Quinoline-based Compounds Research Articles

Quinoline-based HIV Integrase Inhibitors

HIV integrase became an important target for drug development more than twenty years ago. However, progress has been hampered by the lack of assays suitable for high throughput screening, a reliable crystal structure or pharmacophore. Thus, a real breakthrough was only observed in 2007 with the introduction of the first integrase inhibitor, raltegravir, into treatment. To date, the armament of integrase inhibitors is broad and covers several drugs from different classes that are under clinical trials. Among them, quinoline-based compounds and analogues occupy an important place. This review is focused on those compounds that have a quinoline scaffold and attempts to answer the question of whether quinoline is privileged for these activities. In fact, quinoline has been claimed as a privileged structure several times for different fields of activities. A closer look at its structural features may reveal the prerequisites responsible for the popularity of quinoline-based inhibitors of HIV integrase.

Synthesis of 2-ferrocenylquinoline derivatives and evaluation of their antimalarial activity

Some quinoline-based compounds bearing a ferrocenyl unit in the 2-position of the heterocyclic system were synthesized from ferrocenyl-o-nitrochalcones through a simple hydrogenation/intramolecular cyclization sequence and fully characterized. The obtained ferrocenyl derivatives were evaluated in vitro as antimalarial agents against chloroquine-susceptible D10 and chloroquine-resistant W2 strains of Plasmodium falciparum and a beneficial effect of the organometallic moiety was evidenced in comparison with the phenyl-substituted analogues. All the ferrocenyl heterocycles inhibited the parasite growth in μM range and the lowest values of IC50 were determined for derivatives containing a dimethylamino group as additional substituent.

New Quinoline-Based Compounds for Analgesic and Anti-Inflammatory Evaluation

In this study, 2-chloroquinolin-3-carbaldehyde 1 was used as a synthon for the synthesis of some new quinoline; pyrane; indeno[1,2-b]pyrano[2,3-b]quinoline heterocycles. The anti-inflammatory and analgesic activities of the synthesized compounds were evaluated using carrageenan-induced paw edema and writhing assays. The obtained data indicated that the majority of the tested compounds exhibited both analgesic and anti-inflammatory activities, particularly compounds 2 and 6 showed a comparable effect to a well known analgesic and anti-inflammatory, diclofenac sodium. Keywords: Quinoline, Pyranes, Knoevenagel reaction, Analgesic, Anti-inflammatory, X-ray analysis, heterocyclic compounds, 2-chloroquinolin-3-carbaldehydes, synthon, benzoylacetonitrile, NMR spectrum, hot plate test, X-Ray Crystallography, water ad libitum, pyrazole residues

Abstract 2785: Modulating the interaction between cdk2 and cyclin A: Screening, synthesis and characterization of a quinoline-based inhibitor

Abstract Cyclin dependent kinase 2 (CDK2) is aberrantly regulated in a wide range of cancers and small molecule inhibitors should be beneficial in the treatment of cancer. Preclinical and clinical CDK2 inhibitors are ATP competitive and bind at the ATP site in a canonical mode. A novel binding mode for a new class of quinoline-based inhibitors of CDK2 has been discovered using the affinity-based Automated Ligand Identification System (ALIS) technology. While the inhibitors do bind to the ATP site the key mechanism of action for inhibition is the induction of a novel protein conformational change that enables the compound to bind into the core of the kinase domain. Global changes to CDK2 upon compound binding result in a conformation that can no longer bind to its activating protein cyclin A. Therefore, these inhibitors are both ATP competitive and are protein-protein interaction disrupters. The key strategy for discovering this class of protein-protein disrupter compounds was to screen the unphosphorylated monomer CDK2 in ALIS and to perform secondary binding and enzyme mechanism of action assays that identified quinoline-based compounds that only bound to the inactive CDK2 monomer and not the active CDK2/cyclin A heterodimer. Through a series of chemical modifications the affinity (Ki) of the original hit improved from 0.9 μM to 0.005 μM. The screening strategy utilized and the discovery of this new kinase inhibitor binding mode may be applicable to other kinase programs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2785. doi:10.1158/1538-7445.AM2011-2785

