Metal-Free Cascade Formation of C-C and C-N Bond for the Construction of 3-Cyano-2-Pyridones with Insecticidal Properties.

A straightforward and efficient methodology has been developed for the synthesis of 3-cyano-2-pyridones via the C-C and C-N bond formation processes. A total of 51 diverse 3-cyano-2-pyridone derivatives were obtained in moderate to excellent yields. This reaction featured advantages such as a metal-free process, wide functional group tolerance, simple operation, and mild conditions. A plausible mechanism for the reaction was proposed. 3-cyano-2-pyridones as ricinine analogues for insecticidal properties were evaluated, and the compound 3ci (LC50 = 2.206 mg/mL) showed the best insecticidal property.

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,ß-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).

Design of 2-Pyridone Fluorophores for Brighter Emissions at Longer Wavelengths.

The recent discovery of blue fluorophores with high quantum yields based on pyridone structures inspired the development of new low-molecular-weight fluorophores with bright emissions at tunable wavelengths, which are highly attractive for various applications. In this study, we propose a rational design strategy for 2-pyridone-based fluorophores with bright emissions at long wavelengths. With a detailed understanding of the positional substitution effects on each carbon atom of the 2-pyridone core, we developed a bright blue fluorophore (λabs =377 nm; λem =433 nm; ϵ=13,200 M-1 cm-1 ; ϕF =88 %) through C3 -aryl and C4 -ester substitutions followed by cyclization. Furthermore, by applying the intramolecular charge transfer (ICT) principle, we invented a bright green fluorophore through C3 - and C4 -diester and C6 -aryl substitutions. The ICT fluorophore based on the pyridone structure shows large molar absorptivity (ϵ=20,100 M-1 cm-1 ), longer emission wavelength (λem =539 nm), high emission quantum yield (ϕF =74 %), and large Stokes shift (Δv=5720 cm-1 ), which are comparable to those of practical fluorescent probes.

Palladium-Catalyzed ß-C(sp3)-H Bond Arylation of Tertiary Aldehydes Facilitated by 2-Pyridone Ligands.

2-Pyridone ligand-facilitated palladium-catalyzed direct C-H bond functionalization via the transient directing group strategy has become an attractive topic. Here, we report a Pd-catalyzed direct ß-C(sp3)-H arylation reaction of tertiary aliphatic aldehydes by using an α-amino acid as a transient directing group in combination with a 2-pyridone ligand.

Three new metabolites from the endophyte Fusarium proliferatum T2-10.

One new cyclopeptide, cyclo-(L-Trp-L-Phe-L-Phe) (1), one new 2-pyridone derivative, fusarone A (3), and one new natural indole derivative, ethyl 3-indoleacetate (4), along with six known compounds were isolated from the endophytic fungus Fusarium proliferatum T2-10. The planar structures of three new compounds were identified by spectral methods including 1D and 2D NMR techniques, and the absolute configuration of compound 1 was elucidated by Marfey-MS method. In addition, all compounds were evaluated for their cytotoxic and antibacterial activities in vitro. Compound 2 showed remarkable cytotoxic activities against two human hepatoma cell lines SMMC7721 and HepG2 with IC50 values of 5.89 ± 0.74 and 6.16 ± 0.52 µM, and showed moderate antibacterial activities against Staphylococcus aureus and Enterococcus faecalis with MIC values of 7.81 and 15.62 µg/mL, respectively.

2-Hydroxypyridine-based Ligands as Promoter in Ruthenium(II) Catalyzed C-H Bond Activation/Arylation Reactions.

A class of 2-hydroxypyridine based ligands are explored to achieve enhanced catalytic activity for ortho-C-H bond activation/arylation reaction over [(η6 -p-cymene)RuCl2 ]2 catalyst in water. Extensive studies using a series of substituted 2-hydroxypyridine based ligands (L1-L6) inferred that 5-trifluoromethyl-2-hydroxypyridine (L6) exhibited favorable effects to enhance the catalytic activity of Ru(II) catalyst for ortho C-H bond arylation of 2-phenylpyridine by 8 folds compared to those performed without ligands. The (η6 -p-cymene)Ru - L6 system also exhibited enhanced catalytic activity for ortho C-H bond arylation of 2-phenylpyridine using a variety of aryl halides. NMR and mass investigations inferred the presence of several ligand coordinated Ru(II) species, suggesting the involvement of these species in C-H bond activation reaction. Further in concurrence with the experimental findings, the density functional theory (DFT) calculations also evidenced the prominent role of 2-hydroxypyridine based ligands in Ru(II) catalyzed C-H bond arylation of 2-phenylpyridine with lower energy barrier for the C-H activation step.

