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Rearranged during transfection kinase (RET) inhibition has been considered a promising therapeutic approach for treatment of a variety of cancers. However, the clinical therapeutic benefits of the second-generation RET inhibitor selpercatinib are greatly compromised by acquired resistance mediated by solvent-front mutations (e.g., RET G810 R/S/C ). Herein, we report a class of 7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridine derivatives as potent RET and RET solvent-front mutant inhibitors for overcoming selpercatinib resistance. The representative compound 20p exhibited excellent in vitro inhibitory activities against solvent-front mutations (RET G810R , RET G810S , and RET G810C ) with low nanomolar range (IC 50 of 5.7-8.3 nM), which was 15-29-fold more potent than selpercatinib (IC 50 of 95.3-244.1 nM). Additionally, 20p exhibited acceptable pharmacokinetic properties with oral bioavailability of 30.4 %. Importantly, 20p exhibited highly impressive antitumor potency in both a Ba/F3-KIF5B-RET WT -derived xenograft mouse model and a selpercatinib-resistant Ba/F3-KIF5B-RET G810R -positive mutant xenograft mouse model. Overall, 20p represents a novel and promising drug lead for overcoming RET solvent-front mutation-based resistance to selpercatinib., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Myotonic dystrophy type 1 (DM1) is caused by the aberrant expansion of CTG repeats within the DMPK gene. This study investigated the potential binding of "X-linker-Y" type molecules to the CTG/CTG motif present in CTG repeats, using heterocyclic units X and Y capable of forming complementary hydrogen bonds with nucleobases. Among the tested molecules, the heterodimer of 2-amino-1,8-naphthyridine (X) and 3-aminoisoquinoline (Y) showed significant binding to the CTG/CTG motif. NMR analysis suggested hydrogen-bonded interactions between 3-aminoisoquinoline and thymine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A library of 1,5-Naphthyridin-2(1H)-one based 1,2,3-triazole analogues (11a-q) were synthesized via series of reactions such as protection, oxidation, cyclization and click chemistry. The new molecules were tested for their antitubercular activity against M. tuberculosis mc 2 6230 and determined the minimum inhibitory concentration (MIC) employing Rifampicin as reference. The 3-cyano and 4-cyano substituted analogues 11e and 11f displayed superior activity with an MIC value of 4.0 μg/ml. Additionally, these potent molecules were tested for determination of their MBC values and ATP depletion assay showed a hopeful relative luminescence. Additionally, determined the MIC of 11e and 11f against multi-drug resistant strains of M. tuberculosis viz. mc 2 8243, mc 2 8247 and mc 2 8259. The cytotoxicity of these two molecules presented no effects on normal cell. The profound results of these two molecules proved them as potential antitubercular agent. Further, molecular docking studies were portrayed against crystal structure of M. tuberculosis dihydrofolate reductase which garnered promising docking scores and binding interactions such as H-bond and hydrophobic. ADME prediction revealed their favorable drug-likeness characteristics., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

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.

