Quinoline Ring Research Articles

Recent Developments of Quinoline Derivatives and their Potential Biological Activities

Heterocyclic compounds containing the quinoline ring play a significant role in organic synthesis and therapeutic chemistry. Polyfunctionalized quinolines have attracted the attention of many research groups, especially those who work on drug discovery and development. These derivatives have been widely explored by the research biochemists and are reported to possess wide biological activities. This review focuses on the recent progress in the synthesis of heterocyclic compounds based-quinoline and their potential biological activities.

Sterically Demanding 8-(Diphenylphosphino)quinoline Complexes of Group 10 Metal(II): Synthesis, Crystal Structures, and Properties in Solution.

Several series of platinum(II), palladium(II), and nickel(II) complexes bearing 8-(diphenylphosphino)quinoline (PQH) or its 2-methyl or 2-phenyl derivatives (PQMe or PQPh) were synthesized, and their crystal structures and behaviors in solution were investigated. Most of the complexes [M(PQR)2]X2 (MII = PtII, PdII, or NiII; R = H, Me or Ph; X = monoanionic ions) characterized in this study have an approximately square-planar coordination geometry with two bidentate P,N-chelating or monodentate P-donating quinolylphosphine ligands in the cis(P,P) configuration. A large steric requirement from the Me or Ph substituent introduced at the 2-position of the quinoline ring gives the resulting complexes severe distortion. The PtII and PdII complex cations maintained the square-planar coordination geometry, but the MII center was displaced from the chelating ligand plane. This bending of the chelate coordination makes the M-N(quinoline) bond weaker, as demonstrated by the longer M-N bonds. In accord with the bond weakening, the partial dissociation of the PQH or PQMe chelates by substitution with halide anions were observed using UV-vis spectroscopy and X-ray crystallography. In contrast, the PQPh complexes were stable in solution toward the addition of halide anions; the intramolecular π-π stacking interaction between the coordinating quinolyl and the 2-substituted phenyl rings protects the MII center from nucleophilic attack. In the corresponding NiII complexes, the steric congestion arising from the mutually cis-positioned PQR ligands resulted in a large tetrahedral distortion around the NiII center. However, the intramolecular π-π stacking interaction was still effective in the PQPh complex, and this interaction can explain some unusual robustness and electrochemical properties of the NiII-PQPh complex.

Synthesis, Crystal Structures, Fluorescence and Quantum Chemical Investigations of some Multi-Substituted Quinoline Derivatives.

Starting from eugenol (4-allyl-2-methoxyphenol) three new quinoline derivatives, namely 5-bromo-7-(carboxymethoxy)-6-hydroxy-1-methylquinolin-1-ium-3-sulfonate (Q2, C12H10BrNO7S), 5-amino-7-(carboxymethoxy)-6-hydroxyquinolin-1-ium-3-sulfonate (Q4, C11H10N2O7S) and 7-(carboxymethoxy)-5,6-dihydroxylquinolin-1-ium-3-sulfonate (Q6, C11H9NO8), have been synthesized and crystallised as dihydrate. The best planes through the quinoline ring and the carboxymethoxy substituent is 6.60 (14), 7.28 (6) and 4.73 (7)° for Q2, Q4 and Q6, respectively. The crystal packing of Q2 is characterised by O-H…O, π …π and Br …pyridine interactions. The two water molecules bridge three sulphate groups. Infinite chains of Q4 running in the direction [021] are formed by O/N-H …O hydrogen bonds at both ends of the molecule. Parallel chains interact by O/N-H…O hydrogen bonds and π…π and C=O…phenyl stacking. The -NH2 substituent bridges two sulphate groups, while the two water molecules bridge the other functional groups. The packing of Q6 consists of sheets of molecules interaction through O/N-H…O hydrogen bonds while the two water molecules bridge all function groups present. Parallel sheets interact through π…π and C=O…pyridine stacking. An aqueous solution of Q2 and its precursor 7-(carboxymethoxy)-6-hydroxyquinolin-1-ium-3-sulfonate (Q) exhibits fluorescence which is pH dependent. The fluorescence intensity of a 10μM solution of Q containing Zn2+ reaches its maximum for a [Zn2+]:[Q] ratio of 1:1. The fluorescence properties of Q, Q2, Q4 and Q6 were further investigated by DFT calculation methods.

