Pyridone Derivatives Research Articles

Co(III) or Ru(II)-Catalyzed Selective C-H Alkynylation of 2-Pyridones and Their Derivatives with Bromoalkynes.

We successfully reported selective C-H alkynylation of 2-pyridones with bromoalkynes under the catalysis of Co(III) or Ru(II). The alkynylation reaction used easily accessible bromoalkynes instead of high-valent iodine alkynes. There is a broad substrate scope of 2-pyridones with good yields. In addition, 2-pyridone can be used as a weakly directing group for C-H alkynylation of the proximal aryl C-H bond. This method offers an efficient approach for synthesizing diverse 2-pyridone derivatives, yielding alkynylated products up to 95% yield (>40 examples).

A new Rose Bengal glycopolymer: Photosensitization in two stages

Antimicrobial photodynamic therapy is a promising alternative to deal with antimicrobial resistance. However, both the low specificity and low local oxygen molecular concentrations decrease the antimicrobial efficiency limiting its use. An interesting approach to the problem is the use of molecules that can react reversibly with singlet oxygen by the formation of reversible endoperoxides, such as naphthalene, anthracene and pyridone derivatives. Particularly, the use of these molecules with mannosyl derivatives allow the interaction with adhesins presented on pili and fimbriae improving the localization near to bacteria. In this work, we synthesized polymeric nanoparticles able to generate singlet oxygen (under both irradiation and dark conditions) in the vicinity of a center capable of recognizing mannose and oxidize nearby biomolecules. Rose Bengal was used as photosensitizer due to its attractive photophysical properties (vis absorption, high singlet oxygen generation) and biocompatibility. The polymeric nanoparticles were obtained by radical polymerization using polyvinyl alcohol as a template, showing sizes around 300 nm with negative zeta potential by dynamic light scattering. The singlet oxygen generation was monitored following DPBF consumption and showed to be dependent on the amount of pyridone in the feed of polymers. In addition, the release of singlet oxygen was also dependent on pyridone concentration showing a slower rate constant at 40 % pyridone, while for contents of 10 % and 60 % higher rate constants were observed. The specific interaction of glycopolymers with Concanavalin A was demonstrated by successful agglutination assays, but also a low participation of unspecific interactions for polymers without mannosyl derivatives was observed. On the other hand, the oxidation of amino acids of Concanavalin A was monitored by acrylamide gel electrophoresis. Type I and Type II photosensitization were observed with the formation of dimers and fragments with lower molecular weight, while in dark conditions only products with lower molecular weight were observed, result consistent with singlet oxygen released by pyridone endoperoxides.

New Yellow Azo Pyridone Derivatives with Enhanced Thermal Stability for Color Filters in Image Sensors

Two new yellow azo pyridone derivatives, (E)-6-hydroxy-1-(3-methoxypropyl)-4-methyl-2-oxo-5-(p-tolyldiazenyl)-1,2-dihydropyridine-3-carbonitrile (APY-M) and 5,5′-((1E,1′E)-(methylenebis(4,1-phenylene))bis(diazene-2,1-diyl))bis(6-hydroxy-4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile) (APY-D), were designed and synthesized as yellow colorants for image sensors. The properties of these new compounds were evaluated in both solution and color filter film forms, focusing on their optical and thermal characteristics. The molar extinction coefficient values of APY-M and APY-D in solution were found to be 2.7 × 105 and 3.0 × 105 L/mol·cm, respectively. The transmittance of the newly synthesized compounds met commercial requirements, showing values below 0.21% at 435 nm and above 97.1% at 530 nm. APY-D exhibited a molar extinction coefficient value in solution that was 1.15 times higher than that of the commercially used yellow colorant Disperse Yellow 241. Both newly synthesized compounds satisfied the decomposition temperature requirement of over 230 °C, which is essential for the color filter manufacturing process in image sensors. In particular, APY-D, with its dimeric structure and increased molecular weight, demonstrated enhanced thermal stability, with a 50 °C increase in decomposition temperature compared to Disperse Yellow 241. Color filter films for image sensors were fabricated using the new compounds, and their thermal resistance was evaluated. APY-D maintained its transmittance due to the enhanced thermal stability provided by its dimer structure and increased molecular weight. Consequently, APY-D is anticipated to be a promising candidate for use as a yellow colorant in image sensors, owing to its excellent optical and thermal properties.

