arylation of a broad range of pyridines and isoquinolines. The method also allows the meta-selective alkenylation of these heteroarenes using the corresponding alkenyl I(III)-reagents. Late-stage arylation of drug-derived pyridines and larger-scale experiments demonstrate the potential of this synthetic methodology.

Reactivity and Steric Parameters from 2D to 3D Bulky Pyridines: Increasing Steric Demand at Nitrogen with Chiral Azatriptycenes.

Sterically hindered pyridines embedded in a three-dimensional triptycene framework have been synthesized, and their resolution by chiral HPLC enabled access to unprecedented enantiopure pyridines exceeding the known steric limits. The design principles for new axially chiral pyridine derivatives are then described. To rationalize their associations with Lewis acids and transition metals, a comprehensive determination of the steric and electronic parameters for this new class of pyridines was performed. This led to the general parameterization of the steric parameters (percent buried volume %VBur, Tolman cone angle θ, and He8_steric descriptor) for a large set of two- and three-dimensional pyridine derivatives. These parameters are shown to describe quantitatively their interactions with carbon- and boron-centered Lewis acids and were used to predict the ΔG° of association with the prototypical B(C6F5)3 Lewis acid widely used in frustrated Lewis pair catalysis. This first parameterization of pyridine sterics is a fundamental basis for the future development of predictive reactivity models and for guiding new applications of bulky and chiral pyridines in organocatalysis, frustrated Lewis pairs, and transition-metal catalysis.

Copper-Catalyzed C4-selective Carboxylation of Pyridines with CO2 via Pyridylphosphonium Salts.

Pyridine motifs are widespread pharmacophores in many drugs. Installing various substituents through pyridine C-H bond functionalization is significant for new drug design and discovery. Developments of late-stage functionalization reactions enrich the strategies for selective functionalization of pyridines. However, late-stage C-H carboxylation of pyridines is a long-standing challenge, especially selectively carboxylation with CO2 on pyridine motifs. Herein, we describe a practical method for C4-H carboxylation of pyridines via one-pot C-H phosphination and copper-catalyzed carboxylation of the resulted phosphonium salts with CO2 . The reaction is conducted under mild conditions and compatible with multiple active groups and several pyridine drugs, providing diverse valuable isonicotinic acid compounds, demonstrating the application potential of this strategy.

Accessing Pyridines via a Nitrene Internalization Process.

Pyridines are valuable pharmacophores, and their access via direct and selective transmutation of carbon atom with desired nitrogen could become crucial in drug discovery processes. However, only scarce examples can be found when it comes C-to-N-transmutation reactions of aromatics that could lead to the facile synthesis of pyridines or other azaarenes. In this context, Levin and co-workers recently disclosed a process leading to pyridines from the corresponding aryl azides via the regioselective nitrene internalization process. Notably, the transformation did not lead to any further modification of the rest of the aromatic skeleton. This innovative work enabled selectively accessing various pyridine derivatives through direct nitrogen scan operations on benzene derivatives, which were otherwise not feasible.

Mild and efficient synthesis and base-promoted rearrangement of novel isoxazolo[4,5-b]pyridines.

An efficient method for the synthesis of isoxazolo[4,5-b]pyridines has been developed on the basis of readily available 2-chloro-3-nitropyridines via the intramolecular nucleophilic substitution of the nitro group as a key step. The previously unknown base-promoted Boulton-Katritzky rearrangement of isoxazolo[4,5-b]pyridine-3-carbaldehyde arylhydrazones into 3-hydroxy-2-(2-aryl[1,2,3]triazol-4-yl)pyridines was observed.

Synthesis, Molecular Docking, and Dynamic Simulation Targeting Main Protease (Mpro) of New, Thiazole Clubbed Pyridine Scaffolds as Potential COVID-19 Inhibitors.

Many biological activities of pyridine and thiazole derivatives have been reported, including antiviral activity and, more recently, as COVID-19 inhibitors. Thus, in this paper, we designed, synthesized, and characterized a novel series of N-aminothiazole-hydrazineethyl-pyridines, beginning with a N'-(1-(pyridine-3-yl)ethylidene)hydrazinecarbothiohydrazide derivative and various hydrazonoyl chlorides and phenacyl bromides. Their Schiff bases were prepared from the condensation of N-aminothiazole derivatives with 4-methoxybenzaldehyde. FTIR, MS, NMR, and elemental studies were used to identify new products. The binding energy for non-bonding interactions between the ligand (studied compounds) and receptor was determined using molecular docking against the SARS-CoV-2 main protease (PDB code: 6LU7). Finally, the best docked pose with highest binding energy (8a = -8.6 kcal/mol) was selected for further molecular dynamics (MD) simulation studies to verify the outcomes and comprehend the thermodynamic properties of the binding. Through additional in vitro and in vivo research on the newly synthesized chemicals, it is envisaged that the achieved results will represent a significant advancement in the fight against COVID-19.