Crystal structures of four isomeric hydrogen-bonded co-crystals of 6-methyl-quinoline with 2-chloro-4-nitro-benzoic acid, 2-chloro-5-nitro-benzoic acid, 3-chloro-2-nitro-benzoic acid and 4-chloro-2-nitro-benzoic acid.

The structures of the four isomeric compounds of 6-methyl-quinoline with chloro- and nitro-substituted benzoic acids, C7H4ClNO4·C10H9N, namely, 2-chloro-4-nitro-benzoic acid-6-methyl-quinoline (1/1), (I), 2-chloro-5-nitro-benzoic acid-6-methyl-quinoline (1/1), (II), 3-chloro-2-nitro-benzoic acid-6-methyl-quinoline (1/1), (III), and 4-chloro-2-nitro-benzoic acid-6-methyl-quinoline (1/1), (IV), have been determined at 185-190 K. In each compound, the acid and base mol-ecules are linked by a short hydrogen bond between a carboxyl O atom and an N atom of the base. The O⋯N distances are 2.5452 (12), 2.6569 (13), 2.5640 (17) and 2.514 (2) Å, respectively, for compounds (I)-(IV). In the hydrogen-bonded acid-base units of (I), (III) and (IV), the H atoms are each disordered over two positions with O site:N site occupancies of 0.65 (3):0.35 (3), 0.59 (4):0.41 (4) and 0.48 (5):0.52 (5), respectively, for (I), (III) and (IV). The H atom in the hydrogen-bonded unit of (II) is located at the O-atom site. In all of the crystals of (I)-(IV), π-π inter-actions between the quinoline ring system and the benzene ring of the acid mol-ecule are observed. In addition, a π-π inter-action between the benzene rings of adjacent acid mol-ecules and a C-H⋯O hydrogen bond are observed in the crystal of (I), and C-H⋯O hydrogen bonds and O⋯Cl contacts occur in the crystals of (III) and (IV). These inter-molecular inter-actions connect the acid and base mol-ecules, forming a layer structure parallel to the bc plane in (I), a column along the a-axis direction in (II), a layer parallel to the ab plane in (III) and a three-dimensional network in (IV). Hirshfeld surfaces for the title compounds mapped over d norm and shape index were generated to visualize the weak inter-molecular inter-actions.

A Quick Responsive Chitosan‐Oxine Based Thin Film to Recognize and Remove Zn2+ Ions from Potable Water

AbstractThrough the functionalization of chitosan (CS) with an oxine derivative, 8‐hydroxy‐2‐methyl‐quinoline5,7‐ sulfonyl chloride (HQSC), a thin film was prepared (CS‐HQSC). The film can recognize and adsorb Zn2+ ions from the aqueous samples. The sensor performances were characterized by UV‐Visible and fluorescence spectroscopic analysis. The weakly fluorescent thin film becomes highly fluorescent in the presence of Zn2+ ions. The solution‐phase study of the functionalized material shows a 30‐fold fluorescence enhancement in the presence of Zn2+ ions. The chelation of Zn2+ ions with CS‐HQSC could be the reason for the fluorescence enhancement. The chelation restricts the excited‐state proton transfer in the quinoline ring and facilitates chelation enhanced fluorescence. The sensor showed a linear detection of Zn2+ ions from 0.2 to 2 ppm, with the lowest detection limit of 0.08 ppm. The practical applicability studies of the sensor prove that the sensor film is quick responsive (30 seconds) and recyclable in acid solution. Also, the functionalized material CS‐HQSC shows 96 % removal of Zn2+ ions from the water samples.