Synthesis and insecticidal assessment of nitrogenous heterocycles derived from 2-pyridone derivative against Culex pipiens L. Larvae

This study reports the synthesis of a novel 1,6-diamino-4-(2,4-dichlorophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1) and its subsequent functionalization to yield a library of diverse heterocycles (2–10). The nucleophilicity of compound 1 was exploited to react with various electrophiles to afford a range of structurally enriched derivatives. The structures of all synthesized heterocycles were confirmed by elemental analysis and spectroscopic techniques as (FT-IR, 1H NMR, 13C NMR, and mass spectroscopy). Bioassays revealed significant larvicidal activity against mosquito larvae (Culex pipiens L.) for compounds 1–4, 6, 7 and 9. In silico docking studies suggest a potential mode of action through acetylcholinesterase (AChE) inhibition, potentially explaining the observed larvicidal effect. Additionally, interactions with other neuroreceptors were predicted. Finally, analyzing of the structure activity relationship (SAR) of the novel constructed heterocycles gave us a lot of interesting promising results for developing novel and sustainable mosquito control strategies.

Diversity Oriented Strategy (DOS) for the Efficient Synthesis of Benzofuro[2,3-b]pyridine Derivatives with Anticancer Activity.

Benzofuropyridines (BFP) are polycyclic compounds with known applications in neuronal diseases. However, its derivatization patterns and anticancer potential remains unexplored. Leveraging the idea of diversity-oriented synthesis (DOS), we developed a highly efficient synthetic route for BFP to increase the library of available analogs producing three compounds in one reaction set up, including the 2O-, 6O-, and the 1N-substituted species, also producing the unusual 2-pyridone derivatives. Key bromination reaction of the BFP moiety was successfully described which can widen the available variation in the compounds' structure. The cytotoxic activity of the compounds was assessed against SH-SY5Y (neuroblastoma), HepG2 (hepatocellular carcinoma), Kb (human oral epidermoid), HeLa (cervical) and MCF-7 (breast) cancer cell lines. In the series, the m-bromobenzyl (5b), methylcyano (5g) and propargyl (5h) 2O-derivatives demonstrated good selectivity against cancer cells with selectivity index (SI) of >71 for 5g against HeLa over the normal cells, as compared to the standard drug, Doxorubicin (SI = 6.7). The quantitative structure-activity relationship (QSAR) analysis revealed an impressive correlation of the defined descriptors with the bioactivity having an R2 value of 0.971 and 0.893 for Kb and HeLa respectively. Altogether, our work highlighted new information on the synthesis of BFP derivatives with potent cytotoxic activity.

Asymmetric Allylic Amination of Alkyl-Substituted Allylic Carbonates with Pyridones Catalyzed by the Krische Iridium Complex.

An efficient Ir-catalyzed asymmetric allylic amination reaction of alkyl-substituted allylic carbonates is disclosed. With the Krische iridium complex as the catalyst, asymmetric allylic amination of alkyl-substituted allylic carbonates with pyridones proceeds effectively, affording pyridone derivatives containing a stereocenter α to the nitrogen atom in excellent yields and enantioselectivity (up to 99% yield, 95% ee). This catalytic system broadens the substrate scope of the reaction compared with that of the known catalytic systems. This reaction can also be conducted on a gram scale, further enhancing its potential for synthetic application.

