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Autonomic disbalance, i.e., sympathetic overactivation and parasympathetic withdrawal, is a causal driver of disease progression in heart failure. While sympatholytic drugs are established treatments, no drug therapy restoring vagal control of cardiac function is available. We report here the HTS-based discovery of a novel class of 1,8-naphthyridin-4(1H)-one carboxamides acting as positive allosteric modulators (PAMs) of the M2 muscarinic acetylcholine receptor (M2R). M2R is the main postsynaptic myocyte receptor regulating heart rate, electrical conduction, and contractile strength. Extensive optimization of the screening hit in terms of potency, permeation, metabolic stability, and solubility ultimately resulted in the discovery of the first-in-class clinical candidate BAY 2413555 ( 27 ). With an overall technical profile compatible with once-daily oral administration in a phase 1 study, no apparent effects on blood pressure, and a mechanism that largely preserves autonomic regulatory capacity, BAY 2413555 could be the tool to finally study the restoration of autonomic balance.

Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of Plasmodium falciparum ( Pf ) phosphatidylinositol-4-kinase β (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 Pf PI4K 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.

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.

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, NMe 2 -Napy-BF 2 . 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.

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.

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(1 H )-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.

PIP4K2A is an insufficiently studied type II lipid kinase that catalyzes the conversion of phosphatidylinositol-5-phosphate (PI5P) into phosphatidylinositol 4,5-bisphosphate (PI4,5P 2 ). The involvement of PIP4K2A/B in cancer has been suggested, particularly in the context of p53 mutant/null tumors. PIP4K2A/B depletion has been shown to induce tumor growth inhibition, possibly due to hyperactivation of AKT and reactive oxygen species-mediated apoptosis. Herein, we report the identification of the novel potent and highly selective inhibitors BAY-091 and BAY-297 of the kinase PIP4K2A by high-throughput screening and subsequent structure-based optimization. Cellular target engagement of BAY-091 and BAY-297 was demonstrated using cellular thermal shift assay technology. However, inhibition of PIP4K2A with BAY-091 or BAY-297 did not translate into the hypothesized mode of action and antiproliferative activity in p53-deficient tumor cells. Therefore, BAY-091 and BAY-297 serve as valuable chemical probes to study PIP4K2A signaling and its involvement in pathophysiological conditions such as cancer.

Maternal embryo leucine zipper kinase (MELK) is a serine/threonine kinase and is highly expressed in triple-negative breast cancer (TNBC). This study aimed to develop a 18 F-radiolabeled tracer based on the structure of a small-molecule MELK inhibitor OTSSP167 and evaluate its application for PET imaging of MELK expression in TNBC. OTSSP167 was modified with ethylene glycol to adjust its pharmacokinetics and was then radiolabeled with 18 F to obtain [ 18 F]F-ET-OTSSP167 at a labeling yield of 7.14 ± 2.19% and a molar activity of 16.23 ± 1.13 MBq/nmol. In vitro binding assays showed differentiated binding affinities of [ 18 F]F-ET-OTSSP167 in different breast cancer cell lines, with high uptake in MDA-MB-231 (mild MELK expression) and low uptake in MCF-7 (negative MELK expression). PET imaging revealed that MDA-MB-231 tumors could be clearly delineated in vivo , while low tracer uptake was observed in MCF-7 tumors. These findings were confirmed by ex vivo biodistribution studies and were consistent with the immunohistochemistry and tissue staining results. Tracer accumulation in MDA-MB-231 tumors was significantly inhibited by excess amounts of OTSSP167, indicating high specificity of the tracer. In summary, [ 18 F]F-ET-OTSSP167, an easily-prepared probe, can be used to visualize MELK positive tumors, demonstrating its promising clinical potential in selecting patients for MELK inhibitor therapy.

Multifunctional entities have recently been attractive for the development of anticancer chemotherapeutic drugs. However, such entities with concurrent CK2 along with cancer stem cell (CSC) inhibitory activities are rare in a single small molecule. Herein, a series of 5-(3-chlorophenylamino)benzo[ c ][2,6]naphthyridine derivatives were synthesized using a known CK2 inhibitor, silmitasertib ( CX-4945 ), as the lead compound. Among the resulting compounds, 1c exhibited stronger CK2 inhibitory activity with higher Clk2/CK2 selectivity than CX-4945 . Significantly, 1c could modulate the Akt1(ser129)-GSK-3β(ser9)-Wnt/β-catenin signaling pathway and inhibit the expression of the stemness marker ALDH1A1, CSC surface antigens, and stem genes, showing potent CSC inhibitory activity. Moreover, 1c also displayed superior pharmacokinetics and antitumor activity compared with CX-4945 sodium salt, without obvious toxicity. The favorable antiproliferative and antitumor activity of 1c , its high inhibitory selectivity for CK2, and its potent inhibition of cancer cell stemness make this molecule a candidate for the treatment of cancer.

