Structural Requirements for Mutagenic Activities of N-Heterocyclic Bases in the Salmonella Test System

The mutagenic activities of quinoline, isoquinoline, phenanthridine, benzo(f)quinoline, benzo(h)quinoline and their α-amino derivatives were compared in relation to the effect of structural changes using the Salmonella typhimurium test system. All mutagenic compounds tested require the liver microsomal fraction for their mutagenic activity. Phenanthridine, two benzoquinolines and quinoline were mutagenic. α-Amination of two benzoquinolines and quinoline resulted to increase their mutagenic activity intensively. Addition of a benzene ring to the benzene moiety of 2-aminoquinoline, so that two carbon atoms are shared, affected distinctly the increase in the mutagenic activity. The co-existence of benzoquinoline series with 2-aminobenzo(f)quinoline showed the clear synergistic action.     

Investigating the antiproliferative activity of quinoline-5,8-diones and styrylquinolinecarboxylic acids on tumor cell lines

The structure-activity relationships of new quinoline based compounds were investigated. Quinoline-5,8-dione and styrylquinoline scaffolds were used for the design of potentially active compounds. The novel analogues had comparable antiproliferative activity to cisplatin when evaluated in a bioassay against the P388 leukemia cell line. However, these compounds appeared far less efficient against SK-N-MC neuroepithelioma cells. Analogues without the 5,8-dione structure but containing the 8-carboxylic acid group were also found to induce antiproliferative activity. Hydrophobicity as measured by HPLC did not correlate with antiproliferative activity.     

Recent advances in the fight against leishmaniasis with natural products

The active compounds obtained from some medicinal plants used traditionally worldwide for the treatment of leishmaniasis are reviewed. Among these active molecules, described in recent literature are quinoline alkaloids such as alkyl-2 quinoline and aryl-2 quinoline from Galipea longiflora, isoquinoline alkaloids such as isoguattouregidine from Guatteria foliosa, indole alkaloids such as conodurine and gabunine from Pescheiera van heurkii, terpenes such as jatrogrossidione from Jatropha grossidentata, acetogenins such as senegalene from Annona senegalensis and lignans such as (+)nyasol from Asparagus africanus. Other natural compounds with antileishmanial activity are coumarins, chalcones, lactones, tetralones and saponins. Some of them are known antiprotozoal natural products. These compounds could be used as templates to discover new and effective drugs against leishmaniasis.     

Comparison of the mutagenicity of quinoline and all monohydroxyquinolines with a series of arene oxide, trans-dihydrodiol, diol epoxide, N-oxide and arene hydrate derivatives of quinoline in the Ames/Salmonella microsome test.

Fourteen new quinoline derivatives were synthesised and their mutagenicity compared in the Ames test using Salmonella typhimurium TA100 as indicator strain with and without (Aroclor-induced) S9 mix. None of the synthesised quinoline derivatives had to our knowledge been examined before in the Ames test. Quinoline and the monohydroxyquinolines were included as reference compounds. Three of the new derivatives, i.e., quinoline 7,8-oxide, N-methyl-quinoline 5,6-oxide and trans-quinoline-5,6,7,8-dioxide appeared to be mutagenic. Quinoline 7,8-oxide was positive only in the presence of S9 mix, the specific mutagenicity amounting to 2498 +/- 96 and 1289 +/- 120 revertants per mumole with 20 and 10% S9 in the mix, respectively. Both N-methyl-quinoline 5,6-oxide and trans-quinoline-5,6,7,8-dioxide were weakly positive, the former only in the presence of the S9 mix, and the latter irrespective of the presence of S9 mix, the specific mutagenicity amounting to 134 +/- 6 and 123 +/- 10 revertants per mumole, respectively. The mutagenic potency of quinoline 7,8-oxide was of the same order as that of quinoline itself and was distinctly lower than that of 8-hydroxyquinoline. Inconclusive results were obtained with trans-7,8-dihydroxy-7,8-dihydroquinoline, 5,6-dihydroxy-7,8-epoxy-5,6,7,8-tetrahydroquinoline and 8-hydroxyquinoline-N-oxide; if these compounds are mutagenic their mutagenic potency would be at least 20-30 times lower than that of the parent compounds. None of the other chemically synthesised quinoline derivatives showed mutagenic activity with TA100 either in the presence or in the absence of S9 mix. The results obtained with the reference compounds were in accordance with literature data.     

