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This investigation presents a novel, cost-effective approach for creating a 2-pyridone core substituted with an ester group through intramolecular rearrangement. This one-step transformation involves an amide-mediated intramolecular transformation of a pyranone to pyridone scaffold, followed by alcoholic-mediated ester formation, in 75–85% yield. Deuterated alcohol was used to confirm the esterification under alcoholic conditions. The reaction requires a nucleophile source from the solvent, which was observed by performing the reaction of three derivatives in CD3 OD to obtain the desired carboxylate compounds, replacing -OR with -OCD3. All synthesized compounds were characterized by spectroscopic analysis, and six selected compounds were further confirmed by single-crystal X-ray diffraction studies. [ABSTRACT FROM AUTHOR]

Pyridine‐directed regioselective C−H hydroxymethylation to pyridones and isoquinolones using para‐formaldehyde has been developed under manganese catalysis, offering a wide variety of hydroxymethylated products in 40–85% yields. This operationally simple methodology proceeds in one step using an earth‐ abundant first‐row transition metal‐catalyst without the generation of unwanted salt wastes. A mechanistic study revealed that the C−H metalation step is reversible but not the rate‐determining step. The introduction of hydroxymethyl group in the biologically relevant scaffolds could be used as an intermediate for valuable synthetic transformations. [ABSTRACT FROM AUTHOR]

Herein we report the development of an oxidative amination process for the streamlined synthesis of pyridones from cyclopentenones. Cyclopentenone building blocks can undergo in situ silyl enol ether formation, followed by the introduction of a nitrogen atom into the carbon skeleton with successive aromatisation to yield pyridones. The reaction sequence is operationally simple, rapid, and carried out in one pot. The reaction proceeds under mild conditions, exhibits broad functional group tolerance, complete regioselectivity, and is well scalable. The developed method provides facile access to the synthesis of 15N‐labelled targets, industrially relevant pyridone products and their derivatives in a fast and efficient way. [ABSTRACT FROM AUTHOR]

The functionalization of small aromatic heterocycles is a straight and efficient method to access large polycyclic conjugated molecules. However, due to its unique reactivity, the derivatization of acridone usually gives the product in the angular shape and is difficult to obtain the linear ones. Here we report the direct functionalization of acridone to generate its linearly fused derivatives containing cyclobutadienoid via the palladium‐catalyzed arene‐(oxa)norbornene annulation followed by the dehydrated aromatization. The experimental characterizations demonstrate that the antiaromatic cyclobutadienoid ring can extend the molecular conjugation. Theoretical calculations reveal the weakened aromaticity of neighboring benzenoid rings of cyclobutadienoid with no influence on the electronic structure of central pyridone. The molecular stability is enhanced in comparison to that of linear acridone derivatives containing only six‐membered rings. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Nucleosides find applications in medicinal chemistry, chemical biology and diagnostics. Among the nucleosides, C‐nucleosides have attracted particular attention because their carbon‐carbon bond between nucleobase and ribose provides stability against degradation. While several well‐established methods exist for the synthesis of 2′‐deoxy‐C‐nucleosides, the preparation of their ribofuranosyl counterparts is more challenging. Established methods for their synthesis give mixtures of anomers and require harsh reagents or conditions. Here we report a diastereoselective glycosylation method involving a Heck reaction between a glycal and an aryl iodide, followed by oxidation of the silyl enol ether with methyl(trifluoromethyl)dioxirane (TFDO). The resulting ketone is then diastereoselectively reduced to the ribonucleoside. The new route has been applied to pyridones and is expected to also yield other ribo‐C‐nucleosides in diastereoselective fashion. [ABSTRACT FROM AUTHOR]

The behavior of 6‐hydroxypicolinic acid (pic‐6‐OH) and pyridyl‐amides as cooperating ligands in the C−H activation of arenes has been studied experimentally. When deprotonated, both compounds are chelating ligands and bear either a pyridone moiety or an N‐acyl substituent that can assist the C−H cleavage in the same way as the successful bipyridone ligands and MPAAs do. In addition, they are easily available, commercially or via straightforward syntheses. Palladium complexes of formula (NBu4)[Pd(κ2‐O, N‐pic‐6‐O)(C6F5)py] (2) and [Pd(κ2‐N, N‐ py‐CH2N(COCF3)(C6F5)py] (6) have been synthesized and their decomposition in the presence of an arene gives the C6F5‐arene coupling product, showing that the ligands enable the C−H activation of the arene (arene=pyridine, toluene, ethyl benzoate). The amount of C6F5‐arene products observed leads to the following trend in cooperating ability: pic‐6‐OH > pyridyl‐amide. DFT calculations on the pyridine activation are consistent with the experimental findings. The C−H activation does not occur for the isomeric complex (NBu4)[Pd(κ2‐O, N‐pic‐4‐O)(C6F5)py] (4) with the pyridone oxygen far from the metal, showing the involvement of this moiety in the C−H cleavage. The performance of these ligands in the direct arylation of arenes has been evaluated. [ABSTRACT FROM AUTHOR]