CK2α is a ubiquitous, well-studied kinase that is a target for small-molecule inhibition, for treatment of cancers. While many different classes of adenosine 5'-triphosphate (ATP)-competitive inhibitors have been described for CK2α, they tend to suffer from significant off-target activity and new approaches are needed. A series of inhibitors of CK2α has recently been described as allosteric, acting at a previously unidentified binding site. Given the similarity of these inhibitors to known ATP-competitive inhibitors, we have investigated them further. In our thorough structural and biophysical analyses, we have found no evidence that these inhibitors bind to the proposed allosteric site. Rather, we report crystal structures, competitive isothermal titration calorimetry (ITC) and NMR, hydrogen-deuterium exchange (HDX) mass spectrometry, and chemoinformatic analyses that all point to these compounds binding in the ATP pocket. Comparisons of our results and experimental approach with the data presented in the original report suggest that the primary reason for the disparity is nonspecific inhibition by aggregation.

LC-MS-oriented fractionation of the sponge Aaptos suberitoides resulted in the isolation of four heptacyclic alkaloids, aaptodines A-D ( 1 - 4 ), which contain 9,10-dihydrofuro[2,3- f ][1,3]oxazolo[5,4- h ]quinolone and 7,8-dihydrocyclopenta[ de ][1,6]naphthyridine subunits with a spiro carbon atom. The structures were determined on the basis of NMR spectroscopic and single-crystal X-ray diffraction data analysis aided by electronic circular dichroism calculations and Mosher's method. A biosynthetic pathway for the formation of aaptodines A-D is postulated. Aaptodine D exhibits potent inhibition against osteoclast formation.

Dinickel naphthyridine-bis(oxazoline) catalysts promote enantioselective intermolecular [4 + 1]-cycloadditions of vinylidene equivalents and 1,3-dienes. The products of this reaction are methylenecyclopentenes, and the exocyclic alkene is generally obtained with high Z selectivity. E - and Z -dienes react in a stereoconvergent fashion, providing cycloadducts with the same sense of absolute stereochemistry and nearly identical ee values. This feature allows dienes that are commercially available as E / Z mixtures to be used as substrates for the cycloaddition. A DFT model for the origin of asymmetric induction is provided.

Visceral leishmaniasis (VL) is a parasitic infection that results in approximately 26 000-65 000 deaths annually. The available treatments are hampered by issues such as toxicity, variable efficacy, and unsuitable dosing options. The need for new treatments is urgent and led to a collaboration between the Drugs for Neglected Diseases initiative (DND i ), GlaxoSmithKline (GSK), and the University of Dundee. An 8-hydroxynaphthyridine was identified as a start point, and an early compound demonstrated weak efficacy in a mouse model of VL but was hampered by glucuronidation. Efforts to address this led to the development of compounds with improved in vitro profiles, but these were poorly tolerated in vivo . Investigation of the mode of action (MoA) demonstrated that activity was driven by sequestration of divalent metal cations, a mechanism which was likely to drive the poor tolerability. This highlights the importance of investigating MoA and pharmacokinetics at an early stage for phenotypically active series.

Pan-bromodomain and extra terminal (BET) inhibitors interact equipotently with all eight bromodomains of the BET family of proteins. They have shown profound efficacy in vitro and in vivo in oncology and immunomodulatory models, and a number of them are currently in clinical trials where significant safety signals have been reported. It is therefore important to understand the functional contribution of each bromodomain to assess the opportunity to tease apart efficacy and toxicity. This article discloses the in vitro and cellular activity profiles of GSK789, a potent, cell-permeable, and highly selective inhibitor of the first bromodomains of the BET family.