Recent Progresses in the Catalytic Stereoselective Dearomatization of Pyridines.

1,2- and 1,4-dihydropyridines and N-substituted 2-pyridones are very important structural motifs due to their synthetic versatility and vast presence in a variety of alkaloids and bioactive molecules. In this article, we gather and summarize the catalytic and stereoselective synthesis of partially hydrogenated pyridines and pyridones via the dearomative reactions of pyridine derivatives up to mid-2023. The material is fundamentally organized according to the type of reactivity (electrophilic/nucleophilic) of the pyridine nucleus. The material is further sub-divided taking into account the nucleophilic species when dealing with electrophilic pyridines and considering the reactivity manifold of pyridine derivatives behaving as nucleophiles at the nitrogen site. The latter more recent approach allows for an unconventional entry to chiral N-substituted 2- and 4-pyridones in non-racemic form.

Pentaketides and 5-p-Hydroxyphenyl-2-pyridone Derivative from the Culture Extract of a Marine Sponge-Associated Fungus Hamigera avellanea KUFA0732.

Five undescribed pentaketide derivatives, (R)-6,8-dihydroxy-4,5-dimethyl-3-methylidene-3,4-dihydro-1H-2-benzopyran-1-one (1), [(3S,4R)-3,8-dihydroxy-6-methoxy-4,5-dimethyl-1-oxo-3,4-dihydro-1H-isochromen-3-yl]methyl acetate (2), (R)-5, 7-dimethoxy-3-((S)-(1-hydroxyethyl)-3,4-dimethylisobenzofuran-1(3H)-one (4b), (S)-7-hydroxy-3-((S)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran 1(3H)-one (5), and a p-hydroxyphenyl-2-pyridone derivative, avellaneanone (6), were isolated together with the previously reported (R)-3-acetyl-7-hydroxy-5-methoxy-3,4-dimethylisobenzofuran-1(3H)-one (3), (R)-7-hydroxy-3-((S)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3H)-one (4a) and isosclerone (7), from the ethyl acetate extract of a culture of a marine sponge-derived fungus, Hamigera avellanea KUFA0732. The structures of the undescribed compounds were elucidated using 1D and 2D NMR, as well as high-resolution mass spectral analyses. The absolute configurations of the stereogenic carbons in 1, 4b, 5, and 6 were established by X-ray crystallographic analysis. The absolute configurations of C-3 and C-4 in 2 were determined by ROESY correlations and on the basis of their common biosynthetic origin with 1. The crude fungal extract and the isolated compounds 1, 3, 4b, 5, 6, and 7 were assayed for their growth inhibitory activity against various plant pathogenic fungi viz. Alternaria brassicicola, Bipolaris oryzae, Colletotrichum capsici, C. gloeosporiodes, Curvularia oryzae, Fusarium semitectum, Lasiodiplodia theobromae, Phytophthora palmivora, Pyricularia oryzae, Rhizoctonia oryzae and Sclerotium rolfsii.

Elucidation of a Dearomatization Route in the Biosynthesis of Oxysporidinone Involving a TenA-like Cytochrome P450 Enzyme.

Oxidative dearomatization of phenols is an important transformation for synthesis of complex molecules. Oxysporidinone and related 2-pyridones feature a hydroxy-substituted cyclohexanone ring, which has been proposed to form by phenol dearomatization, although the details of the biochemical process are still unknown. In this study, we identified the oxysporidinone biosynthetic gene cluster in Fusarium oxysporum by regulator activation and gene knockout studies. Through in vivo and in vitro studies, we confirmed that the phenol dearomatization process involves two enzymes. OsdM, a TenA-like cytochrome P450 with expected ring-expansion activity, converts the phenol ring and the 4-hydroxy-2-pyridone core into an unexpected fused [6-5-6] ring system. OsdN, on the other hand, catalyzes two successive ene reduction reactions, followed by hydroxylation by OsdM. This new route enriches current knowledge on enzymatic phenol dearomatization and the mechanism of TenA-like P450s.

Synthesis of Highly Heterocyclic Fluorescent Molecules: 2-imino-2H-pyrano[3,2-c] Pyridin-5(6H)-ones Derivatives.

New highly fluorescent 2-imino-2H-pyrano[3,2-c]pyridin-5(6H)-onesderivatives were synthesized using a simple route. The present molecules were prepared by two methods with good yield. The structures were characterized by NMR1H, 13 C, and elemental analysis. Also, the effect of solvent and concentration on the fluorescence properties were demonstrated. However, the high fluorescence intensity in the range of 70,000-75,000 a. u. was obtained with a concentration equal to 10- 6 M of prepared molecules. The intensity was influenced also by the molecule structure and solvent.