We present a systematic review of the methods developed for the synthesis of the aromathecin family of compounds (benz[6,7]indolizino[1,2-b]quinolin-11(13H)-ones) and their derivatives. These methods can be broadly classified into four categories based on the construction of pentacyclic structures: Category 1: by constructing a pyridone moiety (D-ring) on the pyrroloquinoline ring (A/B/C-ring), Category 2: by constructing a pyridine moiety (B-ring) on the pyrroloisoquinolone ring (C/D/E-ring), Category 3: by constructing an indolizidinone moiety (C/D-ring) in a tandem reaction, and Category 4: by constructing a pyrrolidine moiety (C-ring) on the isoquinolone ring (D/E-ring). [ABSTRACT FROM AUTHOR]

[Display omitted] Nitrogen-doped carbons with promising electrochemical performance exhibit a strong dependence on nitrogen configuration. Therefore, accurate control of nitrogen configurations is crucial to clarify their influence. Unfortunately, there is still no well-defined conversion route to finely control nitrogen configuration. Herein, we proposed the concept of 100% conversion from pyridinic to pyrrolic nitrogen in carbon materials through low-temperature pyrolysis and alkali activation of hydroxypyridine-3-halophenol-formaldehyde resins. Their dehalogenation pyrolysis promotes formation of carbon intermediates and conversion of tautomeric pyridone and hydroxypyridine into pyrrolic and pyridinic nitrogen through eliminating carbonyl and hydroxyl functionalities, respectively. Continuous thermal alkali activation introduces hydroxyl groups into carbon materials, converting pyridinic species to intermediate hydroxypyridine and pyridone; subsequently, these configurations transform to pyridinic and pyrrolic nitrogen, respectively, and finally, an excessive alkali ensures 100% conversion from pyridinic to pyrrolic nitrogen. NaOH activation for pyrrolic and pyridinic nitrogen co-doped carbon and KOH activation for model nitrogen-containing compounds including acridine, phenanthridine, and acridone further confirm that alkali activation plays an indispensable role in 100% conversion from pyridinic to pyrrolic units through the tautomeric hydroxypyridine and pyridone intermediates. Low-temperature alkali-induced controllable conversion of nitrogen configuration in carbon materials is suitable modulating nitrogen configurations for almost all nitrogen-doped carbon materials in electrochemical applications. [ABSTRACT FROM AUTHOR]

Two new coordination polymers, [Cu(pz)(L)2(H2O)2](ClO4)2 (L = 2-Cl- (1) or 2-Br-4-pyridone (2); pz = pyrazine), have been synthesized and characterized by X-ray diffraction, EPR and variable temperature magnetic measurements. Both compounds crystallize as well isolated pyrazine-bridged chains with the heterocyclic ligands in the pyridone tautomer and coordinated via the oxygen atom. The Cu ions possess Jahn-Teller elongated octahedral geometries with the Jahn-Teller axis along the Cu-O axis. The water molecules in 2 are inequivalent with one molecule semi-coordinate (dCu...O = 3.225(6) Å) at an occupancy of 0.72. Both compounds exhibited axial powder EPR spectra, as expected. Variable temperature magnetic measurements are well fit by the uniform chain Heisenberg antiferromagnetic model with J = −10.74(4) K (1) or = −10.64(2) K (2). Comparison with the known 3-halo-4-pyridone compounds suggests an inverse relationship between the Cu-pz-Cu distance and the strength of the magnetic exchange. [ABSTRACT FROM AUTHOR]

Endophytic fungi are an important resource for bioactive natural products. In this study, a new tryptophan derivative fusaconate A (1) and three pyridone alkaloids, including one new pyridone derivative 1′-methoxy-6′-epi-oxysporidinone (2) and two known ones (3−4), were identified from the endophytic fungus Fusarium concentricum which was isolated from the medicinal plant Anoectochilus roxburghii. Their structures were elucidated through extensive spectroscopic analysis, including HR-ESI-MS, 1 D and 2 D NMR. Compound 4 exhibited moderate cytotoxicities against HT29 and PC3 cells with IC50 values of 7.60 and 4.99 μM, respectively. [ABSTRACT FROM AUTHOR]

Five new representatives of donor-acceptor stilbazoles (styrylpyridines) were synthesized based on 2-oxo-4-(perfluoroethyl)-1,2-dihydropyridine-3-carbonitrile. The influence of the position (2-MeO, 3-MeO, and 4-MeO) and the nature of donor groups (MeO, Me2N) in the styryl part of the molecule on the photophysical parameters of compounds in solution was studied. Pronounced (fluoro)solvatochromism was revealed for the dye containing a 4-dimethylaminostyryl fragment, with absorption maxima located from 403 to 514 nm, and fluorescence maxima are in the range from 479 to 649 nm. [ABSTRACT FROM AUTHOR]

The synthesis of a novel imidazo[4,5-b]pyridine and its partially saturated derivative relied on Michael addition of 1-methyl-1H-imidazol-4-amine to fumaric/maleic or acetylene dicarboxylates, followed by intramolecular cyclization into target compounds. The common transformations of the resulting pyridine carboxylate were performed to obtain a series of building blocks, i.e. carboxylic acids, amides, and amines. The pyridone fragment was transformed into the fused bromopyridine moiety which was used for Buchwald–Hartwig and Suzuki cross-coupling reactions providing a versatile access to an extended scope of imidazopyridines. All synthesized building blocks could be considered as promising purine bioisosteres for the synthetic and medicinal chemistry. [ABSTRACT FROM AUTHOR]

