Quinoline Compounds Research Articles

Facilely accessible quinoline derivatives as potent antibacterial agents

Quinoline compounds have been extensively explored as anti-malaria and anti-cancer agents for decades and show profound functional bioactivities, however, the studies of these compounds in other medicinal fields have lagged dramatically. In this study, we report the development of a series of facilely accessible quinoline derivatives that display potent antibacterial activity against a panel of multidrug-resistant Gram-positive bacterial strains, especially C. difficile. We also demonstrated that these molecules are effective in vivo against C. difficile. These results revealed that these types of quinoline compounds could serve as prototypes for the development of an appealing class of antibiotic agents used to combat Gram-positive drug-resistant bacterial strains, including C. difficile.

First Examples of Povarov Reaction of Cyclopentadienones

We describe herein the first examples of Povarov reaction of tetrasubstituted cyclopentadienones in the preparation of quinoline compounds. Polycyclic compounds bearing tetrahydro‐3H‐cyclopenta[c]quinoline and dihydro‐1H‐cyclopenta[c]naphtha[2,3‐h]quinoline moieties have been synthesized by one pot reaction of tetrasubstituted cyclopentadienones with N‐arylamines and formaldehyde in the presence of trifluoroacetic acid. The control of the regioselectivity was total as well with symmetrical and non symmetrical cyclopentadienones. The X‐ray structures of new quinolines were reported.

In vitro 4-Aryloxy-7-chloroquinoline derivatives are effective in mono- and combined therapy against Leishmania donovani and induce mitocondrial membrane potential disruption

The present study evaluates in vitro the effect of two synthetic compounds of the 7-chloro-4-aryloxyquinoline series, QI (C17H12ClNO3) and QII (C18H15ClN4O2S), on Leishmania donovani parasites. The results obtained demonstrate that these compounds are able to inhibit the proliferation of L. donovani promastigotes in a dose-dependent way (QI IC50 = 13.03 ± 3.4 and QII IC50 = 7.90 ± 0.6 μM). Likewise, these compounds significantly reduced the percentage of macrophage infection by amastigotesand the number of amastigotes within macrophage phagolysosomes, the clinical relevant phase of these parasites. Compound QI showed an IC50 value of 0.66 ± 0.2 μM, while for derivative QII, the corresponding IC50 was 1.02 ± 0.17 μM. Interestingly, the amastigotes were more susceptible to the drug treatment when compared to promastigotes. Furthermore, no cytotoxic effect of these compounds was observed on the macrophage cell line at the concentrations tested. The combination of these compounds with miltefosine and amphotericin B on both parasite morphotypes was evaluated. The isobolograms showed a synergistic effect for both combinations; with a Fractional Inhibitory Concentration (FIC) Index lower than 1 for promastigotes and less than 0.3 for intracellular amastigotes. The effect of QI and QII on mitochondrial membrane potential was also studied. The combination of quinolone derivatives compounds with miltefosine and amphotericin B showed 5–8-fold stronger depolarization of membrane mitochondrial potential when compared to drugs alone. The present work validates the combination of drugs as an effective alternative to potentiate the action of anti-Leishmania agents and points to the quinoline compounds studied here as possible leishmanicidal drugs.

Highly Selective Hydrogenation with Ionic Liquid Stabilized Nickel Nanoparticles

Nickel nanoparticles (Ni NPs) were conveniently synthesized from the reduction of nickel(II) salt with NaBH4 or hydrazine in the presence of the ionic liquid 1-butyl-2,3-dimethylimidazolium (S)-2-pyrrolidinecarboxylic acid salt. UV/Vis spectroscopy, thermogravimetric analysis, and X-ray photoelectron spectroscopy were employed to characterize the interaction between the metal and the ionic liquid. The face-centered cubic structure of the Ni NPs(0) was confirmed by X-ray diffraction characterization. Transmission electron microscopy images revealed well-dispersed Ni particles of approximately 5.1 nm in average diameter. The ionic liquid immobilized Ni NPs were employed as highly efficient catalysts in chemoselective hydrogenation of quinoline and relevant compounds, as well as aromatic nitro compounds under mild reaction conditions. The Ni NPs can be efficiently recovered and reused.