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways.

The quinoline ring system has long been known as a versatile nucleus in the design and synthesis of biologically active compounds. Currently, more than one hundred quinoline compounds have been approved in therapy as antimicrobial, local anaesthetic, antipsychotic, and anticancer drugs. In drug discovery, indeed, over the last few years, an increase in the publication of papers and patents about quinoline derivatives possessing antiproliferative properties has been observed. This trend can be justified by the versatility and accessibility of the quinoline scaffold, from which new derivatives can be easily designed and synthesized. Within the numerous quinoline small molecules developed as antiproliferative drugs, this review is focused on compounds effective on c-Met, VEGF (vascular endothelial growth factor), and EGF (epidermal growth factor) receptors, pivotal targets for the activation of important carcinogenic pathways (Ras/Raf/MEK and PI3K/AkT/mTOR). These signalling cascades are closely connected and regulate the survival processes in the cell, such as proliferation, apoptosis, differentiation, and angiogenesis. The antiproliferative biological data of remarkable quinoline compounds have been analysed, confirming the pivotal importance of this ring system in the efficacy of several approved drugs. Furthermore, in view of an SAR (structure-activity relationship) study, the most recurrent ligand–protein interactions of the reviewed molecules are summarized.

Tailored Quinolines Demonstrate Flexibility to Exert Antitumor Effects through Varied Mechanisms-A Medicinal Perspective.

Quinoline is considered to be a privileged heterocyclic ring owing to its presence in diverse scaffolds endowed with promising activity profiles. In particular, quinoline containing compounds have exhibited substantial antiproliferative effects through the diverse mechanism of actions, which indicates that the heteroaryl unit is flexible as well as accessible to subtle structural changes that enable its inclusion in chemically distinct anti-tumor constructs. Herein, we describe a medicinal chemistry perspective on quinolines as anticancer agents by digging into the peer-reviewed literature as well as patents published in the past few years. This review will serve as a guiding tool for medicinal chemists and chemical biologists to gain insights about the benefits of quinoline ring installation to tune the chemical architectures for inducing potent anticancer effects. Quinoline ring containing anticancer agents presents enough optimism and promise in the field of drug discovery to motivate the researchers towards the continued explorations on such scaffolds. It is highly likely that adequate efforts in this direction might yield some potential cancer therapeutics in the future.

Targeting the aryl hydrocarbon receptor with a novel set of triarylmethanes

The aryl hydrocarbon receptor (AhR) is a chemical sensor upregulating the transcription of responsive genes associated with endocrine homeostasis, oxidative balance and diverse metabolic, immunological and inflammatory processes, which have raised the pharmacological interest on its modulation. Herein, a novel set of 32 unsymmetrical triarylmethane (TAM) class of structures has been synthesized, characterized and their AhR transcriptional activity evaluated using a cell-based assay. Eight of the assayed TAM compounds (14, 15, 18, 19, 21, 22, 25, 28) exhibited AhR agonism but none of them showed antagonist effects. TAMs bearing benzotrifluoride, naphthol or heteroaromatic (indole, quinoline or thiophene) rings seem to be prone to AhR activation unlike phenyl substituted or benzotriazole derivatives. A molecular docking analysis with the AhR ligand binding domain (LBD) showed similarities in the binding mode and in the interactions of the most potent TAM identified 4-(pyridin-2-yl (thiophen-2-yl)methyl)phenol (22) compared to the endogenous AhR agonist 5,11-dihydroindolo[3,2-b]carbazole-12-carbaldehyde (FICZ). Finally, in silico predictions of physicochemical and biopharmaceutical properties for the most potent agonistic compounds were performed and these exhibited acceptable druglikeness and good ADME profiles. To our knowledge, this is the first study assessing the AhR modulatory effects of unsymmetrical TAM class of compounds.