Covalent proteolysis-targeting chimeras (PROTACs) offer enhanced selectivity, prolonged action, and increased efficacy against challenging target proteins. The conventional approach relies on covalent ligands, but our study presents an innovative method employing an N-sulfonyl pyridone warhead to selectively target tyrosine (Tyr) residues. The von Hippel–Lindau (VHL) moiety is transferred from the warhead to the exposed Tyr, allowing us to design a STING degrader (DC50 0.53 μM, Dmax 56.65%). This approach showcases the potential of nucleophilic amino acid labeling probes, particularly for proteins lacking easily accessible cysteine residues, opening new possibilities for covalent PROTAC design and targeted protein degradation therapies. [ABSTRACT FROM AUTHOR]

This study presents an efficient method for on‐resin dimer generation through self‐condensation of 3,3‐dimethoxypropionic acid‐modified molecules, resulting in 2‐pyridones. The approach demonstrated remarkable versatility by producing homodimers of peptides, peptoids, and non‐peptidic ligands. Its ease of application, broad utility, and mild reaction conditions not only hold significance for peptide and peptoid research but also offer potential for the on‐resin development of a wide range of bivalent ligands. [ABSTRACT FROM AUTHOR]

Enantiomorphous crystals of achiral 2‐pyridone and 4‐aminopyridine served as sources of chirality, to induce the asymmetric autocatalysis of 5‐pyrimidyl alkanol during the asymmetric addition of diisopropylzinc to the corresponding pyrimidine‐5‐carbaldehyde, that is, the Soai reaction. Following a significant amplification of enantiomeric excess through asymmetric autocatalysis, highly enantioenriched 5‐pyrimidyl alkanol could be synthesized with their corresponding absolute configurations to those of chiral crystals of 2‐pyridone and 4‐aminopyridine. [ABSTRACT FROM AUTHOR]

Following on our recently developed biphenyl-ATDP non-nucleoside reverse transcriptase inhibitor ZLM-66 (SI = 2019.80, S = 1.9 μg/mL), a series of novel heterocycle-substituted ATDP derivatives with significantly improved selectivity and solubility were identified by replacement of the biphenyl moiety of ZLM-66 with heterocyclic group with lower lipophilicity. Evidently, the representative analog 7w in this series exhibited dramatically enhanced selectivity and solubility (SI = 12,497.73, S = 4472 μg/mL) in comparison with ZLM-66 (SI = 2019.80, S = 1.9 μg/mL). This new NNRTI conferred low nanomolar inhibition of wild-type HIV-1 strain and tested mutant strains (K103N, L100I, Y181C, E138K, and K103N + Y181C). The analog also demonstrated favorable safety and pharmacokinetic profiles, as evidenced by its insensitivity to CYP and hERG, lack of mortality and pathological damage, and good oral bioavailability in rats (F = 27.1%). Further development of 7w for HIV therapy will be facilitated by this valuable information.

Physicochemical and pharmacokinetic properties represent the fundamental properties of drugs and affect their bioavailability. In this work, these properties are calculated and used to determine the preference of selected tautomers. 2-pyridones are nitrogen-containing heterocyclics that play an important role in drug design. All the Hydroxpyridone (HPYR)/ pyridone (PYR) tautomers studied in this work are lipophilic molecules. We also conclude that HPYRs are more lipophilic (more soluble in n-octanol) than PYRs. The bioavailability of the studied compounds was determined using ADMET analysis. The results showed that most of the 2-pyridones derivatives can be used orally and do not exhibit neurotoxicity effects. We also studied the tautomerization of 2-pyridones which can be done by two possible mechanisms, the classical pathway and dimerization in different phases. The calculations were carried out in the gas phase and in solution using quantum chemistry methods. [ABSTRACT FROM AUTHOR]

In this paper, two novel organic inhibitors, TAP-TPP and TAP-CEQ, were prepared via Schiff base condensation as a green chemistry methodology using an eco-friendly catalyst, ceric ammonium nitrate, with a high yield (87% and 91%), and characterized via elemental analysis, FTIR, 1H, and 13C NMR spectroscopic analysis tools. Weight loss assessment was utilized as a chemical testing method, and the maximum inhibition efficiency of TAP-TPP and TAP-CEQ is 89.4% and 91.8%, respectively. PDP and EIS were electrochemical measures to determine the efficacy of both inhibitors as anticorrosion for carbon steel alloys in 2 M HCl aggressive media. The collected electrochemical results demonstrated that both inhibitors behaved as excellent anticorrosion agents for metallic constructions. According to the potentiodynamic polarization (PDP) analysis, these organic inhibitors worked as mixed-type inhibitors. The adsorption isotherm revealed that undertaken compounds obeyed Langmuir adsorption isotherm with the free energies of adsorption of ranged from ΔG = − 34.29 to − 34.63 kJ Mol−1. Also, electrochemical impedance spectroscopy (EIS) data confirmed that the values charge transfer resistance (Rct) was increased by increasing the concentration of the injected inhibitor molecules. In contrast, the electrochemical double layer (Cdl) was dramatically decreased. The work was supported by two-surface analysis methods such as SEM and EDX. For more details, the values of percentage inhibition efficiency can be ordered as follows: TAP-CEQ > TAP-TPP. Finally, a suitable inhibition mechanism and theoretical studies including EHOMO, ELUMO, diploe moment (µ), and electrophilicity index (ω) were assumed and discussed in detailed. [ABSTRACT FROM AUTHOR]

