2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors of Plasmodium falciparum Phosphatidylinositol-4-kinase and Hemozoin Formation with In Vivo Efficacy.

Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of Plasmodium falciparum (Pf) phosphatidylinositol-4-kinase ß (PI4K), identified 1,5-naphthyridines with basic groups at 8-position, which retained Plasmodium PI4K inhibitory activity but switched primary mode of action to the host hemoglobin degradation pathway through inhibition of hemozoin formation. These compounds showed minimal off-target inhibitory activity against the human phosphoinositide kinases and MINK1 and MAP4K kinases, which were associated with the teratogenicity and testicular toxicity observed in rats for the PfPI4K inhibitor clinical candidate MMV390048. A representative compound from the series retained activity against field isolates and lab-raised drug-resistant strains of Pf. It was efficacious in the humanized NSG mouse malaria infection model at a single oral dose of 32 mg/kg. This compound was nonteratogenic in the zebrafish embryo model of teratogenicity and has a low predicted human dose, indicating that this series has the potential to deliver a preclinical candidate for malaria.

Discovery of 2,6-Naphthyridine Analogues as Selective FGFR4 Inhibitors for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is responsible for 90% of cases. Approximately 30% of patients diagnosed with HCC are identified as displaying an aberrant expression of fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4) as an oncogenic-driver pathway. Therefore, the control of the FGF19-FGFR4 signaling pathway with selective FGFR4 inhibitors can be a promising therapy for the treatment of HCC. We herein disclose the design and synthesis of novel FGFR4 inhibitors containing a 2,6-naphthyridine scaffold. Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1-3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC.

Two-Photon-Responsive "TICT + AIE" Active Naphthyridine-BF2 Photoremovable Protecting Group: Application for Specific Staining and Killing of Cancer Cells.

The combined effects of twisted intramolecular charge transfer (TICT) and aggregation-induced emission (AIE) phenomena have demonstrated a significant influence on excited-state chemistry. These combined TICT and AIE features have been extensively utilized to enhance photodynamic and photothermal therapy. Herein, we demonstrated the synergistic capabilities of TICT and AIE phenomena in the design of the photoremovable protecting group (PRPG), namely, NMe2-Napy-BF2. This innovative PRPG incorporates TICT and AIE characteristics, resulting in four remarkable properties: (i) red-shifted absorption wavelength, (ii) strong near-infrared (NIR) emission, (iii) viscosity-sensitive emission property, and (iv) accelerated photorelease rate. Inspired by these intriguing attributes, we developed a nanodrug delivery system (nano-DDS) using our PRPG for cancer treatment. In vitro studies showed that our nano-DDS manifested effective cellular internalization, specific staining of cancer cells, high-resolution confocal imaging of cancerous cells in the NIR region, and controlled release of the anticancer drug chlorambucil upon exposure to light, leading to cancer cell eradication. Most notably, our nano-DDS exhibited a substantially increased two-photon (TP) absorption cross section (435 GM), exhibiting its potential for in vivo applications. This development holds promise for significant advancements in cancer treatment strategies.

Luminescent and time-resolved determination of gemifloxacin mesylate in pharmaceutical formulations and spiked blood plasma samples using a lanthanide complex as a probe.

A novel luminescence-based analytical methodology was established employing a europium(III) complex with 3-allyl-2-hydroxybenzohydrazide (HAZ) as the coordinating ligand for the quantification of gemifloxacin mesylate (GMF) in pharmaceutical preparations and human plasma samples spiked with the compound. The stoichiometry of the europium complex with HAZ was determined via the Job plot and exhibited a metal-to-ligand ratio of 1 : 2. The analytical procedure relies on a rapid and significant enhancement of luminescence by the Eu(AZ)2 complex when it interacts with gemifloxacin mesylate, which allowed for the rapid detection of 96 samples within approximately 2 minutes. The thermodynamic parameters of the complexation of GMF with Eu(AZ)2 were evaluated and showed that the complexation of GMF was spontaneous with a negative ΔG. The binding constant K was 4.27 × 105 L mol-1 and DFT calculations supported GMF binding and the formation of Eu(AZ)2-GMF without further ligand exchange. The calibration graph for the luminescence quantitation of GMF was linear over a wide concentration range of 0.11-16 µg mL-1 (2.26 × 10-7 to 3.30 × 10-5 mol L-1), with a limit of quantification (LOQ) of 110 ng mL-1 (230 nmol L-1) and a detection limit (LOD) of 40 ng mL-1 (82 nmol L-1). The proposed method showed good accuracy with an average recovery of 99% with relative standard deviations of less than 5% in spiking experiments, even in complex pharmaceutical dosage forms such as tablets and in human blood plasma. Herein, the ability of the suppression of the luminescence background by using the long lag times of the lanthanide probe in a time-resolved detection scheme provided reliable and precise results, which suggests its potential for use in further real or patient samples.