The methylation of cytosine in the full mutation of the expanded CGG repeat and subsequent deamination to thymine could be a measure of repeat instability. We report the synthesis of NCD-Bpy, which binds to the TGG/CGG site in the repeat hairpin. NCD-Bpy forces the thymine in the TGG/CGG site to flip out from the π-stack, recruits osmium tetroxide in the vicinity of the flipped-out T, and oxidizes the T. The piperidine-induced cleavage band successfully determined the position of the T in the expanded CGG repeat.

We report here a fully organic, self-assembled dimeric receptor, constructed from acyclic naphthyridyl-polypyrrolic building blocks. The cagelike dimer is stable in the solid state, in solution, and in gas phase, as inferred from X-ray diffraction and spectroscopic analyses. This system acts as a receptor for oxalic acid, maleic acid, and malonic acid in the solid state and in THF solution. In contrast, acetic acid, propionic acid, adipic acid, and succinic acid, with p K a values > ca. 2.8, were not bound effectively within the cagelike cavity. It is speculated that oxalic acid, maleic acid, and malonic acid serve to protonate the naphthyridine moieties of the host, which then favors binding of the corresponding carboxylate anions via hydrogen-bonding to the pyrrolic NH protons. The present naphthyridine-polypyrrole dimer is stable under acidic conditions, including in the presence of 100 equiv trifluoroacetic acid (TFA), p -toluenesulfonic acid (PTSA), H 2 SO 4 , and HCl. However, disassembly may be achieved by exposure to tetrabutylammonium fluoride (TBAF). Washing with water then regenerates the cage. This process of assembly and disassembly could be repeated >20 times with little evidence of degradation. The reversible nature of the present system, coupled with its dicarboxylic acid recognition features, leads us to suggest it could have a role to play in effecting the controlled "capture" and "release" of biologically relevant dicarboxylic acids.

The human luteinizing hormone receptor (hLH-R) is a member of the glycoprotein hormone family of G-protein-coupled receptors (GPCRs), activated by luteinizing hormone (hLH) and essentially involved in the regulation of sex hormone production. Thus, hLH-R represents a valid target for the treatment of sex hormone-dependent cancers and diseases (polycystic ovary syndrome, uterine fibroids, endometriosis) as well as contraception. Screening of the Bayer compound library led to the discovery of tetrahydrothienopyridine derivatives as novel, small-molecule (SMOL) hLH-R inhibitors and to the development of BAY-298, the first nanomolar hLH-R antagonist reducing sex hormone levels in vivo. Further optimization of physicochemical, pharmacokinetic, and safety parameters led to the identification of BAY-899 with an improved in vitro profile and proven efficacy in vivo. BAY-298 and BAY-899 serve as valuable tool compounds to study hLH-R signaling in vitro and to interfere with the production of sex hormones in vivo.

Gyrase and topoisomerase IV are the targets of fluoroquinolone antibacterials. However, the rise in antimicrobial resistance has undermined the clinical use of this important drug class. Therefore, it is critical to identify new agents that maintain activity against fluoroquinolone-resistant strains. One approach is to develop non-fluoroquinolone drugs that also target gyrase and topoisomerase IV but interact differently with the enzymes. This has led to the development of the "novel bacterial topoisomerase inhibitor" (NBTI) class of antibacterials. Despite the clinical potential of NBTIs, there is a relative paucity of data describing their mechanism of action against bacterial type II topoisomerases. Consequently, we characterized the activity of GSK126, a naphthyridone/aminopiperidine-based NBTI, against a variety of Gram-positive and Gram-negative bacterial type II topoisomerases, including gyrase from Mycobacterium tuberculosis and gyrase and topoisomerase IV from Bacillus anthracis and Escherichia coli . GSK126 enhanced single-stranded DNA cleavage and suppressed double-stranded cleavage mediated by these enzymes. It was also a potent inhibitor of gyrase-catalyzed DNA supercoiling and topoisomerase IV-catalyzed decatenation. Thus, GSK126 displays a similar bimodal mechanism of action across a variety of species. In contrast, GSK126 displayed a variable ability to overcome fluoroquinolone resistance mutations across these same species. Our results suggest that NBTIs elicit their antibacterial effects by two different mechanisms: inhibition of gyrase/topoisomerase IV catalytic activity or enhancement of enzyme-mediated DNA cleavage. Furthermore, the relative importance of these two mechanisms appears to differ from species to species. Therefore, we propose that the mechanistic basis for the antibacterial properties of NBTIs is bimodal in nature.