In silico toxicity evaluation of Salubrinal and its analogues

This paper reports on a comprehensive in silico toxicity assessment of Salubrinal and its analogues containing a cinnamic acid residue or quinoline ring using the online servers admetSAR, ADMETlab, ProTox, ADVERPred, Pred-hERG and Vienna LiverTox. Apart from rare exceptions, in all 55 studied structures, mild or practical absence of acute toxicity was predicted for rats (III or IV toxicity class). Cardiotoxic, hepatotoxic and immunotoxic effects were predicted for Salubrinal and its analogues. We constructed models of the main predicted anti-targets hERG, BSEP, MRP3, MRP4 and AhR using the principle of homologous modeling. Molecular docking studies were carried out with the obtained models. We carried out molecular docking for all targets using AutoDock Vina, implemented in the PyRx 0.8 software package. According to the results of molecular docking, the compounds analyzed are potential moderate or weak hERG blockers. Induction of cholestasis and, as a consequence, liver damage by these drugs, directly related to inhibition of BSEP, MRP3 and MRP4, most likely will not be observed. Interaction with AhR for the studied compounds is impossible for steric reasons and, as a consequence, toxic effects on the immune and other organ systems associated with the activation of the AhR signaling pathway are excluded.

Synthesis of BI 201420

Key words BI 201420 - HCV NS3/4a protease inhibitor - 4-methylsulfonyl quinolines - quinoline ring formation - SNAr reaction

Effect of Methyl-substitution of the Quinoline Ring of Cinchona Alkaloids on the Performance as a Modifier for the Enantioselective Hydrogenation of (E)-2,3-di(4-methoxyphenyl)propenoic Acid Over Pd/C: Kinetic Analysis

The asymmetric hydrogenation of (E)-2,3-di(4-methoxyphenyl)propenoic acid was conducted over Pd/C chirally modified with cinchona alkaloids methyl-substituted at 2′-position of the quinoline ring. It is revealed that the adsorption strength of the modifiers and the intrinsic enantioselectivity at the modified sites are decreased by the methyl-substitution. The intrinsic enantioselectivity of the modifier is correlated to kinetic parameters.

Aromatic nucleophilic substitution: A case study of the interaction of a lithiated nitronyl nitroxide with polyfluorinated quinoline-N-oxides

A 4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazole-3-oxide-1-oxyl lithium derivative was found to react with 5,6,7,8-tetrafluoro- or 5,7,8-trifluoro-6-(trifluoromethyl)quinoline-N-oxides with the formation of products of aromatic nucleophilic substitution of the H atom at position 2 of the quinoline ring. The reaction regioselectivity is supported by the data of quantum-chemical calculations. Molecular and crystal structures of the obtained nitronyl nitroxides were solved by monocrystal X-ray diffraction analysis, and the nature of the radical was ascertained by electron spin resonance spectroscopy. Heterospin complexes of Cu(hfac)2 with the synthesized quinoline-substituted nitronyl nitroxides were prepared. According to X-ray diffraction analysis, seven-membered metallocycles are formed in the complexes owing to simultaneous coordination of the nitroxyl and N-oxide groups by the Cu atom.

Crystal structure of 7,7'-[(pyridin-2-yl)methyl-ene]bis-(5-chloro-quinolin-8-ol).

In the title compound, C24H15Cl2N3O2, one quinoline ring system is essentially planar and the other is slightly bent. An intra-molecular O-H⋯N hydrogen bond involving the hy-droxy group and a pyridine N atom forms an S(5) ring motif. In the crystal, two mol-ecules are associated into an inversion dimer with two R 2 2(7) ring motifs through inter-molecular O-H⋯N and O-H⋯O hydrogen bonds. The dimers are further linked by an inter-molecular C-H⋯O hydrogen bond and four C-H⋯π inter-actions, forming a two-dimensional network parallel to (001).