Synthesis, anti-inflammatory screening, molecular docking, and COX-1,2/-5-LOX inhibition profile of some novel quinoline derivatives

New quinoline compounds comprising pyrazole scaffold through different amide linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory activity. Eight compounds (5c, 11b,c, 12c, 14a,b, 20a and 21a) were found to exhibit promising anti-inflammatory profiles in acute and sub-acute inflammatory models. They were screened for their ulcerogenic activity and none of them showed significant ulcerogenic activity comparable to the reference drug celecoxib and are well tolerated by experimental animals with high safety margin (ALD50 > 0.3 g/kg). Compounds 5c, 11b,c, 12c, 14a,b, 20a and 21a showed significant in vitro LOX inhibitory activity higher than that of zileuton. In vitro COX-1/COX-2 inhibition study revealed that compounds 12c, 14a,b and 20a showed higher selectivity towards COX-2 than COX-1. Among the tested compounds, 12c, 14a and 14b showed the highest inhibitory activity against COX-2 with an IC50 values of 0.1, 0.11 and 0.11 μM respectively. The docking experiments attempted to postulate the binding mode for the most active compounds in the binding site of COX-2 enzymes and confirmed the high selectivity binding towards COX-2 enzyme over COX-1.

Synthesis and structure-activity relationships of quinolinone and quinoline-based P2X7 receptor antagonists and their anti-sphere formation activities in glioblastoma cells

Screening a compound library of quinolinone derivatives identified compound 11a as a new P2X7 receptor antagonist. To optimize its activity, we assessed structure-activity relationships (SAR) at three different positions, R1, R2 and R3, of the quinolinone scaffold. SAR analysis suggested that a carboxylic acid ethyl ester group at the R1 position, an adamantyl carboxamide group at R2 and a 4-methoxy substitution at the R3 position are the best substituents for the antagonism of P2X7R activity. However, because most of the quinolinone derivatives showed low inhibitory effects in an IL-1β ELISA assay, the core structure was further modified to a quinoline skeleton with chloride or substituted phenyl groups. The optimized antagonists with the quinoline scaffold included 2-chloro-5-adamantyl-quinoline derivative (16c) and 2-(4-hydroxymethylphenyl)-5-adamantyl-quinoline derivative (17k), with IC50 values of 4 and 3 nM, respectively. In contrast to the quinolinone derivatives, the antagonistic effects of the quinoline compounds (16c and 17k) were paralleled by their ability to inhibit the release of the pro-inflammatory cytokine, IL-1β, from LPS/IFN-γ/BzATP-stimulated THP-1 cells (IC50 of 7 and 12 nM, respectively). In addition, potent P2X7R antagonists significantly inhibited the sphere size of TS15-88 glioblastoma cells.

Selective hydrogenation of aromatic compounds using modified iridium nanoparticles

Till now, Ionic liquid‐stabilized metal nanoparticles were investigated as catalytic materials, mostly in the hydrogenation of simple substrates like olefins or arenes. The adjustable hydrogenation products of aromatic compounds, including quinoline and relevant compounds, aromatic nitro compounds, aromatic ketones as well as aromatic aldehydes, are always of special interest, since they provide more choices for additional derivatization. Iridium nanoparticles (Ir NPs) were synthesized by the H2 reduction in imidazolium ionic liquid. TEM indicated that the Ir NPs is worm‐like shape with the diameter around 12.2 nm and IR confirmed the modification of phosphine‐functionalized ionic liquids (PFILs) to the Ir NPs. With the variation of the modifier, solvent and reaction temperature, substrate like quinoline and relevant compounds, aromatic nitro compounds, aromatic ketones as well as aromatic aldehydes could be hydrogenated by Ir NPs with interesting adjustable catalytic activity and chemoselectivity. Ir NPs modified by PFILs are simple and efficient catalysts in challenging chemoselective hydrogenation of quinoline and relevant compounds, aromatic nitro compounds, aromatic ketones as well as aromatic aldehydes. The activity and chemoselectivity of the Ir NPs could be obviously impacted or adjusted by altering the modifier, solvent and reaction temperature.