Following on our recently developed biphenyl-ATDP non-nucleoside reverse transcriptase inhibitor ZLM-66 (SI = 2019.80, S = 1.9 μg/mL), a series of novel heterocycle-substituted ATDP derivatives with significantly improved selectivity and solubility were identified by replacement of the biphenyl moiety of ZLM-66 with heterocyclic group with lower lipophilicity. Evidently, the representative analog 7w in this series exhibited dramatically enhanced selectivity and solubility (SI = 12,497.73, S = 4472 μg/mL) in comparison with ZLM-66 (SI = 2019.80, S = 1.9 μg/mL). This new NNRTI conferred low nanomolar inhibition of wild-type HIV-1 strain and tested mutant strains (K103N, L100I, Y181C, E138K, and K103N + Y181C). The analog also demonstrated favorable safety and pharmacokinetic profiles, as evidenced by its insensitivity to CYP and hERG, lack of mortality and pathological damage, and good oral bioavailability in rats (F = 27.1%). Further development of 7w for HIV therapy will be facilitated by this valuable information. Herein, we reported the discovery of a novel series of heterocycle-substituted ATDP analogs as potent NNRTIs, of which 7w featuring dramatically enhanced selectivity and solubility compared with ZLM-66. [Display omitted] [ABSTRACT FROM AUTHOR]

In this study, a new and efficient Rod-like bifunctional Fe-based MOF@CuO nanocomposites (RL BF Fe-based MOF@CuO NC) were synthesized as new and efficient heterogeneous catalyst through a simple method from easily available 1,3,5-benzenetricarbocylic acid linker, nitrate ferric as a source of iron and copper oxide (CuO) nanoparticles under microwave irradiation. The synthesized nanocatalysts were characterized with different techniques such as Brunauer–Emmett–Teller (BET), energy dispersive spectroscopy (EDS), field emission scanning electron microscopy (FE-SEM), mapping, transmission electron microscopy (TEM), X-ray diffraction (XRD), vibrating sample magnetometer (VSM), thermogravimetric analysis (TGA) and Fourier transform infrared spectroscopy (FT-IR). The RL BF Fe-based MOF@CuO NC had relatively high specific surface area (203 m2 g−1) while exhibiting superparamagnetic properties. The catalytic activity of RL BF Fe-based MOF@CuO NC was explored in a facile and green methodology to prepare diverse N‑amino-2-pyridones by one-pot four component reactions comprising aromatic aldehyde, malononitrile, methyl cyanoacetate and hydrazine hydrate within mild and solvent-free conditions. This protocol enjoys features like providing the final products during low reaction times in excellent yields under solvent-free conditions. The use of easily available and inexpensive reactants for the synthesis of the catalyst, environmental compatibility, low catalyst loading, fast and clean work-up and reusability of catalyst for several cycles with consistent activity are counted as the outstanding features of this procedure. [ABSTRACT FROM AUTHOR]

The synthesis and crystal structure of the title compound, C22H14N2O, are described. The title compound was synthesized by a three-component one-pot reaction in DMSO involving chalcone, cyanoacetamide and elemental sulfur as catalyst. The compound was characterized by spectroscopic methods and single-crystal X-ray diffraction. The structure consists of inversion-related dimers produced by N--H⋯O hydrogen bonding, which further interact through π-π contacts. [ABSTRACT FROM AUTHOR]

Accessible drug modalities have continued to increase in number in recent years. Peptides play a central role as pharmaceuticals and biomaterials in these new drug modalities. Although traditional peptide synthesis using chain-elongation from C- to N-terminus is reliable, it produces large quantities of chemical waste derived from protecting groups and condensation reagents, which place a heavy burden on the environment. Here we report an alternative N-to-C elongation strategy utilizing catalytic peptide thioacid formation and oxidative peptide bond formation with main chain-unprotected amino acids under aerobic conditions. This method is applicable to both iterative peptide couplings and convergent fragment couplings without requiring elaborate condensation reagents and protecting group manipulations. A recyclable N-hydroxy pyridone additive effectively suppresses epimerization at the elongating chain. We demonstrate the practicality of this method by showcasing a straightforward synthesis of the nonapeptide DSIP. This method further opens the door to clean and atom-efficient peptide synthesis. Traditional peptide synthesis iteratively elongates the chain from the C-terminus to the N-terminus (C-to-N), however, this process requires excess N-carbamate-protected amino acids and condensation reagents to minimize epimerization. Here, the authors report an alternative N-to-C elongation strategy by catalytic peptide thioacid formation and oxidative peptide bond formation without requiring condensation reagents and excessive protecting group manipulations. [ABSTRACT FROM AUTHOR]

In this work, the electrooxidation ability of nine pyridones was evaluated using cyclic (CV) and square-wave voltammetry (SWV) in Britton–Robinson (BR) aqueous buffer solutions on a glassy carbon electrode (GC). The dependence of electrochemical activity on pyridone structure was elucidated by means of experimentally obtained spectra and quantum chemical calculations. Firstly, it was shown that electrochemical activity is determined by the –OH group as a substituent in position 6 of the pyridone ring. By coupling the experimentally obtained UV-Vis spectra and DFT calculations, the most stable forms, both protonated and deprotonated, were defined. The calculated values are consistent with the electrochemical behavior observed, indicating that the deprotonated anionic form was the most electrochemically active. Moreover, the impact of the substituent in position 3 of the pyridone scaffold was discussed. [ABSTRACT FROM AUTHOR]