Quinoline as a Privileged Scaffold in Cancer Drug Discovery

Quinoline (1-azanaphthalene) is a heterocyclic aromatic nitrogen compound characterized by a double-ring structure that contains a benzene ring fused to pyridine at two adjacent carbon atoms. Quinoline compounds are widely used as "parental" compounds to synthesize molecules with medical benefits, especially with anti-malarial and anti-microbial activities. Certain quinoline-based compounds also show effective anticancer activity. This broad spectrum of biological and biochemical activities has been further facilitated by the synthetic versatility of quinoline, which allows the generation of a large number of structurally diverse derivatives. This includes numerous analogues derived from substitution of the quinoline ring system, and derivatization of quinoline ring structure. Quinoline and its analogs have recently been examined for their modes of function in the inhibition of tyrosine kinases, proteasome, tubulin polymerization and DNA repair. In this review, we have summarized our knowledge on quinoline compounds with respect to their anticancer activities, mechanisms of action, structure-activity relationship (SAR), and selective and specific activity against various cancer drug targets. In particular, we focus our review on in vitro and in vivo anticancer activities of quinoline and its analogs in the context of cancer drug development and refinement.

8-Hydroxyquinoline as a building block for artificial receptors: binding preferences in the recognition of glycopyranosides

8-Hydroxyquinoline-based receptors 1-3, containing a trisubstituted triethylbenzene core, were prepared and their binding properties towards glycosides were evaluated. (1)H NMR and fluorescence titrations as well as binding studies in two-phase systems, such as dissolution of solid carbohydrates in apolar media and phase transfer of sugars from aqueous into organic solvents, revealed β- vs.α-anomer binding preferences in the recognition of glycosides. Compared to the previously described three-armed aminopyridine-based receptor, compounds 1 and 2 showed significantly increased affinity to β-galactoside. Receptor 2, incorporating two 8-hydroxyquinoline units, was shown to be the most effective receptor for β-galactoside. Compound 3, bearing one 8-hydroxyquinoline group, was found to be a highly effective receptor for β-glucoside and shown to be a more powerful receptor than the quinoline-based compound 4, indicating an important role of the quinoline hydroxy group in the complex formation.

Quinoline-based compounds as modulators of HIV transcription through NF-κB and Sp1 inhibition

18 quinoline-based compounds were tested for antiviral properties against human immunodeficiency syndrome (HIV). The compounds tested here contain quinoline or tetrahydroquinoline rings and can be divided into two main groups: group 1 includes 4-(2-oxopyrrolidinyl-1)-1,2,3,4-tetrahydroquinolines with 2-(3-nitrophenyl) substituent (N-series) or 2-(3-aminophenyl) moiety (H-series), and group 2 includes 2-(3-nitrophenyl)- or 2-(3-aminophenyl)-substituted quinolines (S-series). Two different antiviral assays were performed in order to test the anti-HIV activity of compounds: 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and recombinant virus assay (RVA). Results showed that the most active compounds were 2-aryl quinolines, particularly those containing methoxy substituents or no substituents in the quinoline skeleton. HIV transcription inhibition appears to be their target in both resting and phorbol myristate acetate (PMA) activated primary lymphocytes, and nuclear factor-κB (NF-κB) and specificity protein-1 (SP1) seems to be the most important transcription factors involved in their action.

Platinum(II) complexes of 8-quinolylmethylphosphonates: Synthesis, characterization and antitumour activity