Catalytic wet oxidation of quinoline over Ru/C catalyst

In the present work, catalytic wet air oxidation of the model nitrogenous organic compound quinoline was studied in a slurry reactor over 5% Ru/C catalyst between 423 and 598 K temperature, 0.34 and 2.07 MPa oxygen (O2) partial pressure, and 0.025 and 0.1 kg m−3 catalyst loading. This catalyst was very effective, thereby suggesting its utility for the oxidative destruction of wastewaters polluted by nitrogenous organic compounds. From analysis of the mass transfer effects, it was found that the investigated reaction belonged to the kinetics-controlled reaction regime. Kinetic data on TOC destruction were fitted to a two-step first-order power law model: the first step was fast, whereas the second step was slow. The values of activation energy for the two steps were 29 and 93 kJ mol−1. Among the hyperbolic models tested, the model with a slow surface reaction between chemisorbed TOC and dissociatively adsorbed O2 was most appropriate. The fate of the nitrogen atom in the feed solution and its conversion to nitrite and nitrate ions, ammonia and nicotinic acid was established. Finally, it was corroborated that the reaction was fast when pyrex liner was used inside the reactor because free radicals were not destroyed by the reactor wall.

The Effects of Quinoline and Non-Quinoline Inhibitors on the Kinetics of Lipid-Mediated β-Hematin Crystallization.

The throughput of a biomimetic lipid-mediated assay used to investigate the effects of inhibitors on the kinetics of β-hematin formation has been optimized through the use of 24-well microplates. The rate constant for β-hematin formation mediated by monopalmitoyl-rac-glycerol was reduced from 0.17 ± 0.04 min-1 previously measured in Falcon tubes to 0.019 ± 0.002 min-1 in the optimized assay. While this necessitated longer incubation times, transferring aliquots from multiple 24-well plates to a single 96-well plate for final absorbance measurements actually improved the overall turnaround time per inhibitor. This assay has been applied to investigate the effects of four clinically relevant antimalarial drugs (chloroquine, amodiaquine, quinidine, and quinine) as well as several short-chain 4-aminoquinoline derivatives and non-quinoline (benzamide) compounds on the kinetics of β-hematin formation. The adsorption strength of these inhibitors to crystalline β-hematin (Kads) was quantified using a theoretical kinetic model that is based on the Avrami equation and the Langmuir isotherm. Statistically significant linear correlations between lipid-mediated β-hematin inhibitory activity and Kads values for quinoline (r2 = 0.76, P-value = 0.0046) and non-quinoline compounds (r2 = 0.99, P-stat = 0.0006), as well as between parasite inhibitory activity (D10) and Kads values for quinoline antimalarial drugs and short-chain chloroquine derivatives (r2 = 0.64, P-value = 0.0098), provide a strong indication that drug action involves adsorption to the surface of β-hematin crystals. Independent support in this regard is provided by experiments that spectrophotometrically monitor the direct adsorption of antimalarial drugs to preformed β-hematin.