Design, synthesis, and study of 2-pyridone-based pharmaceutical analogues

2-pyridones are an important class of compounds among the N-heterocycles due to the abundant presence of their structural derivatives in many biologically active compounds. The synthesis of 2-pyridone derivatives (compounds 3A-3C) involves the condensation of aldehyde, malononitrile, and ethyl acetoacetate by a base-catalyzed reaction. Heterocyclic ring rearrangements were carried out using the simplest acid as a catalyst to produce hydroaromatic compounds, followed by dehydrogenation to yield the corresponding aromatic analogues. A sample of the crystals obtained from the synthesized compounds 3A-3C were studied to explore the types of hydrogen bonding and other intermolecular interactions involved in the supramolecular assemblies. Hirsheld surface analyses were also conducted to support the weak interactions and investigate their contributions within the supramolecular assemblies. In silico studies were also performed on the molecular recognition and ADMET properties of the compounds to reveal the most promising compounds for drug development.

Hydrogen bond assisted reactivity of Ylidineketonitriles with 1° amines: A chemoselective synthesis of 2-pyridone and 2-aminopyridine derivatives

Ylidineketonitrile 2 with chlorodifluoromethyl (A = Cl) demonstrated a strong solvent dependence reaction with primary amines to form either 1-N-alkylated-3,5-disubstituted-2-pyridones or 2-N-alkylated-3, 5-trisubstituted pyridines. The methodology was tested for its scope with primary amines and synthesized 29 derivatives in good to excellent yield. Ylidineketonitrile 2e preferrentially forms pyridone derivatives in the majority of the solvents screened except trifluoroethanol, where chemoselective formation of 2-aminopyridine derivatives was observed.

Synthesis and Biological Activity of 2-pyridone Derivatives: A Mini Review

: The 2-pyridone nucleus is an important scaffold present in various compounds with diverse pharmacological activity. Among the reported 2-pyridone analogs, the majority of the compounds either have a substituted ring system or a fused ring system. Till now, several derivatives have been reported by different researchers for their antimicrobial activity, anticancer activity, antiviral activity, antioxidant activity, anti-hepatitis virus activity, and anti-allodynia and anti-obesity activities. In this review, we have attempted to compile synthetic methods of 2-pyridone ring by ring cyclization along with pharmacologi cal aspects related to various synthesized derivatives of the 2-pyridone nucleus.

Design, Synthesis, Nematicidal Evaluation, and Molecular Docking Study of Pyrano[3,2-c]pyridones against Meloidogyne incognita.

Root-knot nematodes pose a serious threat to crops by affecting production and quality. Over a period of time, substantial work has been done toward the development of effective and environmentally benign nematicidal compounds. However, due to the inefficiencies of previously reported synthetics in achieving the target of safe, selective, and effective treatment, it is necessary to develop new efficacious and safer nematicidal agents considering human health and environment on top priority. This work aims to highlight the efficient and convenient l-proline catalyzed synthesis of pyrano[3,2-c]pyridone and their use as potential nematicidal agents. In vitro results of larval mortality and egg hatching inhibition revealed maximum nematicidal activity against Meloidogyne incognita from compounds 15b, 15m, and 15w with LC50 values of 28.8, 46.8, and 49.18 μg/mL at 48 h, respectively. Under similar conditions, pyrano[3,2-c]pyridones derivatives 15b (LC50 = 28.8 μg/mL) was found at par with LC50 (26.92 μg/mL) of commercial nematicide carbofuran. The in vitro results were further validated with in silico studies with the most active compound 15b nematicidal within the binding to the pocket of acetylcholine esterase (AChE). In docking, binding free energy values for compound 15b were found to be -6.90 kcal/mol. Results indicated that pyrano[3,2-c]pyridone derivatives have the potential to control M. incognita.

Iridium-Catalyzed [2 + 2 + 2] Cycloaddition of Bithiophen-Linked Diynes with Nitriles: Scope and Mechanistic Study with Quantum Chemical Calculation.