Mismatched base pairs in DNA are the basis of single-nucleotide polymorphism, one of the major issues in genetic diseases. However, the changes of physical and chemical properties of DNA caused by single-site mismatches are often influenced by the sequence and the structural flexibility of the whole duplex, resulting in a challenge of direct detection of the types and location of mismatches sensitively. In this work, we proposed a synthetic ligand-enhanced protein nanopore analysis of GG mismatch on DNA fragment, inspired by in silico investigation of the specific binding of naphthyridine dimer (ND) on GG mismatch. We demonstrated that both the importing and unzipping processes of the ligand-bound DNA duplex can be efficiently slowed down in α-hemolysin nanopore. This ligand-binding induced slow-down effect of DNA in nanopore is also sensitive to the relative location of the mismatch on DNA duplex. Especially, the GG mismatch close to the end of a DNA fragment, which is hard to be detected by either routine nanopore analysis or tedious nanopore sequencing, can be well differentiated by our ND-enhanced nanopore experiment. These findings provide a promising strategy to localize and discriminate base mismatches in duplex form directly at the single-molecule level., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Herein we describe the synthesis and rearrangement of 1,3-diamino-2,7-naphthyridines and 1-amino-3-oxo-2,7-naphthyridines. In the case of 1,3-diamino-2,7-naphthyridines, it was found that the rearrangement reaction was influenced by both the substituent at the 7th position of the 2,7-naphthyridine ring and by the nature of the cyclic amine at the 1st position. The influence was mainly steric. The reaction of 1-amino-3-oxo-2,7-naphthyridines with amines was studied for the first time. It was revealed that for these substrates, the rearrangement occurs faster and without any influence of the alkyl and cyclic amine groups. We also observed the nucleophilic addition of the amine to the carbonyl group of the rearranged product with the formation of a Schiff base. The calculation of the ESP charges on these substrates indicates a considerable increase in the positive charge on the cyano group that suffers the nucleophilic attack during the rearrangement process, possibly explaining its increased tendency to react and to have a higher reaction velocity.

This study examines the binding properties of six naphthyridine carbamate dimer (NCD) derivatives with varying linker lengths to the CGG/CGG triad, a non-canonical DNA structure linked to repeat expansion disorders. By altering the linker length from 2 to 4 methylene groups, we found changes in thermal stability of the ligand-bound complexes while maintaining a consistent 2 : 1 binding stoichiometry. Among the derivatives, CC23 showed superior binding affinity compared to the parent molecule CC33 (NCD). Spectroscopic analyses revealed that linker length influences the conformational equilibrium of NCD derivatives. Thermal melting temperature measurements demonstrated CC23's enhanced thermal stability over CC33. These findings underscore the potential of optimized NCD derivatives, like CC23, as tools to modulate CGG repeat structures, offering insights for therapeutic strategies targeting repeat expansion disorders., (© 2024 The Author(s). ChemMedChem published by Wiley-VCH GmbH.)

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.

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 0.5-8.4×10 4  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., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

A series of spiro β-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, 1 H-NMR, 13 C 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 (IC 50 =17.68±0.76 μg/mL) and 4 c (IC 50 =18.53±0.52 μg/mL) showed the highest antioxidant activity compared to ascorbic acid (IC 50 =15.16±0.43 μg/mL). Molecular docking studies were also conducted to support the antimicrobial and SAR results., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

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., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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 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 × 10 5 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.

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 15 N-labeled NCD and 1 H- 15 N HSQC. In a fully saturated state, two NCD molecules consistently bind to each CGG/CGG unit, maintaining a 1 : 2 binding stoichiometry.

Two new caulamidines C ( 2 ) and D ( 4 ) and three isocaulamidines B, C, and D ( 1 , 3 , and 5 ) along with the known compound caulamidine B ( 6 ) were isolated from the marine ascidian Polyandrocarpa sp. Their structures were elucidated by analysis of nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) data. Isocaulamidines have an altered pattern of N -methyl substitution (N-15 vs N-13 in the caulamidines) with a concomitant double-bond rearrangement to provide a new C-14/N-13 imine functionality. Caulamidine C ( 2 ) and isocaulamidine C ( 3 ) are the first members of this alkaloid family with two chlorine substituents in the core 6 H -2,6-naphthyridine ring system.

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.

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, 1 H and 13 C 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.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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.