Ultra-long Near-infrared Repeatable Photochemical Afterglow Mediated by Reversible Storage of Singlet Oxygen for Information Encryption.

Photochemical afterglow systems have drawn considerable attention in recent years due to their regulable photophysical properties and charming application potential. However, conventional photochemical afterglow suffered from its unrepeatability due to the consumption of energy cache units as afterglow photons are emitted. Here we report a novel strategy to realize repeatable photochemical afterglow (RPA) through the reversible storage of 1 O2 by 2-pyridones. Near-infrared afterglow with a lifetime over 10 s is achieved, and its initial intensity shows no significant reduction over 50 excitation cycles. A detailed mechanism study was conducted and confirmed the RPA is realized through the singlet oxygen-sensitized fluorescence emission. Furthermore, the generality of this strategy is demonstrated and tunable afterglow lifetimes and colors are achieved by rational design. The developed RPA is further applied for attacker-misleading information encryption, presenting a repeatable-readout.

Structure-based drug design of novel M. tuberculosis InhA inhibitors based on fragment molecular orbital calculations.

2-trans enoyl-acyl carrier protein reductase (InhA) is a promising target for developing novel chemotherapy agents for tuberculosis, and their inhibitory effects on InhA activity were widely investigated by the physicochemical experiments. However, the reason for the wide range of their inhibitory effects induced by similar agents was not explained by only the difference in their chemical structures. In our previous molecular simulations, a series of heteroaryl benzamide derivatives were selected as candidate inhibitors against InhA, and their binding properties with InhA were investigated to propose novel derivatives with higher binding affinity to InhA. In the present study, we extended the simulations for a series of 4-hydroxy-2-pyridone derivatives to search widely for more potent inhibitors against InhA. Using ab initio fragment molecular orbital (FMO) calculations, we elucidated the specific interactions between InhA residues and the derivatives at an electronic level and highlighted key interactions between InhA and the derivatives. The FMO results clearly indicated that the most potent inhibitor has strong hydrogen bonds with the backbones of Tyr158, Thr196, and NADH of InhA. This finding may provide informative structural concepts for designing novel 4-hydroxy-2-pyridone derivatives with higher binding affinity to InhA. Our previous and present molecular simulations could provide important guidelines for the rational design of more potent InhA inhibitors.

Insight into designing of 2-pyridone derivatives for COVID-19 drug discovery - A computational study.

Presently, the prime global focus is on SARS-CoV-2, as no fully established, licensed medicine has been found thus far, in spite of the existence of various reports and administration of partially proven certain class of natural products. However, in case of natural products, the extraction and purification limit their application. This situation drives researchers to explore synthetically viable drugs. In the present investigation, twenty-three 2-pyridone synthetic derivatives (P1-P23) have been theoretically tested for their suitability as potential inhibitors for COVID-19 main protease through DFT, molecular docking, and molecular dynamics simulations. DFT calculations offer insights into structure-property relationships, while ADMET studies indicate the pharmacological characteristics of these molecules. Molecular docking studies ascertain the nature and mode of interactions of these entities with COVID-19 main protease. Furthermore, covalent docking has been carried out to verify the feasibility of the formation of a covalent bond with the active site. The top protein-inhibitor complexes, such as P18, P11, and P12, were identified based on their glide score. These molecules, along with the covalent docked complexes, namely P18 and P16, were selected and subjected to molecular dynamics simulations. The 100 ns simulation process exhibited that the covalent docked ones, due to their stable form could serve as lead compounds against SARS-CoV-2. Hence, this study affirms the potential candidature of 2-pyridone-based inhibitors.

Synthesis, biological evaluation and molecular docking of new triphenylamine-linked pyridine, thiazole and pyrazole analogues as anticancer agents.

