Understanding the Remarkable Stability of Well-Defined Dinuclear Copper(I) Carbene Complexes.

The synthesis of a well-defined dicopper carbene complex supported by the PNNP (2,7-bis(di-tert-butylphosphaneyl)methyl-1,8-naphthyridine) expanded pincer ligand is reported. This carbene complex is remarkably stable, even in the presence of air and water. The reactivity of this complex was explored towards typical carbene transfer substrates and its electronic structure was investigated. Using a combination of experiments and DFT calculations, the principles that underly the stability of dinuclear carbene complexes are probed.

Antioxidant and Antimicrobial Potential of 1,8-Naphthyridine Based Scaffolds: Design, Synthesis and in Silico Simulation Studies within Topoisomerase II.

A series of spiro ß-Lactams (4 a-c, 7 a-c) and thiazolidinones (5 a-c, 8 a-c) possessing 1,8-naphthyridine moiety were synthesized in this study. The structure of the newly synthesized compounds has been confirmed by IR, 1H-NMR, 13C NMR, mass spectra, and elemental analysis. The synthesized compounds were tested in vitro for their antibacterial and antifungal activity against various strains. The antimicrobial data showed that most of the compounds displayed good efficacy against both bacteria and fungi. The structure-activity relationship (SAR) studies suggested that the presence of electron-withdrawing chloro (3 b, 4 b, and 5 b) and nitro groups (7 b, 8 b) at the para position of the phenyl ring improved the antimicrobial activity of the compounds. The free radical scavenging assay showed that all the synthesized compounds exhibited significant antioxidant activity on DPPH. Compounds 8 b (IC50=17.68±0.76 µg/mL) and 4 c (IC50=18.53±0.52 µg/mL) showed the highest antioxidant activity compared to ascorbic acid (IC50=15.16±0.43 µg/mL). Molecular docking studies were also conducted to support the antimicrobial and SAR results.

Bimetallic Nickel Complexes Supported by a Planar Macrocyclic Diphosphoranide Ligand.

Metal-metal cooperativity is emerging as an important strategy in catalysis. This requires appropriate ligand scaffolds that can support two metals in close proximity. Here we report nickel-promoted formation of a dinucleating planar macrocyclic ligand that can support bimetallic dinickel(II) and dinickel(I) complexes. Reaction outcomes can be tuned by variation of the substituents and reaction conditions to favour dinucleating macrocyclic, mononucleating macrocyclic or conventional pincer architectures.

Oxidative Addition and ß-Hydride Elimination by a Macrocyclic Dinickel Complex: Observing Bimetallic Elementary Reactions.

The dinickel(I) complex Ni2 (tBu PONNOPONNO), featuring a planar macrocyclic diphosphoranide ligand tBu PONNOPONNO, offers a unique architectural platform for observing bimetallic elementary reactions. Oxidative addition reactions of alkyl halides produce dinickel(II) complexes of the type Ni2 (µ-R)(µ-X)(tBu PONNOPONNO). However, when R=Et ß-hydride elimination is observed to form a dinickel monohydride, with the rate dependent on the nature of X. DFT studies suggest a new mechanism for bimetallic ß-hydride elimination, where the rate dependence arises from the steric pressure imposed by the X group on the opposing trans face of the dinickel macrocycle. This work enhances understanding of bimetallic elementary reactions, particularly ß-hydride elimination, which have not been well-explored for dinuclear systems.

Identification of a 1, 8-naphthyridine-containing compound endowed with the inhibition of p53-MDM2/X interaction signaling: a computational perspective.

Various studies have established that molecules specific for MDMX inhibition or optimized for dual inhibition of p53-MDM2/MDMX interaction signaling are more suitable for activating the Tp53 gene in tumor cells. Nevertheless, there are sparse numbers of approved molecules to treat the health consequences brought by the lost p53 functions in tumor cells. Consequently, this study explored the potential of a small molecule ligand containing 1, 8-naphthyridine scaffold to act as a dual inhibitor of p53-MDM2/X interactions using computational methods. The results obtained from quantum mechanical calculations revealed our studied compound entitled CPO is more stable but less reactive compared to standard dual inhibitor RO2443. Like RO2443, CPO also exhibited good non-linear optical properties. The results of molecular docking studies predicted that CPO has a higher potential to inhibit MDM2/MDMX than RO2443. Furthermore, CPO was stable over 50 ns molecular dynamics (MD) simulation in complex with MDM2 and MDMX respectively. On the whole, CPO also exhibited good drug-likeness and pharmacokinetics properties compared to RO2443 and was found with more anti-cancer activity than RO2443 in bioactivity prediction. CPO is anticipated to elevate effectiveness and alleviate drug resistance in cancer therapy. Ultimately, our results provide an insight into the mechanism that underlay the inhibition of p53-MDM2/X interactions by a molecule containing 1, 8-naphthyridine scaffold in its molecular structure.