The polynuclear alanine hydroximate metallamacrocyclic complex Nd(C8H7NO4)(H2O)[15-MCCu(II)Alaha-5](CH3COO) with the axial 3-hydroxy-4-pyridinone ligand is synthesized for the first time from the (3-hydroxy-2-methyl-4-oxo-4H-pyridin-1-yl) acetate ligand. The X-ray diffraction (XRD) (CIF file CCDC no. 2242224) and quantum chemical methods show that the interaction of ligand L with the Nd3+ ion retained due to ionic bonds with the oxygen atoms in the copper-containing metallamacrocyclic matrix results in the formation of axial bonds (having a covalent contribution) between Nd3+ and the dioxolene fragment of the pyridinone ligand. In topological and energy characteristics, these axial bond approach the bonds of Cu2+ with the amine nitrogen atoms of the alanine hydroximate metallamacrocycle. [ABSTRACT FROM AUTHOR]

The synthesis of a new class of compounds, namely 1‐((1‐phenyl‐1H‐1,2,3‐triazol‐4‐yl)methyl)pyridin‐2(1H)‐one derivatives starting from 2‐hydroxynicotinic acid was reported. Initially, the carboxylic acid functionality connected to the pyridinone ring was converted to either the ester, amide or aldehyde functionality to obtain the precursor for the propargylation step. The incorporation of a propargyl group into the nitrogen atom of pyridinones was achieved in the presence of K2CO3 as a base. Different organic azides were also synthesized starting from the corresponding aniline derivatives. To obtain target molecules, the facile click cycloaddition reactions of alkynes with aryl azide derivatives in the presence of copper(I) catalyst were applied. Using this protocol, novel 1‐((1‐phenyl‐1H‐1,2,3‐triazol‐4‐yl)methyl)pyridin‐2(1H)‐one derivatives with different substitution patterns were prepared in good to excellent yields under the mild reaction conditions. The structures of the compounds were confirmed by 1D and 2D NMR, FTIR, and HRMS analysis data. Overall, this protocol offers a straightforward method for synthesizing these novel compounds. [ABSTRACT FROM AUTHOR]

New derivatives of 3-methylcytisine with 9-aromatic substituents bonded to the pyridone core of the starting alkaloid through spacers of various natures, e.g., aminomethyl, amide, thio- and carboxamide, ethenyl, and ethyl, were synthesized from 9-amino- and 9-bromo-2-oxomethylcytisine. [ABSTRACT FROM AUTHOR]

Dietary vitamin B3 components, such as nicotinamide and nicotinic acid, are precursors to the ubiquitous redox cofactor nicotinamide adenine dinucleotide (NAD+). NAD+ levels are thought to decline with age and disease. While the drivers of this decline remain under intense investigation, strategies have emerged seeking to functionally maintain NAD+ levels through supplementation with NAD+ biosynthetic intermediates. These include marketed products, such as nicotinamide riboside (NR) and its phosphorylated form (NMN). More recent developments have shown that NRH (the reduced form of NR) and its phosphorylated form NMNH also increases NAD+ levels upon administration, although they initially generate NADH (the reduced form of NAD+). Other means to increase the combined levels of NAD+ and NADH, NAD(H), include the inhibition of NAD+-consuming enzymes or activation of biosynthetic pathways. Multiple studies have shown that supplementation with an NAD(H) precursor changes the profile of NAD(H) catabolism. Yet, the pharmacological significance of NAD(H) catabolites is rarely considered although the distribution and abundance of these catabolites differ depending on the NAD(H) precursor used, the species in which the study is conducted, and the tissues used for the quantification. Significantly, some of these metabolites have emerged as biomarkers in physiological disorders and might not be innocuous. Herein, we review the known and emerging catabolites of the NAD(H) metabolome and highlight their biochemical and physiological function as well as key chemical and biochemical reactions leading to their formation. Furthermore, we emphasize the need for analytical methods that inform on the full NAD(H) metabolome since the relative abundance of NAD(H) catabolites informs how NAD(H) precursors are used, recycled, and eliminated. [ABSTRACT FROM AUTHOR]

A simple and efficient nitrile-directed meta-C-H olefination, acetoxylation, and iodination of biaryl compounds is reported. Compared to the previous approach of installing a complex U-shaped template to achieve a molecular U-turn and assemble the large-sized cyclophane transition state for the remote C-H activation, a synthetically useful phenyl nitrile functional group could also direct remote meta-C-H activation. This reaction provides a useful method for the modification of biaryl compounds because the nitrile group can be readily converted to amines, acids, amides, or other heterocycles. Notably, the remote meta-selectivity of biphenylnitriles could not be expected from previous results with a macrocyclophane nitrile template. DFT computational studies show that a ligand-containing Pd-Ag heterodimeric transition state (TS) favors the desired remote meta-selectivity. Control experiments demonstrate the directing effect of the nitrile group and exclude the possibility of non-directed meta-C-H activation. Substituted 2-pyridone ligands were found to be key in assisting the cleavage of the meta-C-H bond in the concerted metalation-deprotonation (CMD) process.