A series of novel platinum(II) complexes of diethyl (8-dqmp) and monoethyl (8-Hmqmp) ester of 8-quinolylmethylphosphonic acid has been prepared and studied. It was shown that molecular or ionic complexes could be isolated by reaction of these organophosphorus ligands with [PtX 4] 2− (X = Cl, Br), depending on the acidity of the reaction solution. In the neutral medium diester formed dihalide adducts, trans-[Pt(8-dqmp) 2X 2] ( 1 and 2), with N-bonded ligand through the quinoline nitrogen. Under acidic conditions (pH < 3) both ligands gave the quinolinium salt complexes [LH] 2[PtX 4] ( 3 and 4, L = 8-dqmp; 7 and 8, L = 8-Hmqmp), with protonated quinoline ligand as cation and tetrahalidoplatinate complex as anion. By heating in methanol complexes 3 and 4 were converted into the corresponding dimeric hexahalidodiplatinum complexes, [8-Hdqmp] 2[Pt 2X 6] ( 5 and 6). The chelate complex [Pt(8-mqmp) 2] ( 9), with monoester ligand bonded through the quinoline nitrogen and the deprotonated phosphonic acid oxygen and forming two seven-membered {N, O} chelate rings, was obtained in neutral and basic media by reaction of platinum(II) halides either with sodium or hydrochloride salt of this monoester. The complexes were identified and characterized by elemental and thermogravimetric analyses, conductometric measurements, and by spectroscopic studies. In vitro antitumour activity of complexes was evaluated against the human epidermoid KB and murine leukaemia L1210 cell lines. These results were compared with those obtained for the palladium(II) complexes of the same phosphonate ligands and with those of platinum(II) and palladium(II) complexes of diethyl and monoethyl 2-quinolylmethylphosphonate, in order to correlate the structural and biological properties of quinoline-based aminophosphonate compounds.

RETRACTED: A New Class of Quinoline-Based DNA Hypomethylating Agents Reactivates Tumor Suppressor Genes by Blocking DNA Methyltransferase 1 Activity and Inducing Its Degradation

Reactivation of silenced tumor suppressor genes by 5-azacytidine (Vidaza) and its congener 5-aza-2'-deoxycytidine (decitabine) has provided an alternate approach to cancer therapy. We have shown previously that these drugs selectively and rapidly induce degradation of the maintenance DNA methyltransferase (DNMT) 1 by a proteasomal pathway. Because the toxicity of these compounds is largely due to their incorporation into DNA, it is critical to explore novel, nonnucleoside compounds that can effectively reactivate the silenced genes. Here, we report that a quinoline-based compound, designated SGI-1027, inhibits the activity of DNMT1, DNMT3A, and DNMT3B as well M. SssI with comparable IC(50) (6-13 micromol/L) by competing with S-adenosylmethionine in the methylation reaction. Treatment of different cancer cell lines with SGI-1027 resulted in selective degradation of DNMT1 with minimal or no effects on DNMT3A and DNMT3B. At a concentration of 2.5 to 5 micromol/L (similar to that of decitabine), complete degradation of DNMT1 protein was achieved within 24 h without significantly affecting its mRNA level. MG132 blocked SGI-1027-induced depletion of DNMT1, indicating the involvement of proteasomal pathway. Prolonged treatment of RKO cells with SGI-1027 led to demethylation and reexpression of the silenced tumor suppressor genes P16, MLH1, and TIMP3. Further, this compound did not exhibit significant toxicity in a rat hepatoma (H4IIE) cell line. This study provides a novel class of DNA hypomethylating agents that have the potential for use in epigenetic cancer therapy.

Structure−Activity Relationships for a Series of Quinoline-Based Compounds Active against Replicating and Nonreplicating Mycobacterium tuberculosis

Tuberculosis (TB) remains as a global pandemic that is aggravated by a lack of health care, the spread of HIV, and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. New anti-TB drugs are urgently required to shorten the long 6-12 month treatment regimen and to battle drug-resistant Mtb strains. We have identified several potent quinoline-based anti-TB compounds, bearing an isoxazole containing side-chain. The most potent compounds, 7g and 13, exhibited submicromolar activity against the replicating bacteria (R-TB), with minimum inhibitory concentrations (MICs) of 0.77 and 0.95 microM, respectively. In general, these compounds also had micromolar activity against the nonreplicating persistent bacteria (NRP-TB) and did not show toxicity on Vero cells up to 128 microM concentration. Compounds 7g and 13 were shown to retain their anti-TB activity against rifampin, isoniazid, and streptomycin resistant Mtb strains. The results suggest that quinoline-isoxazole-based anti-TB compounds are promising leads for new TB drug development.