Synthesis, structural elucidation, antioxidant, CT-DNA binding and molecular docking studies of novel chloroquinoline derivatives: Promising antioxidant and anti-diabetic agents

The synthesized novel chloroquinoline derivatives 1-(2-chloro-4-phenylquinolin-3-yl)ethanone (CPQE), 1-(2,6-dichloro-4-phenylquinolin-3-yl)ethanone (DCPQE), methyl 2,6-dichloro-4-phenylquinoline-3-carboxylate (MDCPQC),methyl 2-chloro-4-methylquinoline-3-carboxylate (MCMQC) were subjected to the elementary analysis like FT-IR, NMR and Mass spectra using GCMS. Also, single crystal X-ray diffraction study was executed for the compound MDCPQC. The crystal packing is stabilized by C–H…π and π–π interactions and also Chlorine–Chlorine short intermolecular contacts generating a three-dimensional supramolecular network. The antioxidant activity reduces high glucose level in the human body and hence the synthesized compounds were subjected for the estimation of antioxidant activity using DPPH method which exhibited good percentage of inhibition in comparison with ascorbic acid, a well-known anti-oxidant. The binding interaction of the chloroquinoline derivatives with calf thymus DNA (CT-DNA) has been explored by fluorescence quenching studies and molecular docking analysis has been employed to confirm the nature of binding. The prediction of pharmacological properties such as drug-likeness, molecular properties like absorption, distribution, metabolism, excretion and toxicity (ADMET) was carried out by computational studies to compare chloroquinoline derivatives with standard drug. Owing to the various potential biological activities of the quinoline compounds, molecular docking studies were also further carried out for the chloroquinoline derivatives, showing that they may act as effective anti-diabetic agents by inhibiting Glycogen Phosphorylase a protein.

A general three-step one-pot synthesis of novel (E)-6-chloro-2-(aryl/hetarylvinyl)quinoline-3-carboxylic acids.

In this work, a facile and general three-step one-pot synthesis of structurally new (E)-6-chloro-2-(aryl/hetarylvinyl)quinoline-3-carboxylic acid derivatives has been achieved from easily available ethyl 6-chloro-2-(chloromethyl) quinoline-3-carboxylate and aromatic or heteroaromatic aldehydes. This strategy features simple one-pot operation, tolerance of a wide range of substituents, and good yields. Moreover, these newly synthesized compounds belong to a new class of quinoline derivatives and could be good candidates for the development of more complex quinoline compounds for use in medicinal chemistry.

Comparing polyethersulfone and polyurethane-immobilized cells of Comamonas testosteroni QYY in treatment of an accidental dye wastewater

Well-channeled porous polyethersulfone(PES) beads were synthesized and used for the immobilization of Comamonas testosteroni QYY cells for an aerobic reactor to remove quinoline, phenol, and other refractory com-pounds in accidentally-released dye wastewater supplemented with domestic wastewater. The pore size in PES beads mainly depended on the dripping time through the water vapor cylinder. When the cylinder was 2.5 m in length, the pore size in the obtained beads was enlarged to 3 μm, which provided an ideal surface for cells to pass through and grow inside. The reactor with the immobilized C. testosteroni QYY on PES beads resisted organic loading shock and enhanced total organic carbon(TOC) removal, which had 100% removal efficiencies of both quinoline and phenol when the volume ratio of the accidental wastewater to domestic wastewater was increased from 1:2 to 1:1, as compared with the 100% and 34.7% removal efficiencies by the reactor with immobilized C. testosteroni QYY on polyurethane(PU) cube or the 82% and 2.4% removal efficiencies by the reactor with only the suspended C. testosteroni QYY cells, respectively. The PES beads had a specific surface area of 1843 cm2/cm3, which had immobilized (0.024±0.003) g of C. testosteroni QYY cell dry mass/cm3, compared with the specific surface area of 564 cm2/cm3 of the PU cube with (0.018±0.002) g of cell dry mass/cm3. The kinetic study revealed that the quinoline and phenol degradation followed zero-order reactions for all the three reactors. The PES reactor demonstrated the highest quinoline and phenol removal efficiencies. The immobilized C. testosteroni QYY on the low-cost inert PES beads demonstrated good shock resistance and was able to completely remove the toxic compounds, including phenyl carbamate, 2-nitrotoluene, and dioctyl phthalate. Therefore, the beads were ideal for large-scale accidental wastewater treatment.