A new series of pyridine, thiazole, and pyrazole analogues were synthesized. The pyridone analogues 4a-e were synthesized by treating N-aryl-2-cyano-3-(4-(diphenylamino)phenyl)acrylamides 3a-e with malononitrile. Many 4-arylidene-thiazolidin-5-one analogues 6a-d were obtained by Knoevenagel reactions of 4-(diphenylamino)benzaldehyde (1) with their corresponding thiazolidin-5-one derivatives 5a-d. The structural elucidation of the products was proven by the collections of spectroscopic methods such as IR, 1H NMR, 13C NMR, and MS data. Their anti-cancer activity was examined against two cell lines, MDA-MB-231 (mammary carcinomas) and A-549 (lung cancer). Compared with cisplatin as a reference standard drug, 6-amino-4-(4-(diphenylamino)phenyl)-2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3,5-dicarbonitrile (4b) and 6-amino-4-(4-(diphenylamino)phenyl)-1-(4-nitrophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (4e) exhibited better efficiency against the A-549 cell line, with IC50 = 0.00803 and 0.0095 µM, respectively. Also, these compounds 4b and 4e showed the most potency among the examined compounds against MDA-MB-231 with IC50 = 0.0103 and 0.0147 µM, respectively. The newly synthesized compounds were docked inside the active sites of the selected proteins and were found to demonstrate proper binding. 2-Cyano-2-(4,4-(diphenylamino)benzylidene)-5-oxo-3-phenylthiazolidin-2-ylidene)-N-(p-tolyl)acetamide (6c) offered the highest binding affinity (- 8.1868 kcal/mol) when docked into (PDB ID:2ITO), in addition to 2-cyano-N-(4-(diethylamino)phenyl)-2-(4-(4-(diphenylamino)benzylidene)-5-oxo-3-phenylthiazolidin-2-ylidene)acetamide (6a) gave the highest energy score (- 9.3507 kcal/mol) with (PDB ID:2A4L).

Native Amide-Directed C(sp3 )-H Amidation Enabled by Electron-Deficient RhIII Catalyst and Electron-Deficient 2-Pyridone Ligand.

Trivalent group-9 metal catalysts with a cyclopentadienyl-type ligand (CpMIII ; M=Co, Rh, Ir, Cp=cyclopentadienyl) have been widely used for directed C-H functionalizations, albeit that their application to challenging C(sp3 )-H functionalizations suffers from the limitations of the available directing groups. In this report, we describe directed C(sp3 )-H amidation reactions of simple amide substrates with a variety of substituents. The combination of an electron-deficient CpE Rh catalyst (CpE =1,3-bis(ethoxycarbonyl)-substituted Cp) and an electron-deficient 2-pyridone ligand is essential for high reactivity.

Ribonucleotide reductase, a novel drug target for gonorrhea.

Antibiotic-resistant Neisseria gonorrhoeae (Ng) are an emerging public health threat due to increasing numbers of multidrug resistant (MDR) organisms. We identified two novel orally active inhibitors, PTC-847 and PTC-672, that exhibit a narrow spectrum of activity against Ng including MDR isolates. By selecting organisms resistant to the novel inhibitors and sequencing their genomes, we identified a new therapeutic target, the class Ia ribonucleotide reductase (RNR). Resistance mutations in Ng map to the N-terminal cone domain of the α subunit, which we show here is involved in forming an inhibited α4ß4 state in the presence of the ß subunit and allosteric effector dATP. Enzyme assays confirm that PTC-847 and PTC-672 inhibit Ng RNR and reveal that allosteric effector dATP potentiates the inhibitory effect. Oral administration of PTC-672 reduces Ng infection in a mouse model and may have therapeutic potential for treatment of Ng that is resistant to current drugs.

Cytotoxic hexadepsipeptides and anti-coronaviral 4-hydroxy-2-pyridones from an endophytic Fusarium sp.

Three new hexadepsipeptides (1-3), along with beauvericin (4), beauvericin D (5), and four 4-hydroxy-2-pyridone derivatives (6-9) were isolated from the endophytic fungus Fusarium sp. CPCC 400857 that derived from the stem of tea plant. Their structures were determined by extensive 1D and 2D NMR, and HRESIMS analyses. The absolute configuration of hexadepsipeptides were elucidated by the advanced Marfey's method and chiral HPLC analysis. Compounds 4, and 7-9 displayed the cytotoxicity against human pancreatic cancer cell line, AsPC-1 with IC50 values ranging from 3.45 to 29.69 µM, and 7 and 8 also showed the antiviral activity against the coronavirus (HCoV-OC43) with IC50 values of 13.33 and 6.65 µM, respectively.

Inductive Production of the Iron-Chelating 2-Pyridones Benefits the Producing Fungus To Compete for Diverse Niches.