Design, Synthesis, Anticancer Evaluation, and Molecular Docking Studies of Oxazole-Incorporated Naphthyridine Derivatives.

A novel series of oxazole incorporated naphthyridine (21 a-j) derivatives were designed and, synthesized followed by screening of their anticancer activity profiles against human breast cancer (MCF-7), human lung cancer (A549) and human prostate (PC3 & DU-145) cancer cell lines by employing MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay using etoposide as the positive control. Of these compounds, N-(6-chloro-3-(4-(3,4,5-trimethoxyphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine with 3,4,5-trimethoxy substituent on the aryl moiety attached to oxazole ring showed potent anticancer activity against PC3, A549, MCF-7, and DU-145 cell lines with IC50 values of 0.13±0.095 µM; 0.10±0.084 µM; 0.18±0.087 µM and 0.15±0.076 µM respectively. Apart from this, compounds N-(6-chloro-3-(4-(3,5-dimethoxyphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine, N-(6-chloro-3-(4-(4-methoxyphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine, and N-(6-chloro-3-(4-(3,5-dimethylphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine also showed better anticancer activities against four cancer cell lines screened for. These activities were also validated through the molecular docking simulations, which further indicated demonstration of better interaction energy and profile by these compounds.

Anti-Inflammatory Effects of New Naphthyridine from Sponge Aaptos suberitoides in LPS-Stimulated RAW 264.7 Macrophages via Regulation of MAPK and Nrf2 Signaling Pathways.

Two new naphthyridine compounds, 4-methoxycarbonyl-5-oxo-1,6-naphthyridine (1) and 5-methoxycarbonyl-4-oxo-1,6-naphthyridine (2) were obtained from the MeOH extracts of sponge Aaptos suberitoides. Their structures were determined by spectroscopic methods, including HR-ESI-MS, 1D-NMR (1 H-NMR, 13 C-NMR), 2D-NMR (COSY, HSQC, HMBC). The structure of compound 1 was further confirmed via single crystal X-ray diffraction analysis. Compound 1 was found to reduce NO production in LPS-induced RAW 264.7 macrophages with IC50 value of 0.15 mM. In addition, it decreased the mRNA expression levels of pro-inflammatory mediators, such as the tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) in LPS-induced macrophages. It also decreased the protein expression of iNOS and COX-2 in LPS-induced macrophages. Mechanistic studies further revealed that compound 1 inhibited the mitogen-activated protein kinase (MAPK), and activated the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathways in LPS-induced RAW 264.7 macrophages.

Thermal Rearrangement of 5-(2-Hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines.

Some of the most important transformations in organic chemistry are rearrangement reactions, which play a crucial role in increasing synthetic efficiency and molecular complexity. The development of synthetic strategies involving rearrangement reactions, which can accomplish synthetic goals in a very efficient manner, has been an evergreen topic in the synthetic chemistry community. Xanthenes, pyridin-2(1H)-ones, and 1,6-naphthyridines have a wide range of biological activities. In this work, we propose the thermal rearrangement of 7,9-dihalogen-substituted 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines in DMSO. Previously unknown 5,7-dihalogenated 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridines and 10-(3,5-dihalogen-2-hydroxyphenyl)-5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridines were synthesized with excellent yields (90-99%). The investigation of the transformation using 1H-NMR monitoring made it possible to confirm the ANRORC mechanism. The structures of synthesized compounds were confirmed by 2D-NMR spectroscopy.

Tetracopper σ-Bound µ-Acetylide and -Diyne Units Stabilized by a Naphthyridine-based Dinucleating Ligand.