Heterogeneous catalytic synthesis of quinoline compounds from aniline and C1–C4 alcohols over zeolite-based catalysts

The synthesis of quinolines from aniline and a C1–C4 alcohol was conducted under gas-phase reaction conditions over a series of zeolite-based catalysts.

Comprehensive review on various strategies for antimalarial drug discovery

The resistance of malaria parasites to existing drugs carries on growing and progressively limiting our ability to manage this severe disease and finally lead to a massive global health burden. Till now, malaria control has relied upon the traditional quinoline, antifolate and artemisinin compounds. Very few new antimalarials were developed in the past 50 years. Among recent approaches, identification of novel chemotherapeutic targets, exploration of natural products with medicinal significance, covalent bitherapy having a dual mode of action into a single hybrid molecule and malaria vaccine development are explored heavily. The proper execution of these approaches and proper investment from international agencies will accelerate the discovery of drugs that provide new hope for the control or eventual eradication of this global infectious disease. This review explores various strategies for assessment and development of new antimalarial drugs. Current status and scientific value of previous approaches are systematically reviewed and new approaches provide a pragmatic forecast for future developments are introduced as well.

4-phenylselenyl-7-chloroquinoline, a novel multitarget compound with anxiolytic activity: Contribution of the glutamatergic system

A growing body of evidence demonstrates that quinoline compounds have attracted much attention in the field of drug development. Accordingly, 4-phenylselenyl-7-chloroquinoline (4-PSQ) is a new quinoline derivative containing selenium, which showed a potential antioxidant, antinociceptive and anti-inflammatory effect. The present study was undertaken to evaluate the anxiolytic-like properties of 4-PSQ. Mice were orally pretreated with 4-PSQ (5–50 mg/kg) or vehicle, 30 min prior to the elevated plus-maze (EPM), light–dark (LDT) or open field (OFT) tests. A time-response curve was carried out by administration of 4-PSQ (50 mg/kg) at different times before the EPM test. The involvement of glutamate uptake/release and Na+, K+-ATPase activity in the anxiolytic-like effect was investigated in cerebral cortices. In addition, the effectiveness of acute treatment with 4-PSQ was evaluated in a model of kainate (KA)-induced anxiety-related behavior. Finally, acute toxicity of this compound was investigated. 4-PSQ produced an anxiolytic-like action, both in EPM and LDT. In OFT, 4-PSQ did not affect locomotor and exploratory activities. 4-PSQ anxiolytic-like effect started at 0.5 h and remained significant up to 72 h after administration. Treatment with 4-PSQ reduced [3H] glutamate uptake, but the [3H] glutamate release and Na+, K+-ATPase activity were not altered. KA-induced anxiety-related behavior was protected by 4-PSQ pretreatment. Additionally, 4-PSQ exposure did not alter urea levels, aspartate (AST) and alanine aminotrasferase (ALT) activities in plasma. Parameters of oxidative stress in brain and liver of mice were not modified by 4-PSQ. Taken together these data demonstrated that the anxiolytic-like effect caused by 4-PSQ seems to be mediated by involvement of the glutamatergic system.

Degradation of the Nitrogenous Heterocyclic Compound Quinoline by O3/UV

The influences of various factors including initial concentration of quionline solution, static duration after reaction, initial pH, HCO3-on the degradation of quinoline by O3/UV were analyzed in this study. In addition, the degradation mechanism and pathways were also analyzed. The results showed that reaction rate constants and removal rate of quinoline decreased with the increase of the initial concentration of quinoline. The best degradation efficiency of quinoline was achieved under the alkaline conditions (pH 7-9). Removal rate of quinoline was obviously influenced by HCO3-, and was reduced by 42.01% within 6 min when the concentration of HCO3- was 100 mg·L-1. There was neglected effect of static duration after reaction on the removal rate and mineralization rate of quinolone. The intermediate products of quinoline were mainly 8-hydroxyquinoline, 5-hydroxyquinoline, 2(1H)-quinoline ketone, 2-pyridinecarboxaldehyde and so on. The main degradation pathways of quinoline in the O3/UV system were addition reaction, substitution reaction and electrophilic substitution mediated by O3 and·OH.