Pharmaceutical salt of tetrahydroberberine with sulfamic acid prepared via CAHBs

In order to further explore the role of Charge-assisted hydrogen bonds (CAHBs) recognition in the formation of tetrahydroberberine (THB) pharmaceutical salt/cocrystal, based on the analysis of the molecular interactions in forming unit pharmaceutical salts/cocrystal of THB and sulfophenyl acids, we speculate that hydroxyl group of sulfamic acid (SA) may cocrystallize with N atom on the quinoline ring of THB via CAHBs. Consequently, an unreported pharmaceutical salt (C20H22NO4·NH2SO3, THB-SA) of the THB was designed and synthesized. The THB-SA was characterized by single crystal X-ray diffraction, XRPD and TG methods. As expected, structure analysis of the THB-SA revealed that the THB molecule binds to the SA molecule precisely through CAHBs (N+-H···O−) between the N atom on the quinoline ring and sulfonic acid group of SA in asymmetric unit of THB-SA. This successfully implemented work implies that in the preparation of THB pharmaceutical salts/cocrystals, cocrystal formers (CCFs) that can form CAHBs with THB should be selected, which will provide a facilitate way to prepare THB pharmaceutical salts/cocrystals.

Synthesis and Antimicrobial Activities of Novel Rutin Derivatives Carrying Quinoline Moiety

Antimicrobial resistance constitutes a topical subject and it is one of the major threats to public health. According to statistics, the incidence of multidrug-resistant microorganisms, such as bacteria, fungi and protozoa has increased in the last decades and it continues to spread. Therefore, the development of novel antimicrobial agents to combat drug-resistant infections is very important, among other research directions in this field. Quinoline ring is a very interesting structure for researchers because of its diverse biological properties (antimicrobial, anticancer, anticonvulsant, antiinflamatory and cardiovascular). On the other hand several studies showed good antibacterial activity (including anti-Pseudomonas effects) and antifungal properties of rutin or vegetal species with a high flavonoids (especially rutin) concentration. Based on the above considerations, eight novel rutin derivatives carrying 4- and 8-aminoquinoline moiety were designed, synthesized and characterized by FTIR, 1H NMR and elemental analysis. All compounds were evaluated for their in vitro antimicrobial activities against representative Gram-positive, Gram-negative and fungal pathogens. The results indicated that all rutin derivatives exhibited good antibacterial activities, similar to ciprofloxacin.

DNA Photocleavage in the Near-Infrared Wavelength Range by 2-Quinolinium Dicarbocyanine Dyes.

Here, we report the syntheses of two pentamethine cyanine dyes containing quinolinium rings and substituted with either hydrogen (3) or bromine (4) at the meso carbon. The electron withdrawing bromine atom stabilizes dye 4 in aqueous buffer, allowing complex formation to occur between the dye and double-helical DNA. UV–visible, CD, and fluorescence spectra recorded at low DNA concentrations suggest that dye 4 initially binds to the DNA as a high-order aggregate. As the ratio of DNA to dye is increased, the aggregate is converted to monomeric and other low-order dye forms that interact with DNA in a non-intercalative fashion. The brominated dye 4 is relatively unreactive in the dark, but, under 707–759 nm illumination, generates hydroxyl radicals that cleave DNA in high yield (pH 7.0, 22 °C). Dye 4 is also taken up by ES2 ovarian carcinoma cells, where it is non-toxic under dark conditions. Upon irradiation of the ES2 cells at 694 nm, the brominated cyanine reduces cell viability from 100 ± 10% to 14 ± 1%. Our results suggest that 2-quinolinium-based carbocyanine dyes equipped with stabilizing electron withdrawing groups may have the potential to serve as sensitizing agents in long-wavelength phototherapeutic applications.

Effect of relative position of donor and acceptor groups on linear and non-linear optical properties of quinoline system

Quinoline ring although extensively used in designing materials with non-linear optical (NLO) properties, the study of the effect of relative position of various electron-donor and electron-acceptor groups on these properties is still missing. Herein, we present a theoretical analysis of variation of various properties such as polarizability (α), static-hyperpolarizability (β), and one-, two-, and three-photon absorption processes with the relative positions of donor and acceptor groups in substituted quinoline ring using time-dependent density functional response theory. The observed variations in two- and three-photon transition strengths have also been analysed using few-state models.