Photocontrolled Binding of Styrylnaphthyridine Ligands to Abasic Site-Containing DNA by Reversible [2+2] Cycloaddition and Cycloreversion.

Five novel styrylnaphthyridine derivatives were synthesized and shown to operate as photoswitchable, selective ligands for abasic site-containing DNA (AP-DNA), which is an important therapeutic and diagnostic target. These compounds associate with AP-DNA with binding constants of 0.5-8.4×104 M-1 as shown by photometric and fluorimetric titrations. Specifically, these ligands bind preferentially to AP-DNA relative to regularly paired duplex DNA. As a special feature, the association of these ligands with DNA can be controlled by means of a reversible [2+2] photocycloaddition. Upon irradiation at 420 nm the photodimer is formed, which does not bind to AP-DNA. In turn, the naphthyridine is regained with excitation at 315 nm. Most notably, this photoinduced deactivation and release of the DNA ligand can be performed in situ in the presence of AP-DNA, thus providing a tool for on-demand delivery of a DNA binder. Overall, these results provide a promising starting point for the development of functional AP-DNA ligands whose bioactivity can be modulated by light with local and temporal control.

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.

NMR analysis of 15N-labeled naphthyridine carbamate dimer (NCD) to contiguous CGG/CGG units in DNA.

The structure of the complex formed by naphthyridine carbamate dimer (NCD) binding to CGG repeat sequences in DNA, associated with fragile X syndrome, has been elucidated using 15N-labeled NCD and 1H-15N HSQC. In a fully saturated state, two NCD molecules consistently bind to each CGG/CGG unit, maintaining a 1 : 2 binding stoichiometry.

Oxidative Cyclization at ortho-Position of Phenol: Improved Total Synthesis of 3-(Phenethylamino)demethyl(oxy)aaptamine.

A shorter synthesis of the demethyl(oxy)aaptamine skeleton was developed via oxidative intramolecular cyclization of 1-(2-azidoethyl)-6-methoxyisoquinolin-7-ol followed by dehydrogenation with a hypervalent iodine reagent. This is the first example of oxidative cyclization at the ortho-position of phenol that does not involve spiro-cyclization, resulting in the improved total synthesis of 3-(phenethylamino)demethyl(oxy)aaptamine, a potent anti-dormant mycobacterial agent.

Synthesis, characterization, and in silico studies of 1,8-naphthyridine derivatives as potential anti-Parkinson's agents.

1,8-Naphthyridine scaffold is a nitrogen-containing heterocyclic compound known for its versatile biological activities. The structure-activity relationship (SAR) has shown that modification at the 3rd position of the nucleus with various secondary amines enhances the binding efficiency and potency towards the Adenosine receptor (A2A type). In this paper, we have reported some newly synthesized derivatives of 1,8- Naphthyridine, and the prepared compounds were assessed for their potential to constrain A2A receptors through molecular docking. Based on the SAR studies, modifications were done at the 3rd position of the nucleus by incorporating secondary amines. The synthesized compounds were characterized by FT-IR, 1H and 13C NMR. All the synthesized compounds 10a-f and 13a-e showed good binding efficiency towards the A2A receptors and might act as an A2A receptor antagonist, as predicted by in-silico studies. 1-Ethyl-7-methyl-3-(pyrrolidine-1-carbonyl)-1,8-naphthyridine-4(1H)-one (10c) in first series showed the highest docking score of -8.407 and binding energy (MMGBSA dG bind) of -56.60 kcal/mol and N-(4-2-diethylaminoethoxyphenyl)-1-ethyl-7-methyl-4-oxo-1, 4, 4a, 8a- tetrahydro-1,8-naphthyridine-3-carboxamide (13b) showed the highest docking score of -8.562 and free binding energy (MMGBSA dG bind) score of -64.13 kcal/mol which was comparable to the bound ligand. MD simulations study also suggested that compounds 10c and 13b would form stable complex human A2A receptor. These findings need to be validated by further in vitro assays.Communicated by Ramaswamy H. Sarma.

A small molecule binding to TGGAA pentanucleotide repeats that cause spinocerebellar ataxia type 31.

Spinocerebellar ataxia type 31 is an autosomal dominant neurodegenerative disease caused by aberrant insertion of d(TGGAA)n into the intron shared by brain expressed, associated with Nedd4 and thymidine kinase 2 genes in chromosome 16. We reported that a naphthyridine dimer derivative with amidated linker structure (ND-amide) bound to GGA/GGA motifs in hairpin structures of d(TGGAA)n. The binding of naphthyridine dimer derivatives to the GGA/GGA motif was sensitive to the linker structures. The amidation of the linker in naphthyridine dimer improved the binding property to the GGA/GGA motif as compared with non-amidated naphthyridine dimer.