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 IC 50 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 IC 50 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.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Four new aaptamine alkaloids, named as 9-methoxy-N-demethylaaptanone ( 1 ), 3,5-dicarbomethoxy-1,​6-​naphthyridine ( 2 ), aaptosvanphongs A and B ( 3 and 4 ), and three known aaptamine alkaloids as 2-methoxy-3-oxoaaptamine ( 5 ), 8,9,9-trimethoxy-9 H -benzo[ de ][1,6]-naphthyridine ( 6 ), and demethyl(oxy)aaptamine ( 7 ) were isolated from the sponge Aaptos by various chromatographic methods. Their structures were established by extensive spectroscopic analyses (HR-ESI-MS, 1 D and 2 D NMR) and by comparison of the spectral data with those reported in the literature. Compounds 1 - 7 significantly showed cytotoxic effects against SK-LU-1, MCF-7, HepG2, and SK-Mel-2 cell lines with IC 50 values in range from 7.7 ± 0.8 to 51.4 ± 1.8 µM. Among them, compound 7 exhibited the most cytotoxic activity with corresponding IC 50 values of 9.2 ± 1.0, 7.8 ± 0.6, 8.4 ± 0.8, and 7.7 ± 0.8 µM.[Formula: see text].

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

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)-5 H -chromeno[2,3- b ]pyridines in formic acid. The investigation of the reaction mechanism using 1 H-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.

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.

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).

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 (IC 50  = 0.21 µM), A549 (IC 50  = 0.39 µM), and MCF-7 (IC 50  = 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 (IC 50  = 11.77 nM), MEK1 (IC 50  = 10.71 nM), and Flt-3 (IC 50  = 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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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 .

Lung cancer is the leading cause of cancer death. Pyronaridine, a synthetic drug of artemisinin, has been used in China for over 30 years for the treatment of malaria, but its effect on non-small cell lung cancer (NSCLC) cells is rarely reported. In this study, we determined the efficacy of pyronaridine in four different NSCLC cell lines and explored its mechanism in H1975. The data showed that pyronaridine could upregulate the expression of TNF-related apoptosis-inducing ligand (TRAIL)-mediated death receptor 5 to promote cellular apoptosis. Meanwhile, the JNK (c-Jun N-terminal kinase) level was detected to be significantly increased after treating with pyronaridine. We used JNK inhibitor and found that it could partially inhibit cell apoptosis. The results showed that epidermal growth factor receptor (EGFR), PI3K, and AKT were downregulated after the treatment of pyronaridine. In summary, pyronaridine can selectively kill NSCLC by regulating TRAIL-mediated apoptosis and downregulating the protein level of EGFR. It is a promising anticancer drug for NSCLC., (© 2021 John Wiley & Sons Ltd.)

Sensitive, high-throughput methods for pharmacokinetic (PK) profiling are essential for potential therapeutics during critical stages of clinical trials. The application of a microfluidic capillary zone electrophoresis mass spectrometry (CZE-MS) method for PK profiling allows for rapid, sensitive and in-depth analysis of multiple samples within a short timeframe. Here, a CZE-MS approach for PK analysis was compared with a traditional UHPLC-MS approach when analyzing serum extracts from rats treated with a potential Alzheimer's disease therapeutic, BNC-1. Resulting PK data generated from both methods displayed statistical similarities. Additionally, the separation efficiency attributed to the use of the CZE-MS method provided substantial metabolic regulation data that was not apparent in the UHPLC-MS method. Additionally, the coupling of the CZE-MS method to the data processing software, MZmine2, was used to monitor changes in metabolism and observe putative BNC-1-derived metabolites. The ability to perform fast analyses without sacrificing sensitivity or metabolic information suggests that this CZE-MS method is ideal for metabolomics-inclusive, high-throughput PK profiling., (© 2021 John Wiley & Sons, Ltd.)

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., (© 2021 John Wiley & Sons A/S.)