Reactions of a dicopper(I) tert-butoxide complex with alkynes possessing boryl or silyl capping groups resulted in formation of unprecedented tetracopper(I) µ-acetylide/diyne complexes that were characterized by NMR and UV/Vis spectroscopy, mass spectrometry and single-crystal X-ray diffraction. These compounds possess an unusual µ4 -η1 :η1 :η1 :η1 coordination mode for the bridging organic fragment, enforced by the rigid and dinucleating nature of the ligand utilized. Thus, the central π system remains unperturbed and accessible for subsequent reactivity and modification. This has been corroborated by addition of a fifth copper atom, giving rise to a pentacopper acetylide complex. This work may provide a new approach by which metal-metal cooperativity can be exploited in the transformation of acetylide and diyne groups to a variety of substrates, or as a starting point for the controlled synthesis of copper(I) alkyne-containing clusters.

The unique reactivity of 5,6-unsubstituted 1,4-dihydropyridine in the Huisgen 1,4-diploar cycloaddition and formal [2 + 2] cycloaddition.

The three-component reaction of isoquinolines, dialkyl acetylenedicarboxylates, and 5,6-unsubstituted 1,4-dihydropyridines in acetonitrile at room temperature afforded functionalized isoquinolino[1,2-f][1,6]naphthyridines in good yields and with high diastereoselectivity. More importantly, the formal [2 + 2] cycloaddition reaction of dialkyl acetylenedicarboxylates and 5,6-unsubstituted 1,4-dihydropyridines in refluxing acetonitrile gave unique 2-azabicyclo[4.2.0]octa-3,7-dienes as major products and 1,3a,4,6a-tetrahydrocyclopenta[b]pyrroles as minor products via further rearrangement.

CAG repeat-binding small molecule improves motor coordination impairment in a mouse model of Dentatorubral-pallidoluysian atrophy.

Dentatorubral-pallidoluysian atrophy (DRPLA) is a devastating genetic disease presenting myoclonus, epilepsy, ataxia, and dementia. DRPLA is caused by the expansion of a CAG repeat in the ATN1 gene. Aggregation of the polyglutamine-expanded ATN1 protein causes neuro-degeneration of the dentatorubral and pallidoluysian systems. The expanded CAG repeats are unstable, and ongoing repeat expansions contribute to disease onset, progression, and severity. Inducing contractions of expanded repeats can be a means to treat DRPLA, for which no disease-modifying or curative therapies exist at present. Previously, we characterized a small molecule, naphthyridine-azaquinolone (NA), which binds to CAG slip-out structures and induces repeat contraction in Huntington's disease mice. Here, we demonstrate that long-term intracerebroventricular infusion of NA leads to repeat contraction, reductions in mutant ATN1 aggregation, and improved motor phenotype in a murine model of DRPLA. Furthermore, NA-induced contraction resulted in the modification of repeat-length-dependent dysregulation of gene expression profiles in DRPLA mice. Our study reveals the therapeutic potential of repeat contracting small molecules for repeat expansion disorders, such as DRPLA.

Oxidative Cyclization of 5H-Chromeno[2,3-b]pyridines to Benzo[b]chromeno[4,3,2-de][1,6]naphthyridines, Their NMR Study and Computer Evaluation as Material for LED.

Oxidative cyclization is one of the most significant reactions in organic synthesis. Naphthyridine derivatives are often used as luminescence materials in molecular recognition because of their rigid planar structure and as new drugs. Organic light-emitting diodes (OLEDs) have rapidly grown as one of the leading technologies for full-color display panels and eco-friendly lighting sources. In this work, we propose the synthesis of previously unknown benzo[b]chromeno[4,3,2-de][1,6]naphthyridines via intermolecular oxidative cyclization of 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines in formic acid. The investigation of the reaction mechanism using 1H-NMR monitoring made it possible to confirm the proposed mechanism of the transformation. The structure of synthesized benzo[b]chromeno[4,3,2-de][1,6]naphthyridines was confirmed by 2D-NMR spectroscopy. Such a rigid geometry of synthesized compounds is desired to minimize non-radiative energy losses in OLEDs. The quantum chemical calculations are also presented in the study.

Diphosphino-Functionalized 1,8-Naphthyridines: a Multifaceted Ligand Platform for Boranes and Diboranes.