Factors Controlling Adsorption Equilibria from Solution onto Solid Surfaces: The Uptake of Cinchona Alkaloids on Platinum Surfaces

The room-temperature adsorption of four closely related cinchona alkaloids and three reference quinoline-based compounds from CCl4 solutions onto a polycrystalline platinum surface was characterized by in situ reflection-absorption infrared spectroscopy (RAIRS). The adsorption equilibrium constants (Kads) were found to follow the sequence cinchonine > quinidine > cinchonidine > quinine > 6-methoxyquinoline > lepidine > quinoline. Some of this ordering can be explained by differences in solubility, but quinidine displays a much larger Kads than expected on the basis of its large relative solubility; bonding to the surface must also play a role in determining its behavior. It was determined that each alkaloid binds differently on Pt at saturation coverages. While the quinoline ring of cinchonidine tilts along its long axis to optimize pi-pi intermolecular interactions, in cinchonine it tilts along the short axis and bonds through the lone electron pair of the nitrogen atom instead, and both quinine and quinidine exhibit additional bonding via the methoxy oxygen atom at intermediate concentrations. Perhaps a more surprising result from this work is the fact that cinchonine displays a higher Kads than cinchonidine, quinine, or quinidine even though, according to previous work, it can be easily displaced from the surface by any of those other cinchona alkaloids. A full explanation of these observations requires consideration of the solvent above the adsorbed species.

Mechanisms of Drug Resistance in Malaria: Current and New Challenges

Anti-malarial chemotherapy based on a limited number of drugs has been the mainstay of malaria control for many decades. However, the lack of new effective and affordable drugs and the emergence and spread of drug resistant parasites is seriously hindering treatment strategies, and is contributing to the resurgence of malaria, especially that caused by Plasmodium falciparum. Present knowledge indicates that drug resistance in malaria emerges through selection of parasites harbouring genetic mutations that confer a selective advantage over sensitive parasites in the presence of drug pressure. Resistance to antifolates such as Fansidar®, (pyrimethamine in combination with sulphadoxine), is known to be caused by mutations in the genes encoding the drugs therapeutic targets, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS). In the case of quinoline-based compounds, such as chloroquine and mefloquine, resistance is thought to be dependent on the exclusion of the drug from the site of action. This has been shown to be mediated by mutations in two genes denoted pfmdr1 and pfcrt, which encode proteins localized on the membrane of the parasitophorous food vacuole where these drugs are thought to act. In recent years, heath authorities have been increasingly recommending the use of Artemisinin Combination Treatment (ACT) in an effort to halt the spread of antimalarial drug resistance. Resistance to artemisinin derivatives has not yet been reported in natural human parasite populations, but it has already been achieved in rodent malaria models suggesting it may arise also in P. falciparum. Major focus should now be aimed at understanding the mechanisms of resistance to artemisinin derivatives before it becomes a serious public health problem. The post-genomic era of malaria has opened unprecedented opportunities for a better understanding of drug resistance mechanisms and consequently, for rational design of novel compounds less prone to resistance. Keywords: Malaria, drug resistance, mechanisms, genomics, proteomics

Aqueous Coordination Chemistry of Quinoline-Based Fluorescence Probes for the Biological Chemistry of Zinc

Metal-specific fluorescence probes are of increasing importance in understanding the neurobiology and general cell biology of zinc. Several quinoline-based compounds such as TSQ and zinquin have been employed to detect zinc in fluorescence microscopy experiments in vivo; however, the aqueous solution chemistry remains equivocal. In some cases, this family of probes is said to reveal labile pools of Zn(II) inside the cell, yet in other cases, these probes are suggested to remove Zn(II) from tightly bound sites in proteins. Since the binding modes, coordination numbers, and thermodynamics of zinc−zinquin interactions in aqueous solution have not been established, these proposals are difficult to distinguish. Here we show that, under physiological conditions, the various forms of zinquin bind Zn(II) with a high degree of cooperativity forming 2:1 complexes. Potentiometric, UV−visible, and fluorescence methods all yield an overall binding constant of log K = 13.5 under physiological conditions. To put this nu...