Antibiotic resistance is becoming one of the major crises, among which hydrolysis reaction is widely employed by bacteria to destroy the reactive pharmacophore. Correspondingly, antibiotic producer has canonically co-evolved this approach with the biosynthetic capability for self-resistance. Here we discover a self-defense strategy featuring with reductive inactivation of hemiaminal pharmacophore by short-chain dehydrogenases/reductases (SDRs) NapW and homW, which are integrated with the naphthyridinomycin biosynthetic pathway. We determine the crystal structure of NapW·NADPH complex and propose a catalytic mechanism by molecular dynamics simulation analysis. Additionally, a similar detoxification strategy is identified in the biosynthesis of saframycin A, another member of tetrahydroisoquinoline (THIQ) antibiotics. Remarkably, similar SDRs are widely spread in bacteria and able to inactive other THIQ members including the clinical anticancer drug, ET-743. These findings not only fill in the missing intracellular events of temporal-spatial shielding mode for cryptic self-resistance during THIQs biosynthesis, but also exhibit a sophisticated damage-control in secondary metabolism and general immunity toward this family of antibiotics., (© 2021. The Author(s).)

Background: A new UPLC-MS/MS technique for the determination of ripretinib in beagle dog plasma was developed, and the pharmacokinetic effects of voriconazole and itraconazole on ripretinib in beagle dogs were studied., Methods: After extraction with ethyl acetate under alkaline conditions, ripretinib was detected using avapritinib as the internal standard (IS). The mobile phases were 0.1% formic acid-acetonitrile. The scanning method was multi-reaction monitoring using ESI+ source, and the ion pairs for ripretinib and IS were m/z 509.93→416.85 and 499.1→482.09, respectively. This animal experiment adopted a three period self-control experimental design. In the first period, ripretinib was orally administered to six beagle dogs at a dose of 5 mg/kg. In the second period, the same six beagle dogs were orally given itraconazole at a dose of 7 mg/kg, after 30 min, ripretinib was orally given. In the third period, voriconazole at a dose of 7 mg/kg was given orally, and then ripretinib was orally given. At different time points, the blood samples were collected. The concentration of ripretinib was detected, and the pharmacokinetic parameters of ripretinib were calculated., Results: Ripretinib had a good linear relationship in the range of 1-1000 ng/mL. The precision, accuracy, recovery, matrix effect and stability met the requirements of the guiding principles. After erdafitinib combined with itraconazole, the C max and AUC 0→t of ripretinib increased by 38.35% and 36.36%, respectively, and the t 1/2 was prolonged to 7.53 h. After ripretinib combined with voriconazole, the C max and AUC 0→t of ripretinib increased by 37.44% and 25.52%, respectively, and the t 1/2 was prolonged to 7.33 h., Conclusion: A new and reliable UPLC-MS/MS technique was fully optimized and developed to detect the concentration of ripretinib in beagle dog plasma. Itraconazole and voriconazole could inhibit the metabolism of ripretinib in beagle dogs and increase the plasma exposure of ripretinib., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Wang et al.)

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.

Molecular glues are a class of small molecular drugs that mediate protein-protein interactions, that induce either the degradation or stabilization of target protein. A structurally diverse group of chemicals, including 17-β-estradiol (E2), anagrelide, nauclefine, and DNMDP, induces apoptosis by forming complexes with phosphodiesterase 3A (PDE3A) and Schlafen 12 protein (SLFN12). They do so by binding to the PDE3A enzymatic pocket that allows the compound-bound PDE3A to recruit and stabilize SLFN12, which in turn blocks protein translation, leading to apoptosis. In this work, we report the high-resolution cryo-electron microscopy structure of PDE3A-SLFN12 complexes isolated from cultured HeLa cells pre-treated with either anagrelide, or nauclefine, or DNMDP. The PDE3A-SLFN12 complexes exhibit a butterfly-like shape, forming a heterotetramer with these small molecules, which are packed in a shallow pocket in the catalytic domain of PDE3A. The resulting small molecule-modified interface binds to the short helix (E552-I558) of SLFN12 through hydrophobic interactions, thus "gluing" the two proteins together. Based on the complex structure, we designed and synthesized analogs of anagrelide, a known drug used for the treatment of thrombocytosis, to enhance their interactions with SLFN12, and achieved superior efficacy in inducing apoptosis in cultured cells as well as in tumor xenografts., (© 2021. The Author(s).)