Fluorinated aldosterone synthase (CYP11B2)-inhibitors for differential diagnosis between bilateral and unilateral conditions of primary aldosteronism.

The enzyme aldosterone synthase (CYP11B2) is specifically expressed in aldosterone-producing tissue of the adrenal cortex and is overexpressed in aldosterone-producing adenomas (APA). It therefore represents an ideal target for molecular imaging, particularly for the differential diagnosis between bilateral hyperplasia and unilateral APA in primary aldosteronism. However, the presence of the cortisol-producing enzyme 11ß-hydroxylase (CYP11B1) in the adrenal cortex remains very challenging owing to its high homology to CYP11B2. Within this study, we efficiently synthesized a variety of disubstituted fluorinated pyridines and pyrazines by Suzuki coupling reactions. These compounds were evaluated for their ability to inhibit CYP11B1 and CYP11B2 in transfected Y1 cells and in NCI-h295 cells. Several compounds were found to exhibit excellent affinity (IC50 < 10 nM) to CYP11B2 as well as strong selectivity (up to 125-fold) over CYP11B1. These findings support the further development of an analogous 18F-labelled PET tracer.

Design, synthesis, and pharmacological evaluation of [1, 3] dioxolo-chromeno[2,3-b]pyridines as anti-seizure agents.

An efficient one-pot three-component reaction for the synthesis of [1,3]dioxolo[4',5':6,7]chromeno[2,3-b]pyridines 4(a-i) has been developed. Synthesis was achieved by reacting sesamol (1), aromatic aldehydes 2(a-i), and 2-aminopropene-1,1,3-tricarbonitrile (3) in the presence of triethylamine at 100 °C under neat reaction condition. Simple operational procedure, broad substrate scope, column chromatography free separations, and high yield of products make it an efficient and largely acceptable synthetic strategy. Synthesized compounds 4(a-i) were further screened for preliminary anticonvulsant activity using MES and scPTZ tests. These analogs were also checked for neurotoxicity and hepatotoxicity. Selected active compounds have been then screened quantitatively to determine ED50 and TD50 values. Analog 4h was found effective in both preclinical seizure models with significant therapeutic/toxicity profile (4h: ED50 = 34.7 mg/kg, MES test; ED50 = 37.9 mg/kg, scPTZ test; TD50 = 308.7 mg/kg). Molecular dynamic simulation for 100 ns of compound 4h-complexed with GABAA receptor revealed good thermodynamic behavior and fairly stable interactions (4h, Docking score = - 10.94). In conclusion, effective synthetic strategy, significant anticonvulsant activity with good toxicity profile and detailed molecular modeling studies led us to anticipate the emergence of these analogs as valid leads for the development of future effective neurotherapeutic agents.

Investigating catalytic pathways: a comparative review of homogeneous and heterogeneous catalysis for 3-aroylimidazo[1,2-a]pyridine synthesis.

3-aroylimidazo[1,2-a]pyridines represent a class of derivatives in the imidazo[1,2-a]pyridine family known for their important biological and pharmaceutical activities. Consequently, various methodologies have been designed to simplify the synthesis of this structure, with an emphasis on the use of cost-effective starting materials and environmentally friendly protocols. All the methods developed in recent years (from 2016 to 2023) rely on homogeneous or heterogeneous catalysts. Therefore, we aim to perform a comparative analysis between these two approaches, elucidating their respective advantages and limitations. The first part of this work focuses on techniques employing homogeneous catalysts, followed by the next section devoted to heterogeneous catalysts. This comprehensive review should be of substantial interest to researchers in the fields of organic and medicinal chemistry, as it provides a valuable resource for their research.

Design and Synthesis of Pyridine and Thiazole Derivatives as Eco-friendly Insecticidal to Control Olive Pests.