Blue Light-Driven [4+2]-Cycloaddition: Diastereoselective Synthesis of Chromeno[4,3-b]quinoline and Chromeno[4,3-b][1,8]naphthyridine Scaffolds.

A one-pot, metal-free, light-driven [4+2]-cycloaddition reaction is described by accessing a diverse collection of chromeno[4,3-b]quinoline and chromeno[4,3-b][1,8]naphthyridine scaffolds in a diastereoselective manner. This process delivered stereoisomers, which were challenging to produce by an inverse-demand Diels-Alder reaction. The tetracyclic products were provided in good yields, promoted by rose bengal and blue light in a single operation. The developed protocol proceeded efficiently without the need for expensive photosensitizers such as Ir or Ru complexes. The cascade is modular and step-economic, and the substrate scope is wide. Polycyclic architectures can be assembled from readily available aniline, aminoazine, indole, and salicylaldehyde derivatives.

NMR determination of the 2:1 binding complex of naphthyridine carbamate dimer (NCD) and CGG/CGG triad in double-stranded DNA.

Trinucleotide repeat (TNR) diseases are caused by the aberrant expansion of CXG (X = C, A, G and T) sequences in genomes. We have reported two small molecules binding to TNR, NCD, and NA, which strongly bind to CGG repeat (responsible sequence of fragile X syndrome) and CAG repeat (Huntington's disease). The NMR structure of NA binding to the CAG/CAG triad has been clarified, but the structure of NCD bound to the CGG/CGG triad remained to be addressed. We here report the structural determination of the NCD-CGG/CGG complex by NMR spectroscopy and the comparison with the NA-CAG/CAG complex. While the NCD-CGG/CGG structure shares the binding characteristics with that of the NA-CAG/CAG complex, a significant difference was found in the overall structure caused by the structural fluctuation at the ligand-bound site. The NCD-CGG/CGG complex was suggested in the equilibrium between stacked and kinked structures, although NA-CAG/CAG complex has only the stacked structures. The dynamic fluctuation of the NCD-CGG/CGG structure at the NCD-binding site suggested room for optimization in the linker structure of NCD to gain improved affinity to the CGG/CGG triad.

Diminishing hERG inhibitory activity of aminopiperidine-naphthyridine linked NBTI antibacterials by structural and physicochemical optimizations.

Novel bacterial topoisomerase inhibitors (NBTIs) are an important new class of antibacterials targeting bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Notwithstanding their potent antibacterial activity, they suffer from a detrimental class-related hERG blockage. In this study, we designed and synthesized an optimized library of NBTIs comprising different linker moieties that exhibit reduced hERG inhibition and retain inhibitory potencies on DNA gyrase and topoisomerase IV of Staphylococcus aureus and Escherichia coli, respectively, as well as potent antibacterial activities. Substitution of the linker's tertiary amine with polar groups outcome in diminished hERG inhibition. Compound 17 expresses nanomolar enzyme inhibitory potency and antibacterial activity against both Gram-positive and Gram-negative bacteria as well as reduced hERG inhibition relative to our previously published NBTI analogs. Here, we point to some important NBTI's structural features that influence their hERG inhibitory activity.

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.

Synthesis of 1-Amino-3-oxo-2,7-naphthyridines via Smiles Rearrangement: A New Approach in the Field of Chemistry of Heterocyclic Compounds.

In this paper we describe an efficient method for the synthesis of new heterocyclic systems: furo[2,3-c]-2,7-naphthyridines 6, as well as a new method for the preparation of 1,3-diamino-2,7-naphthyridines 11. For the first time, a Smiles rearrangement was carried out in the 2,7-naphthyridine series, thus gaining the opportunity to synthesize 1-amino-3-oxo-2,7-naphthyridines 4, which are the starting compounds for obtaining furo[2,3-c]-2,7-naphthyridines. The cyclization of alkoxyacetamides 9 proceeds via two different processes: the expected formation of furo[2,3-c]-2,7-naphthyridines 10 and the 'unexpected' formation of 1,3-diamino-2,7-naphthyridines 11 (via a Smiles type rearrangement).

Discovery of 1,6-Naphthyridin-2(1H)-one Derivatives as Novel, Potent, and Selective FGFR4 Inhibitors for the Treatment of Hepatocellular Carcinoma.