Substituted quinolines as inhibitors of l-glutamate transport into synaptic vesicles

This study investigated the structure–activity relationships and kinetic properties of a library of kynurenate analogues as inhibitors of 3H- l-glutamate transport into rat forebrain synaptic vesicles. The lack of inhibitory activity observed with the majority of the monocyclic pyridine derivatives suggested that the second aromatic ring of the quinoline-based compounds played a significant role in binding to the transporter. A total of two kynurenate derivatives, xanthurenate and 7-chloro-kynurenate, differing only in the carbocyclic ring substituents, were identified as potent competitive inhibitors, exhibiting K i values of 0.19 and 0.59 mM, respectively. The K m value for l-glutamate was found to be 2.46 mM. Parallel experiments demonstrated that while none of the kynurenate analogues tested effectively inhibited the synaptosomal transport of 3H- d-aspartate, some cross-reactivity was observed with the EAA ionotropic receptors. Molecular modeling studies were carried out with the identified inhibitors and glutamate in an attempt to preliminarily define the pharmacophore of the vesicular transporter. It is hypothesized that the ability of the kynurenate analogues to bind to the transporter may be tied to the capacity of the quinoline carbocyclic ring to mimic the negative charge of the γ-carboxylate of glutamate. A total of two low energy solution conformers of glutamate were identified that exhibited marked functional group overlap with the most potent inhibitor, xanthurenate. These results help to further refine the pharmacological specificity of the glutamate binding site on the vesicular transporter and identify a series of inhibitors with which to investigate transporter function.

Platelet-activating factor synthesis by peritoneal mast cells and its inhibition by two quinoline-based compounds

1. Peritoneal mast cells from rat were co-incubated in vitro in a platelet aggregometer cuvette with washed rabbit platelets. In response to stimulation with calcium ionophore (A23187; 1-5 microM), the mast cells released a substance which stimulated the platelets to aggregate. These concentrations of ionophore did not stimulate platelet aggregation in the absence of mast cells, nor affect the responsiveness of the platelets to aggregation induced by thrombin or PAF. Release of a PAF-like substance was also observed in response to stimulation of the mast cells with antigen. 2. This pro-aggregatory activity is attributable to the release of PAF by the mast cells, since the activity could be abolished by preincubating the platelets with a specific PAF receptor antagonist (WEB 2086; 10 microM). Furthermore, the platelet-aggregating factor co-migrated with PAF on thin-layer chromatographs and could be abolished by incubation with phospholipase A2 (20 micrograms ml-1) or a specific antibody directed against PAF. 3. The release of PAF by peritoneal mast cells could be inhibited, in a concentration-dependent manner, by PF-5901 (IC50 of 3.9 microM) or Wy-50,295 (IC50 of 1.2 microM), two structurally similar compounds with inhibitory effects on leukotriene synthesis, as well as leukotriene D4 (LTD4) receptor antagonist properties. 4. Inhibition of PAF synthesis was not observed when the mast cells were incubated with a structurally unrelated 5-lipoxygenase inhibitor (A-64077), a structurally dissimilar inhibitor of 5-lipoxygenase activating protein (MK-886) or with a structurally related LTD4 receptor antagonist (MK-571) which lacks inhibitory effects on leukotriene synthesis, each at concentrations of up to 100 microM.5. Neither PF-5901 nor Wy-50,295 (1 or 10 microM) significantly affected histamine release or prostaglandin D2 synthesis by peritoneal mast cells in response to calcium ionophore stimulation.6. These results demonstrate the ability of a class of quinoline-based compounds to inhibit PAF synthesis by peritoneal mast cells. This activity does not appear to be related to effects of these compounds on leukotriene synthesis or LTD4 receptors. The ability of these compounds to inhibit PAF synthesis may contribute to their anti-inflammatory properties.