Determination of aniline and quinoline compounds in textiles

A simple method for simultaneous determination of twenty-one analytes, belonging to two classes of compounds, aromatic amines and quinolines, is presented. Several of the analytes considered in this study frequently occur in textiles goods on the open market and have been related to allergic contact dermatitis and/or are proven or suspected carcinogens. The method includes an efficient clean-up step using graphitized carbon black (GCB) that simplifies and improves the robustness of the subsequent GC–MS analysis. Briefly, after solvent extraction of the textile sample, the extract is passed through a GCB SPE cartridge that selectively retain dyes and other interfering compounds present in the matrix, producing a clean extract, suitable for GC–MS analysis, is obtained.The method was evaluated by spiking blank textiles with the selected analytes. Method quantification limits (MQL) ranged from 5 to 720ng/g depending on the analyte. The linear range of the calibration curves ranged over two order magnitude with coefficients of determination (R2) higher than 0.99. Recoveries ranged from 70 to 92% with RSDs 1.7–14%. The effectiveness of the method was tested on a variety of textile materials samples from different origin.In a pilot explorative survey, 2,6-dichloro-4-nitroaniline was detected in all the analysed clothing samples in concentrations ranging from 1.0 to 576μg/g. 2,4-dinitroaniline was detected in four of the seven samples with a highest concentration of 305μg/g. Quinoline was detected in all samples in concentrations ranging from 0.06 to 6.2μg/g.

Cobalt Encapsulated in N-Doped Graphene Layers: An Efficient and Stable Catalyst for Hydrogenation of Quinoline Compounds

Porous nitrogen-doped graphene layers encapsulating cobalt nanoparticles (NPs) were prepared by the direct pyrolysis process. The resulting hybrids catalyze the hydrogenation of diverse quinoline compounds to access the corresponding tetrahydro derivatives (THQs), important molecules present in fine and bulk chemicals. Near-quantitative yields of the corresponding THQs were obtained under optimized conditions. Notably, various useful substituted quinolines and other biologically important N-heteroarenes are also viable. The enhanced stability of the catalyst is ascribed to the encapsulation structure, which can enormously reduce the extent of leaching of base metals and protect metal NPs from growing larger. The achieved success in the encapsulation of metal NPs within graphene layers opens an avenue for the design of highly active and reusable heterogeneous catalysts for more challenging molecules.

Enhancing quinoline and phenol removal by adding Comamonas testosteroni bdq06 in treatment of an accidental dye wastewater

Accidentally released dye wastewater, which contained high concentrations of quinoline, phenol and other phenolics, was successfully treated by adding Comamonas testosteroni bdq06 and supplementing with domestic wastewater. Higher efficiency of 85.1% TOC removal was achieved by the bioaugmentation comparing to the control and no significant shock was observed from increasing the organic loadings. For the control, the removal of TOC was 11.1% less and the recovery of the shock was about 12 days. The addition of C. testosteroni bdq06 enhanced complete degradation of quinoline, phenol and other refractory compounds in the wastewater. DGGE result demonstrated that the inoculated C. testosteroni bdq06 adapted and proliferated in the process and predominated in quinoline degradation. Adding C. testosteroni bdq06 was shown to be an effective method for the treatment of wastewater containing quinoline, phenol and other refractory compounds.

Utilizing Solubility Differences to Achieve Regiocontrol in the Synthesis of Substituted Quinoline-4-carboxylic Acids

A practical method for the regiocontrolled synthesis of substituted quinoline-4-carboxylic acids is described. Solubility differences between the product quinoline regioisomers enable their facile separation, thus avoiding any challenging chromatographic purifications and allowing access to highly substituted quinoline compounds in three steps from commercially available anilines.