Fibroblast growth factor receptor 4 (FGFR4) has been identified as a potential target due to its transmission of the FGF19 signaling pathway, which is critical to hepatocellular carcinoma (HCC). Therefore, focusing on the specific Cys552 of FGFR4 subtype, we designed and synthesized a novel family of 1,6-naphthyridin-2(1H)-one derivatives as potent and highly selective FGFR4 inhibitors. Through detailed structural optimizations, the representative compound A34 exhibited improved FGFR4 inhibitory capability and selectivity and excellent anti-proliferative activities against FGFR4-dependent HCC cell lines. Additionally, A34 demonstrated remarkable antitumor efficacy in a Hep-3B HCC xenograft model, with favorable pharmacokinetic properties, and low risk of hERG toxicity. A34 also showed moderate inhibitory activities against the FGFR4 V550L mutant in vitro, which indicates that it has the potential as a novel anticancer agent for HCC.

Design, synthesis and anticancer evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety as novel multi-target TKIs.

Giving the fact that the disorders of multiple receptor tyrosine kinases (RTKs) are characteristics of various cancers, we assumed that developing novel multi-target drugs might have an advantage in treating the complex cancers. Taking the multi-target c-Met inhibitor Foretinib as the leading compound, we discovered a novel series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety with the help of molecular docking. Among them, the most promising compound 33 showed a prominent activity against Hela (IC50 = 0.21 µM), A549 (IC50 = 0.39 µM), and MCF-7 (IC50 = 0.33 µM), which were 3.28-4.82 times more active than that of Foretinib. Additionally, compound 33 dose dependently induced apoptosis by arresting A549 cells at G1 phase. Enzymatic assays and docking analyses were further confirmed that compound 33 was a multi-target inhibitor with the strong potencies against c-Met (IC50 = 11.77 nM), MEK1 (IC50 = 10.71 nM), and Flt-3 (IC50 = 22.36 nM). In the A549 cells mediated xenograft mouse model, compound 33 inhibited the tumor growth (TGI = 64%) without obvious toxicity, establishing compound 33 as a promising candidate for cancer therapy.

Study of the Structure-Activity Relationship of an Anti-Dormant Mycobacterial Substance 3-(Phenethylamino)Demethyl(oxy)aaptamine to Create a Probe Molecule for Detecting Its Target Protein.

The current tuberculosis treatment regimen is long and complex, and its failure leads to relapse and emergence of drug resistance. One of the major reasons underlying the extended chemotherapeutic regimen is the ability of Mycobacterium tuberculosis to attain a dormant state. Therefore, the identification of new lead compounds with chemical structures different from those of conventional anti-tuberculosis drugs is essential. The compound 3-(phenethylamino)demethyl(oxy)aaptamine (PDOA, 1), isolated from marine sponge of Aaptos sp., is known as an anti-dormant mycobacterial substance, and has been reported to be effective against the drug resistant strains of M. tuberculosis. However, its target protein still remains unclear. This study aims to clarify the structure-activity relationship of 1 using 15 synthetic analogues, in order to prepare a probe molecule for detecting the target protein of 1. We succeeded in creating the compound 15 with a photoaffinity group that retained antimicrobial activity, which proved to be a suitable probe molecule for identifying the target protein of 1.

Aaptamine derivatives with CDK2 inhibitory activities from the South China Sea sponge Aaptos suberitoides.

Three new aaptamines (1-3) together with two known derivatives (4-5) were isolated from the South China Sea sponge Aaptos suberitoides. The structures of all compounds were unambiguously elucidated by spectroscopic analyses as well as the comparison with literature data. All the compounds were evaluated for their cytotoxic activities against five human cancer cell lines including H1299, H520, SCG7901, CNE-2 and SW680 cells. As a result, compounds 3-5 showed moderate cytotoxicities against H1299 and H520 cells with IC50 values ranging from 12.9 to 20.6 µg/mL. Besides, compounds 3-5 also showed potent inhibitory activities toward cyclin-dependent kinase-2 (CDK2) with IC50 values of 14.3, 3.0 and 6.0 µg/mL, respectively. In addition, compounds 3-5 significantly induced G1 arrests of H1299 cells at low concentrations. Drug affinity responsive target stability (DARTS) experiments were carried out and further demonstrated that compound 3 could effectively bind with CDK2 protein and protect it from the degradation by pronase.

Review on marine sponge alkaloid, aaptamine: A potential antibacterial and anticancer drug.

In recent years, biological macromolecules have piqued the interest of researchers owing to their vast variety of biological uses. As a result, the marine sponge is a multicellular heterotrophic parazoan with chemicals for defence against predator assaults, biofouling and microbial diseases. These priceless molecules are known as secondary metabolites, and they are essential for survival in a highly competitive environment. So far, over 5,000 marine natural compounds have been extracted from marine sponges, making them an excellent option for drug formulation. One among them is, aaptamine, a marine alkaloid with a benzo[de][1,6]-napthyridine framework extensively distributed in marine sponges. Due to this reason, aaptamine has been intensively researched for various biological purposes, including cancer and protease inhibition, offering fresh insights into novel treatments. Keeping this in mind, we reviewed the biological significance of the marine sponge alkaloid aaptamine.