Besides the peripheral modification, the introduction of heteroatoms to modulate the property of longer acenes with improved chemical stability has been extensively studied for their potential applications in organic electronics. However, the utilization of 4‐pyridone, a common unit in the air‐ and photo‐stable acridone and quinacridone, to decorate higher acenes with increased stability has not been realized yet. Here we present the synthesis of a series of monopyridone‐doped acenes up to heptacene via the palladium‐catalyzed Buchwald‐Hartwig amination of aniline and dibromo‐ketone. The effect of pyridone on the property of doped acenes were investigated experimentally and computationally. With the π‐extension of doped acenes, the pyridone ring shows the weakened conjugation and gradual loss of aromaticity. The doped acenes demonstrate enhanced stability in solution and maintain the electronic communication between the acene planes. [ABSTRACT FROM AUTHOR]

A two-stage synthesis of 5-aroyl-2-aryl-3-hydroxypyridin-4(1H)-ones (56–66% overall yields) was carried out by refluxing 5-aroyl-3-(benzyloxy)-2-(het)aryl-4H-pyran-4-ones with ammonium acetate in AcOH and subsequent debenzylation. The prepared N-unsubstituted 4-pyridones exist in the pyridone tautomeric form. [ABSTRACT FROM AUTHOR]

The cotton leafworm, Spodoptera littoralis Boisd. is a serious pest attacking a wide range of ornamentals and many field crops. It is well documented that some heterocyclic systems have efficient insecticidal activities. So novel hydrazide‐hydrazone namely, N′,N′′′‐((methylenebis(6‐hydroxy‐3,1‐phenylene))bis(methanylylidene))bis(2‐cyanoacetohydrazide) 3 was exploited as a target to synthesize bis‐heterocyclic moieties such as furan, pyridone, coumarin, thiazole and isoxazole, and also some bis‐heteroarylidenes including heterocycles as indole and pyrazole. The chemical structures of the synthesized compounds were established on the basis of elemental analyses and some spectroscopic tools. All the synthesized compounds were screened for the insecticidal efficacy against the 4th larval instar of Spodoptera littoralis (cotton leafworm). Manifestly, the data showed that compounds 9 and 14 possess remarkable potency but the rest of compounds showed no pronounced activity against cotton leafworm. [ABSTRACT FROM AUTHOR]

(E)-1-ethyl-6-hydroxy-4-methyl-5-((4-nitrophenyl)diazenyl)-2-oxo-1, 2-dihydropyridine-3-carbonitrile and (E)-5-((2, 4-dinitrophenyl)diazenyl)-1-ethyl-6-hydroxy-4-methyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile, namely D1 and D2 were synthesized, color performance in solvents, DMF and CH2Cl2, as well as polyester and polyaimde fabrics are studied to investigate azo-hydrazone tautomerism behaviors of disperse dyes containing pyridone group. The visible absorption spectrophotometry behaviors in solvents are studied, and the heterochromic dyeing performance on polyethylene terephthalate (PET) and polyamide (PA) fabrics is also compared. To reveal azo-hydrazone tautomerism of pyridone disperse dyes induced by circumstances, Gaussian simulation is applied to give optimized geometries, as well as absorption spectrum in solvent and non-solvent environment. Nuclear magnetic resonance (1 H NMR) spectrum shows that the disperse dyes with pyridinone structure exist as azo form in polar solvents and hydrazone tautomer in non-polar solvents. The dyeing performance and quantum calculation show that the dyes exist in hydrazone form on PET fabric and azo structure in PA fabric. Pyridone disperse dyes show excellent light fastness on PET fabrics, but poor light fastness on PA fabrics, which is attributed to azo-hydrazone tautomerism of the dyes. [ABSTRACT FROM AUTHOR]

An N‐heterocyclic carbene (NHC) catalyzed asymmetric [3+3] annulation of α‐bromoenals with 5‐aminopyrazoles is described. Using the established methodology, a structurally diverse set of high value dihydropyrazolo[3,4‐b]pyridine‐6‐ones were efficiently constructed in high yields (up to 99%) with excellent enantioselectivities (up to >99%). The easily available starting materials, broad substrate scope, mild reaction conditions, excellent yield and enantioselectivity make this strategy attractive for the asymmetric construction of pyrazolo‐fused pyridone derivatives. [ABSTRACT FROM AUTHOR]

Controlling the pairing strength of nucleobases in DNA through reactions with compounds found inside the cell is a formidable challenge. Here we report how a thiazolyl substituent turns a strongly pairing ethynylpyridone C‐nucleoside into a reactive residue in oligonucleotides. The thiazolyl‐bearing pyridone reacts with soft nucleophiles, such as glutathione, but not with hard nucleophiles like hydroxide or carbonate. The addition products pair much more weakly with adenine in a complementary strand than the starting material, and also change their fluorescence. This makes oligonucleotides containing the new deoxynucleoside interesting for controlled release. Due to its reactivity toward N, P, S, and Se‐nucleophiles, and the visual signal accompanying chemical conversion, the fluorescent nucleotide reported here may also have applications in chemical biology, sensing and diagnostics. [ABSTRACT FROM AUTHOR]

The novel diazenyl pyridinone heterocyclic ligands and their Cu(II) complexes have been prepared and characterized utilizing miscellaneous analytical tools, thermogravimetric analysis (TGA), and nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR), electron paramagnetic resonance (EPR), and ultraviolet–visible spectroscopies. The investigated ligands are coordinated in a bidentate fashion through the azo nitrogen atom and the hydroxyl oxygen atom to the Cu(II) center. The EPR spectra indicated that the obtained complexes were monomeric, and density functional theory (DFT) calculations confirmed that the Cu(II) atom adopted a six‐coordinated octahedral geometry. The ligands and their complexes were investigated for their in vitro antimicrobial activity against some types of bacteria and fungi. The antioxidant and anticancer activities of the complexes were also assessed. The results show that these complexes exhibit higher antitumor efficiency and selectivity index against the models of human breast adenocarcinoma cells MCF‐7 and human primary hepatocytes THLE‐2 than the reference standard material doxorubicin. The results were supported by DFT calculations, molecular docking, and Hirshfeld surface analysis. [ABSTRACT FROM AUTHOR]