The known benzonaphthyridine alkaloid, albogrisin A ( 1 ), and six new compounds, including two pyrazinone stereoisomers, albogrisin B ( 2 )/B' ( 2' ), together with four 4 H -pyrroloquinolinones, two diastereoisomers, albogrisin C ( 3 )/C' ( 3' ), and their methyl esters, albogrisin D ( 4 )/D' ( 4' ), were isolated from mangrove-derived Streptomyces albogriseolus MGR072. 2 and 2' are converted into 1 in acidic aqueous solution but into 3 / 3' and 4 / 4' in 0.05% trifluoroacetic acid acetonitrile. 4 and 4' are new indoleamine 2,3-dioxygenase 1 inhibitors.

The uranyl-dependent DNAzyme 39E cleaves its nucleic acid substrate in the presence of uranyl ion (UO 2 2+ ). It has been widely utilized in many sensor designs for selective and sensitive detection of UO 2 2+ in the environment and inside live cells. In this work, by inserting a flexible linker (C3 Spacer) into one critical site (A 20 ) of the 39E catalytic core, we successfully enhanced the original catalytic activity of 39E up to 8.1-fold at low UO 2 2+ concentrations. Applying such a modified DNAzyme (39E-A 20 -C3) in a label-free fluorescent sensor for UO 2 2+ detection achieved more than 1 order of magnitude sensitivity enhancement over using native 39E, with the UO 2 2+ detection limit improved from 2.6 nM (0.63 ppb) to 0.19 nM (0.047 ppb), while the high selectivity to UO 2 2+ over other metal ions was fully preserved. The method was also successfully applied for the detection of UO 2 2+ -spiked environmental water samples to demonstrate its practical usefulness.

CK2 is a ubiquitous Ser/Thr protein kinase involved in the control of various signaling pathways and is known to be constitutively active. In the present study, we identified aryl 2-aminothiazoles as a novel class of CK2 inhibitors, which displayed a non-ATP-competitive mode of action and stabilized an inactive conformation of CK2 in solution. Enzyme kinetics studies, STD NMR, circular dichroism spectroscopy, and native mass spectrometry experiments demonstrated that the compounds bind in an allosteric pocket outside the ATP-binding site. Our data, combined with molecular docking studies, strongly suggested that this new binding site was located at the interface between the αC helix and the flexible glycine-rich loop. A first hit optimization led to compound 7, exhibiting an IC 50 of 3.4 μM against purified CK2α in combination with a favorable selectivity profile. Thus, we identified a novel class of CK2 inhibitors targeting an allosteric pocket, offering great potential for further optimization into anticancer drugs.

A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding site on HIV-1 integrase, an attractive target for antiviral chemotherapy, was prepared and screened for activity against HIV-1 infection in cell culture. Small molecules that bind within the LEDGF/p75-binding site promote aberrant multimerization of the integrase enzyme and are of significant interest as HIV-1-replication inhibitors. Structure-activity-relationship studies and rat pharmacokinetic studies of lead compounds are presented.

Nanometer-range distances are important for restraining the three-dimensional structure and oligomeric assembly of proteins and other biological molecules. Solid-state NMR determination of protein structures typically utilizes 13 C- 13 C and 13 C- 15 N distance restraints, which can only be measured up to ∼7 Å because of the low gyromagnetic ratios of these nuclear spins. To extend the distance reach of NMR, one can harvest the power of 19 F, whose large gyromagnetic ratio in principle allows distances up to 2 nm to be measured. However, 19 F possesses large chemical shift anisotropies (CSAs) as well as large isotropic chemical shift dispersions, which pose challenges to dipolar coupling measurements. Here, we demonstrate 19 F- 19 F distance measurements at high magnetic fields under fast magic-angle spinning (MAS) using radiofrequency-driven dipolar recoupling (RFDR). We show that 19 F- 19 F cross-peaks for distances up to 1 nm can be readily observed in two-dimensional 19 F- 19 F correlation spectra using less than 5 ms of RFDR mixing. This efficient 19 F- 19 F dipolar recoupling is achieved using practically accessible MAS frequencies of 15-55 kHz, moderate 19 F radio frequency field strengths, and no 1 H decoupling. Experiments and simulations show that the fastest polarization transfer for aromatic fluorines with the highest distance accuracy is achieved using either fast MAS (e.g., 60 kHz) with large pulse duty cycles (>50%) or slow MAS with strong 19 F pulses. Fast MAS considerably reduces relaxation losses during the RFDR π-pulse train, making finite-pulse RFDR under fast-MAS the method of choice. Under intermediate MAS frequencies (25-40 kHz) and intermediate pulse duty cycles (15-30%), the 19 F CSA tensor orientation has a quantifiable effect on the polarization transfer rate; thus, the RFDR buildup curves encode both distance and orientation information. At fast MAS, the impact of CSA orientation is minimized, allowing pure distance restraints to be extracted. We further investigate how relayed transfer and dipolar truncation in multifluorine environments affect polarization transfer. This fast-MAS 19 F RFDR approach is complementary to 19 F spin diffusion for distance measurements and will be the method of choice under high-field fast-MAS conditions that are increasingly important for protein structure determination by solid-state NMR.