We report a simple and atom-efficient method for the synthesis of bithiophene-fused isoquinolines by iridium-catalyzed [2 + 2 + 2] cycloaddition of bithiophene-linked diynes with nitriles. All three structural isomers of bithiophene-linked diynes underwent [2 + 2 + 2] cycloaddition, and the trend in the reactivity for cycloaddition was diyne 1 = diyne 3 > diyne 2. Dibenzothiophene-linked diyne also reacted with nitriles to form a variety of cycloadducts. Cycloaddition of bithiophene-linked diynes with alkynes and an isocyanate formed naphthodithiophenes and a 2-pyridone derivative, respectively. Cycloadducts bearing a 2-aminopyridine moiety and benzothiophene rings showed intense fluorescence at around 530 nm and gave a fluorescence quantum yield of 0.44. Furthermore, quantum chemical calculations provided insight into the origin of the difference in reactivity of three bithiophene-linked diynes. The different reactivities of the three diynes 1-3 are believed to originate from the step where an iridacyclopentadiene reacts with a coordinated nitrile to form azairidabicyclo[3.2.0]heptatriene. HOMOs of iridacyclopentadiene play a decisive role in this step.

Unlocking Enantioselectivity: Synergy of 2-Pyridone and Chiral Amino Acids in Pd-Catalyzed β-C(sp3)-H Transformations.

Enantioselective C(sp3)-H activation has garnered significant attention in synthetic and computational chemistry. Chiral transient directing groups (TDGs) hold promise for enabling Pd(II)-catalyzed enantioselective C(sp3)-H functionalization. Despite the interest in this strategy, it presents a challenge because the stereogenic center on the chiral TDG is frequently distant from the C-H bond, leading to a mixture of functionalized products. Our computational study on Pd(II)-catalyzed enantioselective β-C(sp3)-H arylation of aliphatic ketone with chiral amino acids provides a sustainable route to synthesizing complex chiral molecular scaffolds. The cooperative action of 2-pyridone derivatives and chiral amino acids is crucial in promoting the enantio-discriminating C-H activation, oxidative addition, and reductive elimination steps. Using 5-nitro-2-pyridone as the optimal external ligand demonstrates its ability to achieve the highest level of enantioselection. In contrast, the modeled 3,5-di((trifluoromethyl)sulfonyl)-2-pyridone ligand facilitates the most straightforward C-H activation. This study underscores the pivotal role of the alkyl substituent at the α-position of the amino acid (TDG) in altering enantioselectivity.

Solvent-Driven Room-Temperature Curtius Rearrangements to Access Nucleotides Bearing Substituted Fused Pyridones.

The intramolecular Curtius rearrangement suffers from a high reaction temperature, low yields, tedious product isolation, and difficult scale up. This study presents a room-temperature Curtius rearrangement that can be novelly driven by the HFIP solvent, followed by light-illuminated intramolecular cyclization. Such a mild reaction allows for the preparation of various fused pyridone derivatives with diverse substituent groups that have rarely been incorporated by previous methods. The roles of HFIP and light are investigated by a set of control experiments through a combination of IR and NMR titration. Furthermore, using the substituted fused pyridones as unnatural bases, we can obtain a panel of new nucleotides.

New thiazole, thiophene and 2-pyridone compounds incorporating dimethylaniline moiety: synthesis, cytotoxicity, ADME and molecular docking studies