Diverse 2-pyridone alkaloids have been identified with an array of biological and pharmaceutical activities, including the development of drugs. However, the biosynthetic regulation and chemical ecology of 2-pyridones remain largely elusive. Here, we report the inductive activation of the silent polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) (tenS) gene cluster for the biosynthesis of the tenellin-type 2-pyridones in the insect-pathogenic fungus Beauveria bassiana when cocultured with its natural competitor fungus Metarhizium robertsii. A pathway-specific transcription factor, tenR, was identified, and the overexpression of tenR well expanded the biosynthetic mechanism of 15-hydroxytenellin (15-HT) and its derivatives. In particular, a tandemly linked glycosyltransferase-methyltransferase gene pair located outside the tenS gene cluster was verified to mediate the rare and site-specific methylglucosylation of 15-HT at its N-OH residue. It was evident that both tenellin and 15-HT can chelate iron, which could benefit B. bassiana to outcompete M. robertsii in cocultures and to adapt to iron-replete and -depleted conditions. Relative to the wild-type strain, the deletion of tenS had no obvious negative effect on fungal virulence, but the overexpression of tenR could substantially increase fungal pathogenicity toward insect hosts. The results of this study well advance the understanding of the biosynthetic machinery and chemical ecology of 2-pyridones. IMPORTANCE Different 2-pyridones have been identified, with multiple biological activities but unclear chemical ecology. We found that the silent tenS gene cluster was activated in the insect pathogen Beauveria bassiana when the fungus was cocultured with its natural competitor Metarhizium robertsii. It was established that the gene cluster is regulated by a pathway-specific regulator, tenR, and the overexpression of this transcription factor expanded the biosynthetic machinery of the tenellin 2-pyridones. It was also found that the paired genes located outside the tenS cluster contribute to the site-specific methylglucosylation of the main compound 15-hydroxytenellin. Both tenellin and 15-hydroxytenellin can chelate and sequester iron to benefit the producing fungus to compete for different niches. This study well advances the biosynthetic mechanism and chemical ecology of 2-pyridones.

Synthesis and Decarboxylation of Functionalized 2-Pyridone-3-carboxylic Acids and Evaluation of their Antimicrobial Activity and Molecular Docking.

The functionalized 2-pyridone-3-carboxylic acids were synthesized starting from 3-formylchromone. Meanwhile, a decarboxylation reaction of 2-pyridone-3-carboxylic acid was performed by potassium carbonate in toluene. All compounds were evaluated against two Gram-negative bacteria (Escherichia coli (E. coli), Acinetobacter baumannii (A. baumannii)) and two Gram-positive (Staphylococcus aureus (S. aureus)) and fungus (Candida albicans (C. albicans)) using serial broth dilution method. The antimicrobial screening revealed that S. aureus is the highest sensitive microorganism towards the synthesized compounds. Among all analogs, derivatives, 4p and 5c showed excellent activities in comparison with the other compounds against S. aureus. Molecular docking showed that the most active anti S. aureus are compounds 4p and 5c exhibiting primary interaction as with fluoroquinolones by cross-linking over DNA gyrase active site via metal ion bridge and H-bonding interaction with Ser84 and Glu88 from GyrA subunit along with Arg458 and Asp437 located at GyrB subunit. In addition, based on the molecular dynamic simulation as like the standard fluoroquinolones, the mentioned compounds were stabilized for significant amount of simulation time over DNA gyrase which potentiate the importance of the mentioned residues in the DNA gate region of DNA gyrase.

Design, synthesis and structure-activity evaluation of novel 2-pyridone-based inhibitors of α-synuclein aggregation with potentially improved BBB permeability.

The treatment of Parkinson's disease (PD), the second most common neurodegenerative human disorder, continues to be symptomatic. Development of drugs able to stop or at least slowdown PD progression would benefit several million people worldwide. SynuClean-D is a low molecular weight 2-pyridone-based promising drug candidate that inhibits the aggregation of α-synuclein in human cultured cells and prevents degeneration of dopaminergic neurons in a Caenorhabditis elegans model of PD. Improving SynuClean-D pharmacokinetic/pharmacodynamic properties, performing structure/activity studies and testing its efficacy in mammalian models of PD requires the use of gr-amounts of the compound. However, not enough compound is on sale, and no synthetic route has been reported until now, which hampers the molecule progress towards clinical trials. To circumvent those problems, we describe here an efficient and economical route that enables the synthesis of SynuClean-D with good yields as well as the synthesis of SynuClean-D derivatives. Structure-activity comparison of the new compounds with SynuClean-D reveals the functional groups of the molecule that can be disposed of without activity loss and those that are crucial to interfere with α-synuclein aggregation. Several of the derivatives obtained retain the parent's compound excellent in vitro anti-aggregative activity, without compromising its low toxicity. Computational predictions and preliminary testing indicate that the blood brain barrier (BBB) permeability of SynuClean-D is low. Importantly, several of the newly designed and obtained active derivatives are predicted to display good BBB permeability. The synthetic route developed here will facilitate their synthesis for BBB permeability determination and for efficacy testing in mammalian models of PD.