A novel 2,8-disubstituted-1,5-naphthyridine hit compound stemming from the open access Medicines for Malaria Venture Pathogen Box formed a basis for a hit-to-lead medicinal chemistry program. Structure-activity relationship investigations resulted in compounds with potent antiplasmodial activity against both chloroquine sensitive (NF54) and multidrug resistant (K1) strains of the human malaria parasite Plasmodium falciparum. In the humanized P. falciparum mouse efficacy model, one of the frontrunner compounds showed in vivo efficacy at an oral dose of 4 × 50 mg·kg -1 . In vitro mode-of-action studies revealed Plasmodium falciparum phosphatidylinositol-4-kinase as the target.

While interest in the synthetic chemistry of radical cations continues to grow, controlling enantioselectivity in the reactions of these intermediates remains a challenge. Based on recent insights into the oxidation of tryptophan in enzymatic systems, we report a photocatalytic method for the generation of indole radical cations as hydrogen-bonded adducts with chiral phosphate anions. These noncovalent open-shell complexes can be intercepted by the stable nitroxyl radical TEMPO· to form alkoxyamine-substituted pyrroloindolines with high levels of enantioselectivity. Further elaboration of these optically enriched adducts can be achieved via a catalytic single-electron oxidation/mesolytic cleavage sequence to furnish transient carbocation intermediates that may be intercepted by a wide range of nucleophiles. Taken together, this two-step sequence provides a simple catalytic method to access a wide range of substituted pyrroloindolines in enantioenriched form via a standard experimental protocol from a common synthetic intermediate. The design, development, mechanistic study, and scope of this process are presented, as are applications of this method to the synthesis of several dimeric pyrroloindoline natural products.

A novel three-component, two-step, one-pot nucleophilic aromatic substitution (S N Ar)-intramolecular cyclization-Suzuki coupling reaction was developed for the synthesis of benzo[h][1,6]naphthyridin-2(1H)-ones (Torins). On the basis of the new efficiently convergent synthetic route, a library of Torin analogs was synthesized. The antimalarial activities of these compounds were evaluated against asexual parasites using a growth inhibition assay and gametocytes using a viability assay.

Integrase mutations can reduce the effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogues of this scaffold. While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with the best compound (6p) retaining better efficacy against a broad panel of known INSTI resistant mutants than any analogues we have previously described.

Opioid therapeutics are excellent analgesics, whose utility is compromised by dependence. Morphine (1) and its clinically relevant derivatives such as OxyContin (2), Vicodin (3), and Dilaudid (4) are "biased" agonists at the μ opioid receptor (OR), wherein they engage G protein signaling but poorly engage β-arrestin and the endocytic machinery. In contrast, endorphins, the endogenous peptide agonists for ORs, are potent analgesics, show reduced liability for tolerance and dependence, and engage both G protein and β-arrestin pathways as "balanced" agonists. We set out to determine if marine-derived alkaloids could serve as novel OR agonist chemotypes with a signaling profile distinct from morphine and more similar to the endorphins. Screening of 96 sponge-derived extracts followed by LC-MS-based purification to pinpoint the active compounds and subsequent evaluation of a mini library of related alkaloids identified two structural classes that modulate the ORs. These included the following: aaptamine (10), 9-demethyl aaptamine (11), demethyl (oxy)-aaptamine (12) with activity at the δ-OR (EC 50 : 5.1, 4.1, 2.3 μM, respectively) and fascaplysin (17), and 10-bromo fascaplysin (18) with activity at the μ-OR (EC 50 : 6.3, 4.2 μM respectively). An in vivo evaluation of 10 using δ-KO mice indicated its previously reported antidepressant-like effects are dependent on the δ-OR. Importantly, 17 functioned as a balanced agonist promoting both G protein signaling and β-arrestin recruitment along with receptor endocytosis similar to the endorphins. Collectively these results demonstrate the burgeoning potential for marine natural products to serve as novel lead compounds for therapeutic targets in neuroscience research.