Luminescent properties of chameleon-like metal-organic framework between zinc(II) dichloride and two quinoline-N-oxide molecules.

Zinc compounds in the form of inorganic/organic hybrids containing both zinc halides and heterocyclic ligands show various interesting optical and physicochemical properties. Due to these properties, there is a potential for development of various innovative technologies and applications within the life sciences. In this study, experimental and theoretical results on the absorption and emission (steady state and time-resolved) properties of the hybrid ZnCl2(QO)2 complex formed between ZnCl2 and quinoline N-oxide, have been reported. Single crystal X-ray analysis revealed the tetragonal cell (Z=4) with P41212 space group and a slight crystal distortion. Interestingly, experiments in aprotic solvents show that both absorption and emission spectra peak in the ultraviolet (UV) region suggesting a weak CT character of the emissive S1 state, confirmed by a middle Stokes shift values. The results of the nanosecond time-resolved emission spectroscopy suggest two different structures of the complex described by the two different lifetimes and variable amplitudes dependent on the polarity of the medium. In the solid state, a relatively strong, bright blue luminescence appears at 413nm (τ=2.26ns). Theoretical calculations (DFT and TD DFT) confirm experimental studies and reveal the solvent-dependent chameleon properties of ZnCl2(QO)2 by two different structures in two solvents of a contrast polarity. In apolar cyclohexane (CHX, μ=5.612 D), the planes of both lateral quinoline N-oxide (QO) rings show to be nearly parallel each to another, resembling the crystal structure, while in a strongly polar acetonitrile (AN, μ=9.328 D) they are nearly perpendicular. Such parallel arrangement of quinoline rings of ZnCl2(QO)2 complex in weakly polar methylcyclohexane can hinder the process of Photoinduced Electron Transfer, resulting in a stronger emission and significant quantum yield in comparison to more polar media.

Construction of Helically Stacked π‐Electron Systems in Poly(quinolylene‐2,3‐methylene) Stabilized by Intramolecular Hydrogen Bonds

Abstractπ‐Stacked polymers, which consist of layered π‐electron systems in a polymer, can be expected to be used in molecular electronic devices. However, the construction of a stable π‐stacked structure in a polymer is considerably challenging because it requires sophisticated designs and precise synthetic methods. Herein, we present a novel π‐stacked architecture based on poly(quinolylene‐2,3‐methylene) bearing alanine derivatives as the side chain, obtained through the living cyclo‐copolymerization of an o‐allenylaryl isocyanide. In the resulting polymer, the neighboring quinoline rings of the main chain form a layered structure with π–π interactions, which is stabilized by intramolecular hydrogen bonds. The vicinal quinoline units form two independent helices and the whole molecule is a twisted‐tape structure. This structure is established on the basis of UV/CD spectra, theoretical calculations, and atomic‐force microscopy.

Construction of Helically Stacked π-Electron Systems in Poly(quinolylene-2,3-methylene) Stabilized by Intramolecular Hydrogen Bonds.

π-Stacked polymers, which consist of layered π-electron systems in a polymer, can be expected to be used in molecular electronic devices. However, the construction of a stable π-stacked structure in a polymer is considerably challenging because it requires sophisticated designs and precise synthetic methods. Herein, we present a novel π-stacked architecture based on poly(quinolylene-2,3-methylene) bearing alanine derivatives as the side chain, obtained through the living cyclo-copolymerization of an o-allenylaryl isocyanide. In the resulting polymer, the neighboring quinoline rings of the main chain form a layered structure with π-π interactions, which is stabilized by intramolecular hydrogen bonds. The vicinal quinoline units form two independent helices and the whole molecule is a twisted-tape structure. This structure is established on the basis of UV/CD spectra, theoretical calculations, and atomic-force microscopy.