Identification of 4-hydroxyquinolines inhibitors of p300/CBP histone acetyltransferases

We identified a series of 4-hydroxyquinolines bearing a C1 to C15 alkyl chain at the C2 position and a carbethoxy/carboxy group at the C3 position of the quinoline nucleus (MC compounds), endowed with selective inhibitory activity against the p300/CBP HAT enzymes. Enzyme inhibition was investigated using in vitro HAT assays and by western blot analysis of cellular lysates to examine the acetylation levels of histone H3 and α-tubulin. When tested in U937 cells, some compounds displayed pro-apoptotic or cytodifferentiating properties.     

Investigating biological activity spectrum for novel quinoline analogues 2: hydroxyquinolinecarboxamides with photosynthesis-inhibiting activity

Two series of amides based on quinoline scaffold were designed and synthesized in search of photosynthesis inhibitors. The compounds were tested for their photosynthesis-inhibiting activity against Spinacia oleracea L. and Chlorella vulgaris Beij. The compounds lipophilicity was determined by the RP-HPLC method. Several compounds showed biological activity similar or even higher than that of the standard (DCMU). The structure-activity relationships are discussed.     

Quinoline and quninaldine as naturally occurring inhibitors specific for type A monoamine oxidase

Type A monoamine oxidase (MAO-A) in human placental mitochondria was competitively inhibited by naturally occurring substances, quinoline and quinaldine, using kynuramine as substrate. Quinoline had a higher affinity for MAO than kynuramine. MAO-A in human brain synaptosomal mitochondria was also competitively inhibited by quinoline, while type B MAO (MAO-B) was reversibly and non-competitively inhibited by quinoline. Quinoline inhibited MAO-A much more potently than MAO-B. Of several compounds structurally similar to quinoline, isoquinoline noncompetitively inhibited MAO-A and -B activity.     

Synthesis of 2-,4,-6-, and/or 7-substituted quinoline derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors and anticancer agents: 3D QSAR-assisted design

Following our research for human dihydroorotate dehydrogenase (hDHODH) inhibitors as anticancer agents, herein we describe 3D QSAR-based design, synthesis and in vitro screening of 2-,4,-6-, and/or 7-substituted quinoline derivatives as hDHODH inhibitors and anticancer agents. We have designed 2-,4,-6-, and/or 7-substituted quinoline derivatives and predicted their hDHODH inhibitory activity based on 3D QSAR study on 45 substituted quinoline derivatives as hDHODH inhibitors, and also predicted toxicity. Designed compounds were docked into the binding site of hDHODH. Designed compounds which showed good predictive activity, no toxicity, and good docking score were selected for the synthesis, and in vitro screening as hDHODH inhibitors in an enzyme inhibition assay, and anticancer agents in MTT assay against cancer cell lines (HT-29 and MDA-MB-231). Synthesized compounds 7 and 14 demonstrated IC₅₀ value of 1.56?µM and 1.22?µM, against hDHODH, respectively, and these are our lead compounds for the development of new hDHODH inhibitors and anticancer agents.     

Quinoline Hydrazone Derivatives as New Antibacterials against Multidrug Resistant Strains

To develop novel antimicrobial agents a series of 2(4)-hydrazone derivatives of quinoline were designed, synthesized and tested. QSAR models of the antibacterial activity of quinoline derivatives were developed by the OCHEM web platform using different machine learning methods. A virtual set of quinoline derivatives was verified with a previously published classification model of anti-E. coli activity and screened using the regression model of anti-S. aureus activity. Selected and synthesized 2(4)-hydrazone derivatives of quinoline exhibited antibacterial activity against the standard and antibiotic-resistant S. aureus and E. coli strains in the range from 15 to 30 mm by the diameter of growth inhibition zones. Molecular docking showed the complex formation of the studied compounds into the catalytic domain of dihydrofolate reductase with an estimated binding affinity from −8.4 to −9.4 kcal/mol.     