Synthesis of oxazolonone, benzoxazolononeby using amino hydroxy compound, alkyl haloformate, trialkylamine and DMF as solvents. Herein used simple carbonylation agent such as alkylhaloformate instead of phosgene and Triphosgene. Developed novel and simple synthesis method. [ABSTRACT FROM AUTHOR]

In this study, a series of novel thieno [3, 2- b ]pyridinone derivatives were designed and synthesized using a scaffold hopping strategy. Six compounds showed potent anti-mycobacterial activity (minimum inhibitory concentration (MIC) ≤ 1 μg/mL) against Mycobacterium tuberculosis (Mtb) UAlRa. Compound 6c displayed good activity against Mtb UAlRv (MIC = 0.5–1 μg/mL). Compounds 6c and 6i also showed activity against Mtb UAlRa in macrophages and exhibited low cytotoxicity against LO-2 cells. The selected compounds displayed a narrow antibacterial spectrum, with no activity against representative Gram-positive, Gram-negative bacteria, as well as fungi. Furthermore, compound 6c demonstrated favorable oral pharmacokinetic properties with a T 1/2 value of 47.99 h and exhibited good in vivo activity in an acute mouse model of tuberculosis (TB). The target of compound 6c was identified as a NADH-dependent enoyl-acyl carrier protein reductase (InhA) by genome sequencing of spontaneously compound 6c -resistant Mtb mutants, indicating that compound 6c may not require activation and can directly target InhA. In vitro antimicrobial assays against a recombinant M. smegmatis overexpressing the Mtb-InhA, along with InhA inhibition assays, confirmed that InhA is the target of thieno [3, 2- b ]pyridinone derivatives. Overall, this study identified thieno [3, 2- b ]pyridinone scaffold as a novel chemotype that is promising for the development of anti-TB agents. [Display omitted] • We synthesized a series of novel thieno [3, 2- b ]pyridinone derivatives with potent inhibitory activities against Mtb. • Compound 6c displayed a long elimination half-life (T 1/2 = 47.99 h) and an accepted oral bioavailability in vivo. • Compound 6c showed potent in vivo efficacy in an acute mouse TB model. • Studies in target of compound 6c revealed that InhA may be the direct target without activation by KatG. [ABSTRACT FROM AUTHOR]

New applications for bioluminescence imaging require an expanded set of luciferase enzymes and luciferin substrates. Here, we report two novel luciferins for use in vitro and in cells. These molecules comprise regioisomeric pyridone cores that can be accessed from a common synthetic route. The analogues exhibited unique emission spectra with firefly luciferase, although photon intensities remained weak. Enhanced light outputs were achieved by using mutant luciferase enzymes. One of the luciferin-luciferase pairs produced light on par with native probes in live cells. The pyridone analogues and complementary luciferases add to a growing set of designer probes for bioluminescence imaging.

We report that O‐selective arylation of 2‐ and 4‐pyridones with arylboronic acids is affected by a modular, bismacycle‐based system. The utility of this umpolung approach to pyridyl ethers, which is complementary to conventional methods based on SNAr or cross‐coupling, is demonstrated through the concise synthesis of Ki6783 and picolinafen, and the formal synthesis of cabozantib and golvatinib. Computational investigations reveal that arylation proceeds in a concerted fashion via a 5‐membered transition state. The kinetically‐controlled regioselectivity for O‐arylation—which is reversed relative to previous BiV‐mediated pyridone arylations—is attributed primarily to the geometric constraints imposed by the bismacyclic scaffold. [ABSTRACT FROM AUTHOR]

A chromeno[4,3-d]pyrazolo[3,4-b]pyridinone derivative 3 bearing thieno[2,3-d]pyrimidine moiety, 5-methyl-1-phenyl-3-(thieno[2,3-d]pyrimidin-4-yl)chromeno[4,3-d]pyrazolo[3,4-b]pyridin-6(3H)-one, was efficiently prepared in 75% yield by the reaction of 3-phenyl-1-(thieno[2,3-d]pyrimidin-4-yl)-1H-pyrazol-5-amine 1 with 3-acetyl-2H-chromen-2-one 2 in the presence of FeCl3-SiO2 as a catalyst in refluxing ethanol for 6 h. The structure of the new synthesized compound was characterized by 1H-, 13C- NMR, IR spectroscopy, mass-spectrometry, and elemental analysis. [ABSTRACT FROM AUTHOR]

A steroidal‐based synthetic protocol has been developed for the synthesis of substituted steroidal pyridones in the presence of L‐proline. A wide variety of steroidal pyridones were synthesized in better yields. Initially, steroidal benzylidenes were prepared by the aldol condensation of pregnenolone with various substituted aromatic aldehydes under basic conditions. After that heterocyclization of resulting benzylidenes with cyanoacetamide in the presence of L‐proline gives the desired products. With the mild reaction conditions, good conversions, operational simplicity, and inexpensive and readily available catalyst, it is a practical and appealing approach for pyridone synthesis. Structural and quantum chemical insights of synthesized steroidal pyridone derivatives have been also presented using the density functional theory (DFT) approach. [ABSTRACT FROM AUTHOR]