Treatment of p-tosyloxybenzaldehyde (1) with ethyl cyanoacetate afforded ethyl 2-cyano-3-(4-{[(4-methylphenyl)sulfonyl]oxy}phenyl)acrylate (2) which reacted with some active methylene derivatives under microwave irradiation in presence of ammonium acetate yielded pyridine derivatives 3-7. On the other hand, when treatment of compound 1 with thiosemicarbazide gave 4-tosyloxybenzylidenethiosemicarbazone (8), which allowed to react with some active methylene compounds, such as: ethyl bromoacetate, chloroacetonitrile or phenacyl bromide derivatives gave thiazole derivatives 9-13. The structure of all products were confirmed by elemental and spectroscopic analyses such as IR, 1 H-NMR, 13 CNMR and mass spectra. The advanced of this method are short reaction time (3-7 min), excellent yield, pure products, and low-cost processing. In the final category, the toxicological characteristics of all compounds were tested towards Saissetia oleae (Olivier, 1791) (Hemiptera: Coccidae). With respect to the LC50 values. It has been found that compound 3 possesses the highest insecticidal bioefficacy compared with other products, with values of 0.502 and 1.009 ppm, for nymphs and adults female, respectively. This study paves the way towards discovering new materials for potential use as insecticidal active agents.

Design, synthesis, and biological evaluation of furan-bearing pyrazolo[3,4-b]pyridines as novel inhibitors of CDK2 and P53-MDM2 protein-protein interaction.

The novel series of furan-bearing pyrazolo[3,4-b]pyridines were designed as cyclin-dependent kinase 2 (CDK2) inhibitors and as p53-murine double minute 2 (MDM2) inhibitors. The newly synthesized compounds were screened for their antiproliferative activity toward hepatocellular carcinoma (HepG2) and breast cancer (MCF7) cell lines. The most active compounds on both cell lines were additionally evaluated for their in vitro CDK2 inhibitory activity. Compounds 7b and 12f displayed enhanced activity (half-maximal inhibitory concentration [IC50 ] = 0.46 and 0.27 µM, respectively) in comparison to the standard roscovitine (IC50 = 1.41 ± 0.03 µM), in addition to, cell cycle arrest at S phase and G1/S transition phase in MCF7 cells treated with both compounds, respectively. Moreover, the most active spiro-oxindole derivative against MCF7 cell line, 16a, exhibited enhanced inhibitory activity against p53-MDM2 interaction in vitro (IC50 = 3.09 ± 0.12 µM) compared to nutlin, and increased the levels of both p53 and p21 by nearly fourfold in comparison to the negative control. Molecular docking studies demonstrated the plausible interaction patterns of the most potent derivatives 17b and 12f in the CDK2 binding pocket and the spiro-oxindole 16a with p53-MDM2 complex, respectively. Consequently, the new chemotypes 7b, 12f, and 16a can be presented as promising antitumor hits for further studies and optimization.

Synthesis and Anti-Proliferative Activity of 5-Benzoyl and 5-Benzylhydroxy Derivatives of 3-Amino-2-Arylcarboxamido-Thieno[2-3-b]Pyridines.

3-Amino-2-arylcarboxamido-thieno[2-3-b]pyridines have been previously described as having potent anti-proliferative activity against MDA-MB-231 and HCT116 cancer cell lines. The mechanism by which these molecules prevent cancer cell growth is proposed to be through interfering with phospholipid metabolism via inhibition of PI-PLC, along with other cellular processes. Previously, 5-cinnamyl derivatives of these thieno[2-3-b]pyridines have been shown to have enhanced anti-proliferative activity compared to compounds lacking this moiety, indicating a tethered aromatic ring is important for this western region of the pharmacophore. Herein, we report the synthesis and biological evaluation of a library of 40 novel thieno[2-3-b]pyridine analogues containing shorter benzoyl or secondary benzyl alcohol tethers at the 5-position, in addition to various substituents on the two phenyl rings present on the molecule. Compounds bearing alcohol functionality had improved efficacy compared to their benzoyl counterparts, in addition to a 2-methyl-3-halogen substitution on the 2-arylcarboxamide ring being important for maximising anti-proliferative activity. The most potent molecules 7h and 7i demonstrated IC50 concentrations of 25-50 nM against HCT116 and MDA-MB-231 cells, a similar level of activity as previous thienopyridine compounds bearing cinnamyl moieties, suggesting that these novel derivatives with shorter tethers were able to maintain potent anti-proliferative activity, while allowing for a more concise synthesis.