A mini-HTS on 4000 compounds selected using 2D fragment-based similarity and 3D pharmacophoric and shape similarity to known selective tau aggregate binders identified N-(6-methylpyridin-2-yl)quinolin-2-amine 10 as a novel potent binder to human AD aggregated tau with modest selectivity versus aggregated β-amyloid (Aβ). Initial medicinal chemistry efforts identified key elements for potency and selectivity, as well as suitable positions for radiofluorination, leading to a first generation of fluoroalkyl-substituted quinoline tau binding ligands with suboptimal physicochemical properties. Further optimization toward a more optimal pharmacokinetic profile led to the discovery of 1,5-naphthyridine 75, a potent and selective tau aggregate binder with potential as a tau PET tracer.

The development of a practical asymmetric total synthesis of the potent HIV-1 integrase inhibitor 5 is described. Key transformations include construction of the naphthridine core in a highly efficient manner followed by cyclization of the 8-membered ring. Control of the atropisomers of intermediates and final compound 5 is also described.

Two highly luminescent and water-soluble Eu(III) complexes, Eu1 and Eu2, based on novel carboxyl-functionalized 1,5-naphthyridine derivatives 8-hydroxy-1,5-naphthyridine-2-carboxylic acid (H 2 L1) and 7-cyano-8-hydroxy-1,5-naphthyridine-2-carboxylic acid (H 2 L2), respectively, are designed and synthesized. The crystal structure of Eu2 indicates that the central Eu(III) ion is nine-coordinated by three tridentate ligands (O^N^O). Both Eu1 and Eu2 show strong luminescence in aqueous solution with quantum yields (lifetimes) of 28% (1.1 ms) and 14% (0.76 ms), respectively. The chelates display unique UV-light stability in solution and remain highly emissive after 100 min of strong UV irradiation (∼300 W·m -2 at 345 nm). Moreover, they exhibit reversible luminescence intensity changes with varied pH values, and the response mechanism is investigated. "Turn-on" of the Eu(III) emission upon increasing pH is realized by ligand structure change from keto to enol anion form, resulting in red-shifted absorption band and suppressed quenching from solvents and N-H vibration upon deprotonating. The results show that these novel Eu(III) complexes are quite intriguing for potential application as bioimaging agents and pH probes.

Small molecule Toll-like receptor 7 (TLR7) agonists have been used as vaccine adjuvants by enhancing innate immune activation to afford better adaptive response. Localized TLR7 agonists without systemic exposure can afford good adjuvanticity, suggesting peripheral innate activation (non-antigen-specific) is not required for immune priming. To enhance colocalization of antigen and adjuvant, benzonaphthyridine (BZN) TLR7 agonists are chemically modified with phosphonates to allow adsorption onto aluminum hydroxide (alum), a formulation commonly used in vaccines for antigen stabilization and injection site deposition. The adsorption process is facilitated by enhancing aqueous solubility of BZN analogs to avoid physical mixture of two insoluble particulates. These BZN-phosphonates are highly adsorbed onto alum, which significantly reduced systemic exposure and increased local retention post injection. This report demonstrates a novel approach in vaccine adjuvant design using phosphonate modification to afford adsorption of small molecule immune potentiator (SMIP) onto alum, thereby enhancing co-delivery with antigen.

Selective inhibitors of bromodomain-containing protein 9 (BRD9) may have therapeutic potential in the treatment of human malignancies and inflammatory diseases. A selective small molecule inhibitor that is well tolerated and has proper pharmacokinetic properties is required to explore the function of BRD9 in diseases. BI-9564 (2) is a cell permeable and noncytotoxic BRD9 inhibitor provided to the scientific community to explore BRD9 biology and determine its potential as a drug target.