The development of ligands to stabilize G-quadruplexes (G4s) or induce G4s to transition from metastable topology to stable topology is a potential strategy for inhibiting cancer cell proliferation. In this study, a novel G-quadruplex (G4) ligand based on a naphthyridine scaffold with two indole pendants, L5-DA, is reported to convert hybrid to the parallel topology. Circular dichroism (CD) and fluorescence spectroscopies were used to investigate the interactions between L5-DA and G4s. The CD spectra revealed that the L5-DA induced the conformational conversion from hybrid topologies to parallel topologies with a melting temperature increase of more than 30 °C. According to Förster resonance energy transfer assays, the presence of excess duplex competitor had no effect on the ligand-induced stabilization of the hybrid topology, confirming the L5-DA's selectivity for G4s over ds26. With IC 50 values of 4.3 μM, the ligand showed significant cytotoxicity against HeLa cells and effectively induced growth inhibition and apoptosis in HeLa cells. Immunofluorescence microscopy revealed an increase in BG4 foci in the presence of the L5-DA, confirming ligand-induced G4s stabilization in HeLa cells. According to these results, the combination of naphthyridine and indole scaffold was an effective design strategy for G4s stabilization and conformational conversion of metastable G4 topology for inhibiting cancer cell growth., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Novel non-camptothecin (non-CPT) class of conformationally constrained, hitherto unknown 7,12-dihydrodibenzo[b,h][1,6] naphthyridine and 7H-Chromeno[3,2-c] quinoline derivatives have been designed, synthesized and evaluated for anti-cancer activity. In vitro anti-proliferation evaluation against human cancer cell lines (A549 and MCF-7) exhibited significant cytotoxicity. Among the derivatives (8-24), 8 (IC 50 0.44 μM and IC 50 0.62 μM) and 12 (IC 50 0.69 μM and IC 50 0.54 μM) were identified as the most promising candidate against A-549 and MCF-7 cancer cell lines respectively. Topo I inhibitory activity of 8 and 12 suggested that, they may be developed as potential anti-cancer molecules in future and rationalized by docking analysis with effective binding modes. Further, in silico ADME prediction studies of all derivatives were found promising, signifying the drug like properties. In precise, the present investigation displays a new strategy to synthesize and emphasis on anticancer activities of conformationally constrained dibenzo[b,h][1,6] naphthyridine derivatives and Chromeno[3,2-c] quinoline derivatives in the context of cancer drug development and refinement., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We report the first isolation of the alkaloid aaptamine from the Philippine marine sponge Stylissa sp. Aaptamine possessed weak antiproliferative activity against HCT116 colon cancer cells and inhibited the proteasome in vitro at 50 µM. These activities may be functionally linked. Due to its known, more potent activity on certain G-protein coupled receptors (GPCRs), including α-adrenergic and δ-opioid receptors, the compound was profiled more broadly at sub-growth inhibitory concentrations against a panel of 168 GPCRs to potentially reveal additional targets and therapeutic opportunities. GPCRs represent the largest class of drug targets. The primary screen at 20 µM using the β-arrestin functional assay identified the antagonist, agonist, and potentiators of agonist activity of aaptamine. Dose-response analysis validated the α-adrenoreceptor antagonist activity of aaptamine (ADRA2C, IC 50 11.9 µM) and revealed the even more potent antagonism of the β-adrenoreceptor (ADRB2, IC 50 0.20 µM) and dopamine receptor D4 (DRD4, IC 50 6.9 µM). Additionally, aaptamine showed agonist activity on selected chemokine receptors, by itself (CXCR7, EC 50 6.2 µM; CCR1, EC 50 11.8 µM) or as a potentiator of agonist activity (CXCR3, EC 50 31.8 µM; CCR3, EC 50 16.2 µM). These GPCRs play a critical role in the treatment of cardiovascular disease, diabetes, cancer, and neurological disorders. The results of this study may thus provide novel preventive and therapeutic strategies for noncommunicable diseases (NCDs).

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.