Various sets of thiazole, thiophene, and 2-pyridone ring structures containing a dimethylaniline component were synthesized. Substituted thiazoles 2–3 and thiophenes 5–7 were produced by reacting thiocarbamoyl compound 4 with α-halogenated reagents in different basic conditions. Also, a series of 2-pyridone derivatives 9a–f substituted with dimethylaniline was synthesized through Michael addition of malononitrile to α,β-unsaturated nitrile derivatives 8a–f. The synthesized products were structurally proven by spectroscopic methods such as IR, 1H NMR, 13C NMR, and MS data. Furthermore, the anti-cancer efficacy of the compounds was assessed using the MTT assay on two cell lines: hepatocellular carcinoma (HepG-2) and breast cancer (MDA-MB-231). The results showed the highest growth inhibition for derivatives 2, 6, 7, and 9c, which were further examined for their IC50 values. The IC50 for compound 2 showed equipotent activity (IC50 = 1.2 µM) against the HepG-2 cell line compared to Doxorubicin (IC50 = 1.1 µM). Compounds 2, 6, 7 and 9c showed very good ADME assessments for further drug administration. Moreover, the PASS theoretical prediction for the compounds showed high antimitotic and antineoplastic activities for compounds 2, 6, 7, and 9c, as well as potent inhibition activity for the insulysin enzyme (IDE). Molecular docking stimulations were performed on CDK1/CyclinB1/CKS2 (PDB ID: 4y72) and BPTI (PDB ID: 2ra3). When docked into (PDB ID: 4y72), all of the tested compounds showed considerable inhibition, and the 2-pyridone derivative 9d had the maximum binding affinity (− 8.1223 kcal/mol). While thiophene derivative 6 offered the maximum binding affinity (− 7.5094 kcal/mol) when docked into (PDB ID: 2ra3).Graphical

Synthesis, molecular self-assembly and anti-carcinogenic study of 2-pyridone molecules

4H-pyrans obtained from the multicomponent reactions of aromatic aldehyde, malononitrile, and ethyl acetoacetate were used as a starting scaffold for synthesizing 2-pyridone derivatives (1–3). Two catalytic methods were reported for the conversion of 4H-pyrans to 3,4-dihydropyridones. The non-aromatic 3,4-dihydropyridones obtained were then oxidized to give the final desired 2-pyridone derivatives (1–3). Crystals of the synthesized compounds were prepared and subjected to single-crystal X-ray crystallography (SCXRD) to acquire their structural parameters. Non-covalent interactions in the supramolecular systems 1–3 were studied, and it found that NH∙∙∙O interactions between the lactam groups are the most dominant hydrogen bonds. It is also observed that the aromatic rings are involved in lone pair∙∙∙π, CH∙∙∙π, and weak π∙∙∙π interactions in assisting the supramolecular framework. Hirshfeld surface studies are also performed to validate the interactions within the supramolecular crystals. The 2-pyridone derivatives (1–3) were also analyzed by in vitro techniques to evaluate their cytotoxic activities using human lung adenocarcinoma (A549). It is also found that ethyl 5-cyano-2-methyl-4-(3-nitrophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (1) has shown the highest cytotoxic potency amongst the synthesized compound.

The curious case of the colored crystals of N‐substituted 2‐oxo‐1,2‐dihydropyridinyl‐3‐yl amines and amides: Self‐association in the solid state

AbstractDuring a previous investigation of pyridone derivatives as inhibitors of glycogen phosphorylase, we observed that some N‐substituted 2‐oxo‐1,2‐dihydropyridinyl‐3‐yl amines and amides exhibited different colors, ranging from red to green to blue to teal. Remarkably, one compound (compound 8) could be crystallized in both a red form and a green form. To try to understand these observations, we have carried out further spectroscopic studies in the solid state and in solution employing UV‐visible spectroscopy, NMR spectroscopy, and X‐ray crystallography, along with molecular mechanics and DFT calculations on selected compounds. Evidence was obtained in the solid state for the self‐association of pyridones into dimeric complexes or near‐planar dimers induced by intermolecular hydrogen bonding and possible π‐stacking, whereas monomeric structures for two compounds were proposed in chloroform, in agreement with the DFT calculated chemical shifts. In this study, it was determined that the colors observed could not be attributed to hydrogen bonding or possible π‐bond stacking in the novel relatively unconjugated pyridone derivatives. A possible explanation for the colors is suggested: a contaminant formed by aerial oxidation of trace amounts of the 3‐aminopyridone starting material. This result contrasts with existing literature reports of UV and fluorescence spectra, which indicated distinct coloration for conjugated 2‐pyridone compounds. The spectroscopic results, including X‐ray structural data for five pyridones, contribute to a deeper understanding of structural interactions in pyridone derivatives.

