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

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

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

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

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

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

Discovery of IDO1 inhibitors containing a decahydroquinoline, decahydro-1,6-naphthyridine, or octahydro-1H-pyrrolo[3,2-c]pyridine scaffold.

A series of IDO1 inhibitors containing a decahydroquinoline, decahydro-1,6-naphthyridine, or octahydro-1H-pyrrolo[3,2-c]pyridine scaffold were identified with good cellular and human whole blood activity against IDO1. These inhibitors contain multiple chiral centers and all diastereomers were separated. The absolute stereochemistry of each isomers were not determined. Compounds 15 and 27 stood out as leads due to their good cellular as well as human whole blood IDO1 inhibition activity, low unbound clearance, and reasonable mean residence time in rat cassette PK studies.

Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain.

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-[18F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([18F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [18F]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.

Design and synthesis of novel conformationally constrained 7,12-dihydrodibenzo[b,h][1,6] naphthyridine and 7H-Chromeno[3,2-c] quinoline derivatives as topoisomerase I inhibitors: In vitro screening, molecular docking and ADME predictions.

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 (IC50 0.44 µM and IC50 0.62 µM) and 12 (IC50 0.69 µM and IC50 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.

Fused chromeno and quinolino[1,8]naphthyridines: Synthesis and biological evaluation as topoisomerase I inhibitors and antiproliferative agents.

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.

Synthesis and Anticancer Properties of Functionalized 1,6-Naphthyridines.

The burgeoning interest in synthesis and biological applications of 1,6-naphthyridines reflects the importance of 1,6-naphthyridines in the synthetic as well as medicinal chemistry fields. Specially, 1,6-naphthyridines are pharmacologically active, with variety of applications such as anticancer, anti-human immunodeficiency virus (HIV), anti-microbial, analgesic, anti-inflammatory and anti-oxidant activities. Although collective recent synthetic developments have paved a path to a wide range of functionalized 1,6-naphthyridines, a complete correlation of synthesis with biological activity remains elusive. The current review focuses on recent synthetic developments from the last decade and a thorough study of the anticancer activity of 1,6-naphthyridines on different cancer cell lines. Anticancer activity has been correlated to 1,6-naphthyridines using the literature on the structure-activity relationship (SAR) along with molecular modeling studies. Exceptionally, at the end of this review, the utility of 1,6-naphthyridines displaying activities other than anticancer has also been included as a glimmering extension.

Design, synthesis and biological evaluation of 7H-pyrrolo[2,3-d]pyrimidine derivatives containing 1,8-naphthyridine-4-one fragment.

In this study, a series of pyrrolo [2,3-d]pyrimidine derivatives containing 1,8-naphthyridine-4-one fragment were synthesized and their biological activity were tested. Most of the target compounds displayed moderate to excellent activity against one or more cancer cell lines and low activity against human normal cell LO2 in vitro. The most promising compound 51, of which the IC50 values were 0.66 µM, 0.38 µM and 0.44 µM against cell lines A549, Hela and MCF-7, shown more remarkable activity and better apoptosis effect than the positive control Cabozantinib. The structure-activity relationships (SARs) indicated that double-EWGs (such as R3 = 2-Cl-4-CF3) on the terminal phenyl rings was a key factor in improving the biological activity. In addition, the further research on compound 51 mainly included c-Met kinase activity and selectivity, concentration dependence, and molecular docking.

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

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

1,8-Naphthyridine Derivatives: A Privileged Scaffold for Versatile Biological Activities.

1, 8- Naphthyridine nucleus belongs to significant nitrogen-containing heterocyclic compounds which has garnered the interest of researchers due to its versatile biological activities. It is known to be used as an antimicrobial, anti-psychotic, anti-depressant, anti-convulsant, anti- Alzheimer's, anti-cancer, analgesic, anti-inflammatory, antioxidant, anti-viral, anti-hypertensive, antimalarial, pesticides, anti-platelets, and CB2 receptor agonist, etc. The present review highlights the framework of biological properties of synthesized 1, 8-naphthyridine derivatives developed by various research groups across the globe.

Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFα Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches.

Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.

Discovery of the first potent and selective αvß5 integrin inhibitor based on an amide-containing core.

Integrins αvß5 and αvß3 are closely related, proangiogenic members of the wider RGD-binding integrin family. Due to their high sequence homology, the development of αvß5-selective compounds has remained elusive to synthetic and medicinal chemists. Herein, we describe a survey of SAR around a series of amide-containing 3-aryl-succinamic acid-based RGD mimetics. This resulted in the discovery of α,α,α-trifluorotolyl 12 which exhibits 800 × selectivity for αvß5versus αvß3 with a pyrrolidine amide linker that confers selectivity for αvß5 by positioning a key aryl ring in the SDL of αvß5 with good complementarity; binding in this mode is disfavoured in αvß3 due to clashes with key residues in the ß3-subunit. Compound 12 exhibits selective inhibition by a cell adhesion assay, high passive permeability and solubility which enables potential use of this inhibitor as an αvß5-selective in vitro tool compound.