Among all nitrogen-containing heterocycles, the 1,8-naphthyridine scaffold has recently gained an immense amount of curiosity from numerous researchers across fields of medicinal chemistry and drug discovery. This new attention can be ascribed to its versatility of synthesis, its reactiveness and the variety of biological activities it has exhibited. Over the past half-decade, numerous diverse biological evaluations have been conducted on 1,8-naphthyridine and its derivatives in a quest to unravel novel pharmacological facets to this scaffold. Its potency to treat neurodegenerative and immunomodulatory disorders, along with its anti-HIV, antidepressant and antioxidant properties, has enticed researchers to look beyond its broad-spectrum activities, providing further scope for exploration. This review is a consolidated update of previous works on 1,8-naphthyridines and their analogs, focusing on the past 5 years.

Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis -[ 18 F]1-(4-fluorobutyl- N -((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([ 18 F] LU14 ) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [ 18 F] LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression.

Marine and terrestrial environments are rich sources of various bioactive substances, which have been used by humans since prehistoric times. Nowadays, due to advances in chemical sciences, new substances are still discovered, and their chemical structures and biological properties are constantly explored. Drugs obtained from natural sources are used commonly in medicine, particularly in cancer and infectious diseases treatment. Naphthyridines, isolated mainly from marine organisms and terrestrial plants, represent prominent examples of naturally derived agents. They are a class of heterocyclic compounds containing a fused system of two pyridine rings, possessing six isomers depending on the nitrogen atom's location. In this review, biological activity of naphthyridines obtained from various natural sources was summarized. According to previous studies, the naphthyridine alkaloids displayed multiple activities, i.a., antiinfectious, anticancer, neurological, psychotropic, affecting cardiovascular system, and immune response. Their wide range of activity makes them a fascinating object of research with prospects for use in therapeutic purposes.

The synthesis of 1,8-naphthyridine derivatives fused with other heterocycles, such as chromenes and quinolines, as well as their behaviour as topoisomerase I inhibitors is studied. The preparation is carried out through a direct and simple process as an intramolecular [4 + 2] cycloaddition reaction between functionalized aldimines, obtained by the condensation of 2-aminopyridine and unsaturated aldehydes, and olefins. In particular, while no clear inhibitory activity is observed for chromeno[4,3-b][1,8]naphthyridine fused heterocycles, a very different result is observed for quinolino[4,3-b][1,8]naphthyridine derivatives. Experimental assays indicated that quinolino[4,3-b][1,8]naphthyridines inhibited the topoisomerase I enzymatic reaction behaving like a poison, as occurs with the natural TopI inhibitor, camptothecin. Furthermore, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549), human ovarian carcinoma (SKOV3), and on non-cancerous lung fibroblasts cell line (MRC5) was also screened., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

G-quadruplex (GQ) ligands as potential anti-cancer drugs have received extensive attention. Large aromatic systems are usually considered in the design of the ligands to improve the binding with GQs, which are typically constructed by the combination of small modules with covalent bonds. In this study, we presented a non-covalent bond approach to construct GQ ligands with an extended planar structure. The ligands were stable dimers assembled through quadruplex intermolecular hydrogen bonds between two molecules of naphthyridine derivatives. Spectroscopic analyses showed that dimeric ligands could stabilize GQs with an increase of the melting temperature up to 12 °C and induced conformational conversion of hybrid GQs. Confocal fluorescence microscopy confirmed the enrichment of naphthyridine ligands in the nucleus. The ligands showed moderate cytotoxicity against HeLa cells with an IC50 value of 7.5 μg mL-1 and effectively induced growth inhibition and apoptosis in HeLa cells. These results confirmed the feasibility of the quick building of GQ ligands through intermolecular interactions of simple molecules that are easily obtained during synthesis, which is helpful for GQ ligand design and quick establishment of a ligand library through the self-assembly of easily available molecular components.

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.