Imparting aromaticity to 2-pyridone derivatives by O-alkylation resulted in new competitive and non-competitive PIM-1 kinase inhibitors with caspase-activated apoptosis

New aromatic O-alkyl pyridine derivatives were designed and synthesised as Proviral Integration Moloney (PIM)-1 kinase inhibitors. 4c and 4f showed potent in vitro anticancer activity against NFS-60, HepG-2, PC-3, and Caco-2 cell lines and low toxicity against normal human lung fibroblast Wi-38 cell line. Moreover, 4c and 4f induced apoptosis in the four tested cancer cell lines with high percentage. In addition, 4c and 4f significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 4c and 4f showed potent PIM-1 kinase inhibitory activity with IC50 = 0.110, 0.095 µM, respectively. Kinetic studies indicated that 4c and 4f were both competitive and non-competitive inhibitors for PIM-1 kinase enzyme. In addition, in silico prediction of physiochemical properties, pharmacokinetic profile, ligand efficiency, ligand lipophilic efficiency, and induced fit docking studies were consistent with the biological and kinetic studies, and predicted that 4c and 4f could act as PIM-1 kinase competitive non-adenosine triphosphate (ATP) mimetics with drug like properties.

Singlet oxygen storage and controlled release for improving photodynamic therapy against hypoxic tumor.

Photodynamic therapy (PDT) is considered to be a promising tumor treatment method due to its non-invasiveness and low risk. However, there are two factors that affect the efficacy of this therapy. One is the light source and the other is the tumor hypoxia. An emerging PDT strategy has been developed to break these limits. This strategy is to adopt compounds, such as 2-pyridone, anthracene, and naphthalene derivatives, that have the ability to store and controlledly release the singlet oxygen (1O2) to achieve PDT in the dark. In this review, we focus on the construction strategies for integrated antitumor drugs containing these 1O2 storage/release units and photosensitizers and summarize their PDT performance in hypoxic tumors or in the dark. The methods to integrate these compounds with photosensitizers or nanocarriers are also discussed in detail to provide insightful design guidelines for the design of highly efficient antitumor systems based on 1O2 storage and controlled release.

Photoinduced cobalt catalyzed site selective alkylation of 2-pyridones

A selective C3- and C6-alkylation reaction of 2-pyridone by a direct C–H functionalization approach was used to access 2-pyridone derivatives, utilizing a photo-induced cobalt-catalyzed alkyl radical selective addition process.

New 2-pyridone-based donor-acceptor dyes: the effect of the donor group position, type of π-linker and acid-base characteristics of the medium on the photophysical properties.

A series of novel donor-acceptor pyrid-2-ones was synthesized. The influence of the donor group on the photophysical properties of chromophores in solution was shown by varying the methoxy group position in the electron-rich aromatic ring. The effect of the π-linker was also demonstrated by the comparison of the D-π-A pyridone with its spacer-free analogue (D-A) and with the chromophore bearing an additional thiophene bridge (D-π-π-A). It was found that the presence of a π-linker plays a crucial role in the implementation of an intramolecular charge transfer (ICT) from the donor aryl moiety to the pyridone acceptor. Thus, for the synthesized D-A, D-π-A and D-π-π-A derivatives, the photoluminescence quantum yield in DMSO solution decreases from 56.8 to 4.3 and 3.5%, respectively, along with a strong bathochromic shift both for absorption (66 nm) and emission (162 nm) bands. Also, the possibility of shifting the equilibrium in DMSO solution towards either the pyridone form or the anionic form by the addition of a strong acid (TFA) and base (DBN) respectively was shown. Drastic changes in the photoluminescence of the solutions showed prospects for the application of the synthesized donor-acceptor pyridone derivatives as naked-eye acid-base indicators in organic media.