Ethyne-linked naphthyridine-aniline conjugated molecules are selective sensors of decylguanine in dichloromethane and guanosine monophosphate in water (Kass = 16,000 M(-1)). The 2-acetamido-1,8-naphthyridine moiety binds with guanine in a DAA-ADD triply hydrogen-bonded motif. The aniline moiety enhances an electron-donating effect, and the substituent is tuned to attain extra hydrogen bonds, π-π stacking, and electrostatic interactions. The proposed binding modes are supported by a Job plot, ESI-MS, (1)H NMR, UV-vis, and fluorescence spectral analyses.

A heterocycle-to-heterocycle strategy is presented for the preparation of highly fluorescent and solvatochromic dibenzonaphthyridinones (DBNs) via methodology that leads to the formation of a tertiary, spiro-fused carbon center. A linear correlation between the results of photophysical experiments and time dependent density functional theory calculations was observed for the λ(max) of excitation for DBNs with varying electronic character.

Facile, straightforward, and asymmetric total syntheses of (+)-chimonanthine (1), (+)-folicanthine (2), and (-)-calycanthine (3) were accomplished in four to five steps from commercially available tryptamine. The synthesis features copper-mediated asymmetric cyclodimerization of chiral tryptamine derivative, which established a new entry into constructing the sterically hindered vicinal quaternary stereogenic carbon centers of dimeric hexahydropyrroloindole alkaloids in one procedure. An unprecedented base-induced isomerization from the chimonanthine skeleton to the calycanthine skeleton was observed and facilitated the synthesis of (-)-calycanthine (3).

Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis.

ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.

A rhodium-catalyzed [2 + 2 + 2] cycloaddition of cyano-yne-allene scaffolds followed by a dehydrogenative process enabling the direct synthesis of unsaturated pyridine-containing compounds that can be conveniently converted to 2,6-naphthyridine derivatives is reported.

The rhodium-catalyzed dehydrogenative coupling of N-pyridylindoles with alkynes proceeds smoothly through rollover cyclometalation to produce indolo[1,2-a][1,8]naphthyridine derivatives. A number of tetra-, penta-, and hexacyclic N-containing heteroaromatics can also be readily constructed in a similar manner. The L-shaped π-conjugated molecules exhibit intense solid-state fluorescence.

Chloroquine (CQ) has been used as first line malaria therapeutic drug for decades. Emergence of CQ drug-resistant Plasmodium falciparum malaria throughout endemic areas of the world has limited its clinical value. Mefloquine (MQ) has been used as an effective malaria prophylactic drug due to its being long-acting and having a high potency against blood stage P. falciparum (Pf). However, serious CNS toxicity of MQ has compromised its clinical value as a prophylaxis drug. Therefore, new and inexpensive antimalarial drugs with no cross-resistance to CQ or CNS toxicity are urgently needed to combat this deadly human disease. In this study, a series of new 4-amidinoquinoline (4-AMQ) and 10-amidinobenzonaphthyridine (10-AMB) derivatives were designed, prepared, and assessed to search for new therapeutic agents to replace CQ and MQ. The new derivatives displayed high activity in vitro and in vivo, with no cross-resistance to CQ, and none were toxic in mice up to 160 mpk × 3. The best compound shows IC50 < 1 ng/mL against D6, W2 and C235 Pf clones, low inhibitory activity in hERG K(+) channel blockage testing, negativity in the Ames test, and 5/5 cure @ <15 mpk × 3 in mice infected with Plasmodium berghei. In addition to these desirable pharmacological profiles, compound 13b, one of the most active compounds, is metabolically stable in both human and mouse liver microsomal preparations and has a plasma t(1/2) of 50 h in mice, which made it a good MQ replacement candidate.

The synthesis of (-)-1, a potent antibacterial agent, was achieved stereoselectively in nine steps from readily available starting materials. Directed metalations were developed to assemble a pentasubstituted pyridine with appropriately positioned aldehyde and dimethylmorpholine substituents for a key tertiary amino effect reaction (T-reaction) that led to the spirocylic architecture. Ultimately, (-)-1 was isolated as the thermodynamically most favored stereoisomer.