Structure-activity relationship study of novel quinazoline-based 1,6-naphthyridinones as MET inhibitors with potent antitumor efficacy.

As a privileged scaffold, the quinazoline ring is widely used in the development of EGFR inhibitors, while few quinazoline-based MET inhibitors are reported. In our ongoing efforts to develop new MET-targeted anticancer drug candidates, a series of quinazoline-based 1,6-naphthyridinone derivatives were designed, synthesized, and evaluated for their biological activities. The preliminary SARs studies indicate that the quinazoline scaffold was also acceptable for the block A of class II MET inhibitors. The further pharmacokinetic studies led to the identification of the most promising compound 22a with favorable in vitro potency (MET, IC50 = 9.0 nM), human microsomal metabolic stability (t1/2 = 621.2 min) and oral bioavailability (F = 42%). Moreover, 22a displayed good in vivo antitumor efficacy (IR of 81% in 75 mg/kg) in MET-positive human glioblastoma U-87 MG xenograft model. These positive results indicated that 22a is a potential new MET-targeted antitumor drug lead, which is worthy of further development.

Enantioselective Total Synthesis of (-)-Finerenone Using Asymmetric Transfer Hydrogenation.

(-)-Finerenone is a nonsteroidal mineralocorticoid receptor antagonist currently in phase III clinical trials for the treatment of chronic kidney disease in type 2 diabetes. It contains an unusual dihydronaphthyridine core. We report a 6-step synthesis of (-)-finerenone, which features an enantioselective partial transfer hydrogenation of a naphthyridine using a chiral phosphoric acid catalyst with a Hantzsch ester. The process is complicated by the fact that the naphthyridine exists as a mixture of two atropisomers that react at different rates and with different selectivities. The intrinsic kinetic resolution was converted into a kinetic dynamic resolution at elevated temperature, which enabled us to obtain (-)-finerenone in both high yield and high enantioselectivity. DFT calculations have revealed the origin of selectivity.

Fused 1,5-Naphthyridines: Synthetic Tools and Applications.

Heterocyclic nitrogen compounds, including fused 1,5-naphthyridines, have versatile applications in the fields of synthetic organic chemistry and play an important role in the field of medicinal chemistry, as many of them have a wide range of biological activities. In this review, a wide range of synthetic protocols for the construction of this scaffold are presented. For example, Friedländer, Skraup, Semmlere-Wolff, and hetero-Diels-Alder, among others, are well known classical synthetic protocols used for the construction of the main 1,5-naphthyridine scaffold. These syntheses are classified according to the nature of the cycle fused to the 1,5-naphthyridine ring: carbocycles, nitrogen heterocycles, oxygen heterocycles, and sulphur heterocycles. In addition, taking into account the aforementioned versatility of these heterocycles, their reactivity is presented as well as their use as a ligand for metal complexes formation. Finally, those fused 1,5-naphthyridines that present biological activity and optical applications, among others, are indicated.

Synthetic Strategies, Reactivity and Applications of 1,5-Naphthyridines.

This review covers the synthesis and reactivity of 1,5-naphthyridine derivatives published in the last 18 years. These heterocycles present a significant importance in the field of medicinal chemistry because many of them exhibit a great variety of biological activities. First, the published strategies related to the synthesis of 1,5-naphthyridines are presented followed by the reactivity of these compounds with electrophilic or nucleophilic reagents, in oxidations, reductions, cross-coupling reactions, modification of side chains or formation of metal complexes. Finally, some properties and applications of these heterocycles studied during this period are examined.

Chemical Probing of Thymine in the TGG/CGG Triad to Explore the Deamination of 5-Methylcytosine in the CGG Repeat.

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.

1,4,5,6,7,8-Hexahydroquinolines and 5,6,7,8-tetrahydronaphthalenes: A new class of antitumor agents targeting the colchicine binding site of tubulin.

New series of 2-amino-1,4,5,6,7,8-hexahydroquinoline-3-carbonitriles 3a,b and 2-amino-5,6,7,8-tetrahydronaphthalene-1,3-dicarbonitriles 4a-h were synthesized and evaluated for their antitumor activity. In vitro antitumor screening of the new members against HepG2, HCT-116 and MCF-7 cancer cells showed that the tetrahydronaphthalene-1,3-dicarbonitrile 4c has the highest potency against the three tested cancer cells (IC50 = 6.02, 8.45 and 6.28 µM, respectively). In addition, 4c displayed low cytotoxicity against WI38 and WISH normal cells (IC50 = 51.78 and 42.36 µM, respectively), and it might be utilized as a potent and selective antitumor agent. Compound 4c was further studied for its effect on tubulin polymerization, different phases of cell cycle, apoptosis and caspases 3/9 levels. Results revealed that analog 4c has good tubulin polymerization inhibitory activity (IC50 = 3.64 µM). Additionally, it induced significant accumulation of the tested cancer cells in G2/M phase, and induced cell death primarily via apoptosis. Besides, it showed evident increase in caspase-3 level in HepG2 and HCT-116 cells, and caspase-9 level in MCF-7 cells. Further, docking studies proved the exact fit of 4c into the colchicine binding site of tubulin.