A 1,8-naphthyridine diphosphine (NDP) reacts with boron-containing Lewis acids to generate complexes featuring a number of different naphthyridine bonding modes. When exposed to diborane B2 Br4 , NDP underwent self-deprotonation to afford [NDP-B2 Br3 ]Br, an unsymmetrical diborane comprised of four fused rings. The reaction of two equivalents of monoborane BBr3 and NDP in a non-polar solvent provided the simple phosphine-borane adduct [NDP(BBr3 )2 ], which then underwent intramolecular halide abstraction to furnish the salt [NDP-BBr2 ][BBr4 ], featuring a different coordination mode from that of [NDP-B2 Br3 ]Br. Direct deprotonation of NDP by KHMDS or PhCH2 K generates mono- and dipotassium reagents, respectively. The monopotassium reagent reacts with one or half an equivalent of B2 (NMe2 )2 Cl2 to afford NDP-based diboranes with three or four amino substituents.

Targeting Expanded Repeats by Small Molecules in Repeat Expansion Disorders.

Recent technological advancements in genetic analysis have allowed for the consecutive discovery and elucidation of repeat expansion disorders: diseases caused by the abnormal expansion of repeat sequences in the genome. Many of these repeat expansion disorders are neurodegenerative movement disorders. Radical cures for these disorders have yet to be established. Although conventional treatments for repeat expansion disorders have mainly targeted the abnormal mRNA and proteins encoded by the affected genes, therapeutic approaches targeting repeat DNA, the root cause of repeat disorders, is also being explored in current research. In particular, a small molecule has been found that binds to abnormally expanded CAG repeats, the cause of Huntington's disease, and shortens them. Such small molecules targeting nucleic acids are expected to be developed into groundbreaking therapeutic drugs capable of ameliorating the symptoms of repeat expansion disorders and preventing their onset. © 2020 International Parkinson and Movement Disorder Society.

Novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines as potent and selective agonists of the 5-HT2C receptor.

A series of novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines were identified as potent and selective agonists of the 5-HT2C receptor. Optimizations performed on a previously reported series of racemic tetrahydroquinoline-based tricyclic amines, delivered an advanced drug lead, (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine, which displayed excellent in vitro and in vivo pharmacological profiles.

Spectroscopic Studies on the Interaction of Naphthyridines with DNA and Fluorescent Detection of DNA in Agarose Gel.

Four new naphthyridine derivatives (R1-R4) possessing amino acid or boronic acid moieties have been synthesized and characterized using 1H and 13C NMR, FT-IR, and mass spectral techniques. The mechanism of binding of these probes with calf thymus DNA (CT-DNA) has been delineated through UV-Vis, fluorescence, and circular dichroism (CD) spectral techniques along with thermodynamic and molecular docking studies. Small hypochromicity in absorption maximum of the probes without any shift in wavelength of absorption suggests groove binding mode of interaction of these probes with CT-DNA, confirmed by CD and 1H NMR spectral data competitive binding assay with ethidium bromide (EB). CT-DNA quenches the fluorescence of these probes via a static quenching mechanism. In the case of R1 and R4, the observed ΔHo < 0 and ΔSo > 0suggest that these probes interact with CT-DNA through H-bonding and hydrophobic interactions, while in the interaction of R2 and R3, van der Walls and H-boding forces are found to be dominant (ΔHo < 0 and ΔSo < 0). Results of molecular docking investigations corroborate well with that of spectral studies, and these probes bind in the minor groove of DNA. These probes are found to be effective fluorescent staining agents for DNA in agarose gel in gel electrophoresis experiment with sensitivity comparable to that of EB, and DNA amounts as low as 37.5 ng are visually detectable in the gel.

A Novel 1,8-Naphthyridine-2-Carboxamide Derivative Attenuates Inflammatory Responses and Cell Migration in LPS-Treated BV2 Cells via the Suppression of ROS Generation and TLR4/Myd88/NF-κB Signaling Pathway.

Novel 1,8-naphthyridine-2-carboxamide derivatives with various substituents (HSR2101-HSR2113) were synthesized and evaluated for their effects on the production of pro-inflammatory mediators and cell migration in lipopolysaccharide (LPS)-treated BV2 microglial cells. Among the tested compounds, HSR2104 exhibited the most potent inhibitory effects on the LPS-stimulated production of inflammatory mediators, including nitric oxide (NO), tumor necrosis factor-α, and interleukin-6. Therefore, this compound was chosen for further investigation. We found that HSR2104 attenuated levels of inducible NO synthase and cyclooxygenase 2 in LPS-treated BV2 cells. In addition, it markedly suppressed LPS-induced cell migration as well as the generation of intracellular reactive oxygen species (ROS). Moreover, HSR2104 abated the LPS-triggered nuclear translocation of nuclear factor-κB (NF-κB) through inhibition of inhibitor kappa Bα phosphorylation. Furthermore, it reduced the expressions of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) in LPS-treated BV2 cells. Similar results were observed with TAK242, a specific inhibitor of TLR4, suggesting that TLR4 is an upstream regulator of NF-κB signaling in BV2 cells. Collectively, our findings demonstrate that HSR2104 exhibits anti-inflammatory and anti-migratory activities in LPS-treated BV2 cells via the suppression of ROS and TLR4/MyD88/NF-κB signaling pathway. Based on our observations, HSR2104 may have a beneficial impact on inflammatory responses and microglial cell migration involved in the pathogenesis of various neurodegenerative disorders.