Novel yellow azo pyridone dye derivatives were synthesized for use in image-sensor color filters. The synthesized compounds have a basic chemical structure composed of azo, hydroxy, amide, and nitrile groups as well as different halide groups. New materials were evaluated on the basis of their optical, thermal, and surface properties under conditions mimicking those of a commercial device fabrication process. A comparison of their related performance revealed that, among the four prepared compounds, 5-((4,6-dichlorocyclohexa-2,4-dien-1-yl)diazenyl)-6-hydroxy-1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (Cl-PAMOPC) exhibited the best performance as an image-sensor color filter material, including a solubility greater than 0.1 wt% in propylene glycol monomethyl ether acetate solvent, a high decomposition temperature of 263 °C, and stable color difference values of 4.93 and 3.88 after a thermal treatment and a solvent-resistance test, respectively. The results suggest that Cl-PAMOPC can be used as a green dye additive in an image-sensor colorant. [ABSTRACT FROM AUTHOR]

Pyridone adenine dinucleotides (ox-NADs) are redox inactive derivatives of the enzyme cofactor and substrate nicotinamide adenine dinucleotide (NAD) that have a carbonyl group at the C2, C4, or C6 positions of the nicotinamide ring. These aberrant cofactor analogs accumulate in cells under stress and are potential inhibitors of enzymes that use NAD(H). We studied the conformational landscape of ox-NADs in solution using molecular dynamics simulations. Compared to NAD+ and NADH, 2-ox-NAD and 4-ox-NAD have an enhanced propensity for adopting the anti conformation of the pyridone ribose group, whereas 6-ox-NAD exhibits greater syn potential. Consequently, 2-ox-NAD and 4-ox-NAD have increased preference for folding into compact conformations, whereas 6-ox-NAD is more extended. ox-NADs have distinctive preferences for the orientation of the pyridone amide group, which are driven by intramolecular hydrogen bonding and steric interactions. These conformational preferences are compared to those of protein-bound NAD(H). Our results may help in identifying enzymes targeted by ox-NADs. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

On the basis of 4-(thien-2-yl)-3-aminopyridine-2(1H)-one, the corresponding chloroacetamide and condensed 1H-pyrido[2,3-b][1,4]oxazine-2(3H)-one were synthesized by the reaction of acylation with chloroacetyl chloride. Thioureide derivatives of 3-aminopyridine-2(1H)-one were obtained by reactions with a number of isothiocyanates. It was shown that the carbamothionylmethacrylamide derivative cyclizes rather easily into substituted 1,3-thiazine. Molecular docking of synthesized derivatives for antithrombotic activity was carried out, which showed that the presence of a thiourea fragment in the pyridone core leads to an increase in affinity for the selected protein. The hemorheological study of the compounds using the in vitro model of the increased blood viscosity syndrome also showed activity at the level of the reference drug pentoxifylline. [ABSTRACT FROM AUTHOR]

A new series of pyridine-2-one and pyrazole derivatives were designed and synthesized based on cyanoacrylamide derivatives containing 2,4-dichlro aniline and 6-methyl 2-amino pyridine as an aryl group. Condensation of cyanoacrylamide derivatives 3a–d with different active methylene (malononitrile, ethyl cyanoacetate cyanoacetamide, and ethyl acetoacetate) in the presence of piperidine as basic catalyst afforded the corresponding pyridinone derivatives 4a–c, 5, 9, and 13. Furthermore, the reaction of cyanoacrylamide derivatives 3a–d with bi-nucleophile as hydrazine hydrate and thiosemicarbazide afforded the corresponding pyrazole derivatives 14a,b and 16. The newly designed derivatives were confirmed and established based on the elemental analysis and spectra data (IR, 1H NMR, 13C NMR, and mass). The in vitro antibacterial activity was evaluated against four bacterial strains with weak to good antibacterial activity. Moreover, the results indicated that the most active derivatives 3a, 4a, 4b, 9, and 16 might lead to antibacterial agents, especially against B. subtilis and P. vulgaris. The DFT calculations were performed to estimate its geometric structure and electronic properties. In addition, the most active pyridinone and pyrazole derivatives were further evaluated for in silico physicochemical, drug-likeness, and toxicity prediction. These derivatives obeyed all Lipinski's and Veber's rules without any violation and displayed non-immunotoxin, non-mutagenic, and non-cytotoxic. Molecular docking simulation was performed inside the active site of Topoisomerase IV (PDB:3FV5). It displayed binding energy ranging from -14.97 kcal/mol to -18.86 kcal/mol with hydrogen bonding and arene–cation interaction. Therefore, these derivatives were suggested to be good antibacterial agents via topoisomerase IV inhibitor. [ABSTRACT FROM AUTHOR]

Rhodium(III)‐catalyzed C6‐selective C−H 3‐oxoalkylation of 2‐pyridones was developed with commercially available allylic alcohols as the 3‐oxoalkyl sources. In this reaction, the excellent site selectivity was controlled by the 2‐pyridyl directing group on the nitrogen of the pyridone ring. This reaction features good functional group tolerance and the generation of 6‐(3‐oxoalkyl) pyridones in moderate to good yields. [ABSTRACT FROM AUTHOR]