β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) has been pursued as a prime target for the treatment of Alzheimer's disease (AD). In this report, we describe the discovery of BACE1 inhibitors with a 1-amino-3,4-dihydro-2,6-naphthyridine scaffold. Leveraging known inhibitors 2a and 2b, we designed the naphthyridine-based compounds by removing a structurally labile moiety and incorporating pyridine rings, which showed increased biochemical and cellular potency, along with reduced basicity on the amidine moiety. Introduction of a fluorine atom on the pyridine culminated in compound 11 which had improved cellular activity as well as further reduced basicity and demonstrated a robust and sustained cerebrospinal fluid (CSF) Aβ reduction in dog. The crystal structure of compound 11 bound to BACE1 confirmed van der Waals interactions between the fluorine on the pyridine and Tyr71 in the flap., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Oral submucous fibrosis (OSMF) is considered a premalignant condition characterized by aggressive fibrosis of the submucosal tissues of the oral cavity reflecting its malignant transformation potential. Activation of transforming growth factor beta (TGF- β ) signaling has been reported to lead increased collagen production and fibrosis. Recently, significant upregulation of TGF- β 1 has been reported in OSMF as compared to normal tissues. Therefore, inhibition of the TGF- β 1 may pave for the development of therapeutics of OSMF. Based on the structure-assisted drug designing, we found "silmitasertib" as potent inhibitor of TGF- β 1. We suggest that this molecule can be validated and implemented for the treatment of OSMF., Competing Interests: The authors reported no declarations of interest., (Copyright © 2021 Nezar Boreak.)

A series of 8-substituted sampangine derivatives have been designed, synthesized and tested for their ability to inhibit cholinesterase and penetrate the blood-brain barrier. Their chelating ability toward Zn 2+ and other biologically relevant metal ions was also demonstrated by isothermal titration calorimetry. The new derivatives exhibited high acetylcholinesterase inhibitory activity, high blood-brain barrier penetration ability and high chelating selectivity for Zn 2+ . Moreover, compound 10 with the strongest binding affinity to Zn 2+ was selected for further research. Western blotting analysis, transmission electron microscopy, DCFH-DA assay and paralysis experiment indicated that compound 10 suppressed the formation of Zn 2+ -Aβ complexes, alleviated the Zn 2+ induced neurotoxicity and inhibited the production of ROS catalyzed by Zn 2+ in Aβ42 transgenic C. elegans. Furthermore, compound 10 also inhibited the expressions of pro-inflammatory cytokines, such as NO, TNF-α, IL-6 and IL-1β, induced by Zn 2+ + Aβ 1-42 in BV2 microglial cells. In general, this work provided new insights into the design and development of potent metal-chelating agents for Alzheimer's disease treatment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A series of 11-substituted sampangine derivatives have been designed, synthesized, and tested for their ability to inhibit cholinesterase. Their chelating ability and selectivity for Cu 2+ over other biologically relevant metal ions were demonstrated by isothermal titration calorimetry. Their blood-brain barrier permeability was also tested by parallel artificial membrane permeation assay. Among the synthesized derivatives, compound 11 with the strong anti-acetylcholinesterase activity, high blood-brain barrier penetration ability and high binding affinity to Cu 2+ was selected for further research. Western blotting analysis, transmission electron microscopy, DCFH-DA assay and paralysis experiment indicated that compound 11 suppressed the formation of Cu 2+ -Aβ complexes, alleviated the Cu 2+ induced neurotoxicity and inhibited the production of ROS catalyzed by Cu 2+ in Aβ42 transgenic C. elegans. Moreover, compound 11 also inhibited the expressions of proinflammatory cytokines, such as NO, TNF-α, IL-6 and IL-1β, induced by Cu 2+ + Aβ 1 - 42 in BV2 microglial cells. In general, this work provided new insights into the design and development of potent metal-chelating agents for AD treatment., Competing Interests: Declaration of competing interest Huang Tang declare no conflict of interest., (Copyright © 2018 Elsevier B.V. All rights reserved.)