Enhancement of Antibiotic Activity by 1,8-Naphthyridine Derivatives against Multi-Resistant Bacterial Strains.

The search for new antibacterial agents has become urgent due to the exponential growth of bacterial resistance to antibiotics. Nitrogen-containing heterocycles such as 1,8-naphthyridine derivatives have been shown to have excellent antimicrobial properties. Therefore, the purpose of this study was to evaluate the antibacterial and antibiotic-modulating activities of 1,8-naphthyridine derivatives against multi-resistant bacterial strains. The broth microdilution method was used to determine the minimum inhibitory concentration (MIC) of the following compounds: 7-acetamido-1,8-naphthyridin-4(1H)-one and 3-trifluoromethyl-N-(5-chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide. The antibiotic-modulating activity was analyzed using subinhibitory concentrations (MIC/8) of these compounds in combination with norfloxacin, ofloxacin, and lomefloxacin. Multi-resistant strains of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus were used in both tests. Although the compounds had no direct antibacterial activity (MIC ≥ 1.024 µg/mL), they could decrease the MIC of these fluoroquinolones, indicating synergism was obtained from the association of the compounds. These results suggest the existence of a structure-activity relationship in this group of compounds with regard to the modulation of antibiotic activity. Therefore, we conclude that 1,8-naphthyridine derivatives potentiate the activity of fluoroquinolone antibiotics against multi-resistant bacterial strains, and thereby interesting candidates for the development of drugs against bacterial infections caused by multidrug resistant strains.

Structural Characterization, Antimicrobial Activity and BSA/DNA Binding Affinity of New Silver(I) Complexes with Thianthrene and 1,8-Naphthyridine.

Three new silver(I) complexes [Ag(NO3)(tia)(H2O)]n (Ag1), [Ag(CF3SO3)(1,8-naph)]n (Ag2) and [Ag2(1,8-naph)2(H2O)1.2](PF6)2 (Ag3), where tia is thianthrene and 1,8-naph is 1,8-naphthyridine, were synthesized and structurally characterized by different spectroscopic and electrochemical methods and their crystal structures were determined by single-crystal X-ray diffraction analysis. Their antimicrobial potential was evaluated against four bacterial and three Candida species, and the obtained results revealed that these complexes showed significant activity toward the Gram-positive Staphylococcus aureus, Gram-negative Pseudomonas aeruginosa and the investigated Candida species with minimal inhibitory concentration (MIC) values in the range 1.56-7.81 µg/mL. On the other hand, tia and 1,8-naph ligands were not active against the investigated strains, suggesting that their complexation with Ag(I) ion results in the formation of antimicrobial compounds. Moreover, low toxicity of the complexes was detected by in vivo model Caenorhabditis elegans. The interaction of the complexes with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) was studied to evaluate their binding affinity towards these biomolecules for possible insights into the mode of antimicrobial activity. The binding affinity of Ag1-3 to BSA was higher than that for DNA, indicating that proteins could be more favorable binding sites for these complexes in comparison to the nucleic acids.

Grignard Reagent Utilization Enables a Practical and Scalable Construction of 3-Substituted 5-Chloro-1,6-naphthyridin-4-one Derivatives.

A robust, practical, and scalable approach for the construction of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives 13 via the addition of Grignard reagents to 4-amino-2-chloronicotinonitrile (15) was developed. Starting with various Grignard reagents, a wide range of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives 13 were conveniently synthesized in moderate-to-good yields through addition-acidolysis-cyclocondensation. In addition, the robustness and applicability of this synthetic route was proven on a 100 g scale, which would enable convenient sample preparation in the preclinical development of 1,6-naphthyridin-4-one-based MET-targeting antitumor drug candidates.