We report a rapid and specific aptamer-based method for one-step cocaine detection with minimal reagent requirements. The feasibility of aptamer-based detection has been demonstrated with sensors that operate via target-induced conformational change mechanisms, but these have generally exhibited limited target sensitivity. We have discovered that the cocaine-binding aptamer MNS-4.1 can also bind the fluorescent molecule 2-amino-5,6,7-trimethyl-1,8-naphthyridine (ATMND) and thereby quench its fluorescence. We subsequently introduced sequence changes into MNS-4.1 to engineer a new cocaine-binding aptamer (38-GC) that exhibits higher affinity to both ligands, with reduced background signal and increased signal gain. Using this aptamer, we have developed a new sensor platform that relies on the cocaine-mediated displacement of ATMND from 38-GC as a result of competitive binding. We demonstrate that our sensor can detect cocaine within seconds at concentrations as low as 200 nM, which is 50-fold lower than existing assays based on target-induced conformational change. More importantly, our assay achieves successful cocaine detection in body fluids, with a limit of detection of 10.4, 18.4, and 36 μM in undiluted saliva, urine, and serum samples, respectively.

We have recently identified 1,8-naphthyridin-2(1H)-one-3-carboxamide as a new scaffold very suitable for the development of new CB2 receptor potent and selective ligands. In this paper we describe a number of additional derivatives in which the same central scaffold has been variously functionalized in position 1 or 6. All new compounds showed high selectivity and affinity in the nanomolar range for the CB2 receptor. Furthermore, we found that their functional activity is controlled by the presence of the substituents at position C-6 of the naphthyridine scaffold. In fact, the introduction of substituents in this position determined a functionality switch from agonist to antagonists/inverse agonists. Finally, docking studies showed that the difference between the pharmacology of these ligands may be in the ability/inability to block the Toggle Switch W6.48(258) (χ1 g+ → trans) transition.

This work features the base-promoted on-water synthesis of [1,6]-naphthyridines from methyl ketones, malononitrile and phenols or thiols. The reaction conditions were carefully tuned to drive the product selectivity from 3H-pyrroles to [1,6]-naphthyridines. The advantages of this method lie in its simplicity, cost effectiveness, and environmental friendliness, representing a new effort toward the on-water synthesis of [1,6]-naphthyridines without starting from a nitrogen-containing heterocycle and highlighting the versatility of the nitrile functional group.

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu5 PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu5 as well as antagonist activity at mGlu3. Structure-activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu5 PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.

There are currently three HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) approved by the FDA for the treatment of AIDS. However, the emergence of drug-resistant mutants emphasizes the need to develop additional agents that have improved efficacies against the existent resistant mutants. As reported herein, we modified our recently disclosed 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides IN inhibitors to develop compounds that have improved efficacies against recombinant IN in biochemical assays. These new compounds show single-digit nanomolar antiviral potencies against HIV vectors that carry wild-type (WT) IN in a single round replication assay and have improved potency against vectors harboring the major forms of drug resistant IN mutants. These compounds also have low toxicity for cultured cells, which in several cases, results in selectivity indices (CC50/EC50) of greater than 10000. The compounds have the potential, with additional structural modifications, to yield clinical agents that are effective against the known strains of resistant viruses.

New multicomponent domino reactions of arylglyoxals with pyrazol-5-amines have been established, providing selective access to unprecedented pyrazolo-fused 1,7-naphthyridines, 1,3-diazocanes, and pyrroles (up to 52 examples). The unreported dipyrazolo-fused 1,7-naphthyridines were regioselectively synthesized through a special double [3 + 2 + 1] heteroannulation accompanied by direct C-C formation between two electrophilic sites of arylglyoxals. The unusual [3 + 3 + 1 + 1] cyclization resulted in 20 examples of novel dipyrazolo-fused 1,3-diazocanes, whereas pyrrolo[2,3-c]pyrazoles were obtained in good yields by varying arylglyoxals 1 and pyrazol-5-amines 2 in the ratio 1:2. Mechanisms of formation of these three new types of heterocycles are also proposed.

A facile and efficient one-pot procedure for the preparation of functionalized benzo[b][1,8]naphthyridine derivatives by three-component reaction of 2-chloroquinoline-3-carbaldehyde, 1,3-dicarbonyl compounds, and enaminones catalyzed by l-proline is described. This new protocol has the advantages of environmental friendliness, good yields, and convenient operation.

A general Rh(III)-catalyzed synthesis of naphthyridinone derivatives is described. It relies on a double-activation and directing approach leveraging nicotinamide N-oxides as substrates. In general, high yields and selectivities can be achieved using low catalyst loadings and mild conditions (room temperature) in the couplings with alkynes, while alkenes require slightly more elevated temperatures.