Monoamine oxidase inhibition by pyrrole quinoline derivatives

The effect of 1-(beta-aminoethyl)-3H-pyrrole[2,3-h]quinoline (I), 3-(beta-aminoethyl)-1H-pyrrole[2,3-h]quinoline (I'), 8-amino-3H-pyrrole[2,3-h]quinoline (II), 6-amino-3H-pyrrole[2,3-h]quinoline (II') and 8-amino-1H-pyrrole[2,3-h]quinoline (III) on tyramine, serotonin and 2-phenylethylamine deaminase activities of mitochondrial monoamine oxidase from bovine brain were studied. All the compounds tested appeared to be reversibly inhibit MAO without preliminary incubation. Compounds II, II' and III specifically inhibited type A MAO; compound III exhibited the highest selectivity. The inhibition was of a mixed type. The effects of compounds I and I' were competitive and inconsistent with a classical concept on the dual activity of MAO, i. e., deamination of tyramine, a substrate common for MAO type A and MAO type B was inhibited in a greater degree than the deamination of specific substrates of MAO type A (serotonin) or type B (2-phenylethylamine). Possible reasons for the observed phenomenon are discussed.     

Structure–activity relationships amongst 4-position quinoline methanol antimalarials that inhibit the growth of drug sensitive and resistant strains of Plasmodium falciparum

Utilizing mefloquine as a scaffold, a next generation quinoline methanol (NGQM) library was constructed to identify early lead compounds that possess biological properties consistent with the target product profile for malaria chemoprophylaxis while reducing permeability across the blood–brain barrier. The library of 200 analogs resulted in compounds that inhibit the growth of drug sensitive and resistant strains of Plasmodium falciparum. Herein we report selected chemotypes and the emerging structure–activity relationship for this library of quinoline methanols.     

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.     

Synthesis of quinoline coupled [1,2,3]-triazoles as a promising class of anti-tuberculosis agents

A series of quinoline coupled 1,2,3-triazoles compounds have been synthesized by ‘click chemistry’ from azidomethyl quinoline with different alkynes. The efficiency and fidelity of the Cu(I)-catalyzed azide–alkyne reaction are substantiated by good yields and exclusive formation of the expected 1,4-disubstituted triazole product. All the synthesized compounds were screened for anti-tubercular activity against Mycobacterium tuberculosis H37Rv by luciferase reporter phage (LRP) assay. Quinoline coupled triazole sugar hybrid, 20 is the most potent compound in the series with 76.41% and 78.37% reduction calculated based on percentage reduction in Relative Light Units at 5 and 25 μg/mL, respectively.     

Benzimidazole tethered pyrrolo[3,4-b]quinoline with broad-spectrum activity against fungal pathogens

Fungal infections caused by Candida and Cryptococcus are particularly dangerous for immunocompromised individuals. In this study, we identified that benzimidazole fused pyrrolo[3,4-b]quinoline compounds have potent antifungal activity against several clinical isolates of pathogenic fungal strains. Specifically, the compound 6a did not show cytotoxicity against mammalian cells at a concentration that inhibits the growth of fungal strains. In addition, the compound 6a also significantly reduced the metabolic activity of fungal cells in the Candida albicans biofilms. Collectively, our results indicate that benzimidazole fused quinoline compounds have a potential to develop as an antifungal agents.     

Synthesis and biological evaluation of novel 6-nitro-5-substituted aminoquinolines as local anesthetic and anti-arrhythmic agents: molecular modeling study

A series of 6-nitro-5-[1-oxo-2-(substituted amino)ethylamino and 2-(substituted amino)propylamino] quinoline was synthesized and evaluated for their local anesthetic and anti-arrhythmic activity. The detailed synthesis, spectroscopic, and biological data are reported. Molecular modeling methods are used to study the local anesthetic activity of lidocaine and the active compounds by means of the AM1 method. The superposition of the stable conformations of these compounds was studied using the HyperChem 5.11 program.     

Cytotoxicity and induction of apoptosis by 4-amino-3-acetylquinoline in murine leukemia cell line L1210

Nitrogen heterocyclic compounds are used in the pharmaceutical industry, in medicine and in agriculture for their biological activity. 4-Amino-3-acetylquinoline, a new synthetically prepared quinoline derivative, was the most effective compound in our primary cytotoxic screening. In this study, we evaluated cytotoxic/antiproliferative activity of quinoline using murine leukemia cell line L1210. Its ability to induce apoptosis was studied, too. Quinoline derivative acted cytotoxically on tumor cell line L1210, the IC(100) value were 50 microg/ml (for 24 h), 25 microg/ml (for 48 h) and 10 microg/ml (for 72 h). The IC(50) values was found to be less than 4 microg/ml, a limit put forward by the National Cancer Institute (NCI) for classification of he compound as a potential anticancer drug. The cytotoxic concentrations of 4-amino-3-acetyl quinoline induced morphological changes of L1210 cells and the apoptotic DNA fragmentation.     

Synthesis of acridine derivatives of amino acid hydrazines and their antimalarial activity

2-Methoxy-6-chloroacridine-9-yl- and 2-ethoxy-6-nitroacridine-9-yl-hydrazides of glycine, alpha- and beta-alanines, gamma-aminobutiric acid, epsilon-aminocaproic acid have been synthesized and their antimalarial activity has been investigated. The compounds were found to inhibit the growth of malaria parasite P. falciparum in in vitro cultures. Fifty per cent inhibitory concentrations ranged from 2 x 10(-7) to 6 x 10(-7) M and corresponded to therapeutic concentrations of known quinoline and acridine antimalarial drugs. The beta-alanine and gamma-aminobutiric acid derivatives were the most active and showed high activity against a chloroquine resistant strain of P. falciparum.     

Novel pyrazole derivatives: Synthesis and evaluation of anti-angiogenic activity

The synthesis of a series of novel trisubstituted pyrazole derivatives and their PIFA-mediated conversion to molecules bearing the fused pyrazolo[4,3-c]quinoline ring system is reported. The anti-angiogenic activity of these compounds was evaluated by using in vitro assays for endothelial cell proliferation and migration, and in the chicken chorioallantoic membrane (CAM) assay. Compounds containing the fused pyrazolo[4,3-c]quinoline motifs emerged as potent anti-angiogenic compounds, which also had the ability to inhibit the growth of human breast (MCF-7) and cervical (Hela) carcinoma cells in vitro.     

Synthesis and evaluation of antioxidant activity of new quinoline-2-carbaldehyde hydrazone derivatives: bioisosteric melatonin analogues

Overproduction of reactive oxygen species results in oxidative stress that can cause fatal damage to vital cell structures. It is known that the use of antioxidants could be beneficial in the prevention or delay of numerous diseases associated with oxidative stress. Melatonin (MLT) is known as a powerful free-radical scavenger and antioxidant. It was found that indole ring of MLT can be employed by bioisosteric replacement by other aromatic rings. Quinoline derivatives constitute an important class of compounds for new drug development. Owing to quinoline and hydrazones appealing physiological properties and are mostly found in numerous biologically active compounds a series of quinoline-2-carbaldehyde hydrazone derivatives were synthesized as bioisosteric analogues of MLT, characterized and in vitro antioxidant activity was investigated by evaluating their reducing effect against oxidation of a redox-sensitive fluorescent probe. Cytotoxicity potential of all compounds was investigated both by lactate dehydrogenase leakage assay and by MTT assay.     

Mutagenic potency of heterocyclic amines towards Salmonella typhimurium; possible causes of variability in the results observed.

The potent food mutagens and carcinogens 2-amino-3-methylimidazol[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MEIQ) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) are probably the most active bacterial mutagens so far discovered. Important discrepancies were found, however, in the specific mutagenicities published for these compounds. This paper analyzes a number of experimental factors that could explain these differences: purity of the compounds, stability under the experimental conditions employed, solvents used, bacterial toxicity, testing procedure, amount and age of the S9 fraction, dose-effect relationships, day-to-day variability, origin of the compounds investigated or of the bacterial strain and age of the strain culture used. None of these factors was found to play a critical role, when the other experimental conditions were strictly standardized. The in-house testing procedure used probably explains the interlaboratory variations observed.