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PubMed2004

Reductive activation and thiol reactivity of benzazolo[3,2-a]quinolinium salts.

Derivatives of benzazolo[3,2-a]quinolium salts (QSDs) are reductively activated by the enzymatic reducing agents hypoxanthine (or xanthine)/xanthine oxidase and NADH dehydrogenase as evidenced by the increase in rates of ferricytochrome c (Cyt(III)c) reduction and oxygen consumption, respectively. No correlation between Michaelis-Menten parameters and QSDs redox potentials was found regarding anaerobic or aerobic Cyt(III)c reduction, although maximum rates were observed for nitro-containing QSDs. However, oxygen consumption rates correlate with QSDs redox potentials when NADH dehydrogenase is used as reducing agent. QSDs bind covalently to bovine serum albumin (BSA) under anaerobic conditions, in the presence, and less in the absence, of HX/XO and only if the nitro group is present at the QSD. QSDs react with glutathione (GSH) in the presence of HX/XO but not in its absence, under anaerobic conditions. The amount of reacted GSH increases, and the relative amount of GSSG formed decreases, with an increase in the QSD reduction potential, thus indicating that GSH reacts with reduced nitro-containing QSDs mainly in a manner which does not involve the production of GSSG, presumably, through the formation of the nitroso-QSD-GSH conjugate. QSDs are, thus, novel nitro-containing heterocyclic compounds which could be bioreductively activated to react with oxygen and thiols.

Animals↗
PubMed1991

Cell-permeable fluorescent indicator for cytosolic chloride.

A major limitation of quinolinium-based fluorescent indicators for cytosolic Cl- has been the necessity of invasive cell loading because the positively charged ring nitrogen confers high polarity and membrane impermeability. A novel approach to mask the positive nitrogen was developed and evaluated for rapid, noninvasive indicator loading into living cells and effective intracellular trapping. The nonpolar and lipophilic compound 6-methoxy-N-ethyl-1,2-dihydroquinoline (diH-MEQ) was Cl- insensitive but was readily oxidized to the membrane-impermeable and Cl(-)-sensitive fluorescent indicator 6-methoxy-N-ethylquinolium chloride (MEQ), MEQ had 344-nm absorbance and 440-nm emission maxima, 0.70 quantum yield, and 4100 M-1 cm-1 molar extinction coefficient. In aqueous buffers, the fluorescence of MEQ was quenched by Cl- by a collisional mechanism with a Stern-Volmer constant (KCl) of 145 M-1. MEQ fluorescence was quenched by other anions (KBr = 275 M-1, KI = 360 M-1, KSCN = 300 M-1) but not by NO3-, SO4(2-), cations, and pH. Swiss 3T3 fibroblasts and colonic T84 cells were loaded with MEQ by incubation at 37 degrees C with 25-50 microM diH-MEQ for 5-10 min followed by diH-MEQ-free buffer for 15 min. MEQ stained cells brightly and uniformly and was nontoxic in studies of cell growth, cAMP and Ca2+ signaling, and electrophysiological properties. MEQ leaked out of cells by less than 10% in 60 min and was sensitive to cytosolic Cl- with KCl = 19 M-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Anti-bacterial activity of synthetic N-heterocyclic oxidizing compounds.

Synthetic chlorochromate derivatives of pyridine and quinoline were active in vitro against type cultures of Escherichia coli (ATCC 128), Staphylococcus aureus (ATCC 14775), Pseudomonas aeruginosa (ATCC 10145) and Bacillus subtilis (NCTC 8236). The minimum inhibitory concentrations (MIC) were 125-250 micrograms ml-1 and 250-500 micrograms ml-1 for pyridinium chlorochromate and quinolinium chlorochromate, respectively. An established derivative of quinoline (Perfloxacin) had an MIC of 125-250 micrograms ml-1. The extinction time for 10(5) cfu in broth was 90 min for pyridinium chlorochromate and 120 min for quinolinium chlorochromate, except for B. subtilis which survived up to about 180 min and 360 min. A combination of the two compounds produced an antagonistic effect. The 50% lethal dose (LD50 toxicity) in mice was estimated at 76 micrograms g-1 and 33 micrograms g-1 body weight for the quinolinium and pyridinium chlorochromates. The compounds also exhibited some potential for suppressing a simulated staphylococcal infection in mice at the dosage levels of ca 22 micrograms g-1 for pyridinium chlorochromate and 45 micrograms g-1 for quinolinium chlorochromate.

Animals↗
PubMed1989

Synthesis and characterization of improved chloride-sensitive fluorescent indicators for biological applications.

A class of N-substituted quinoline compounds has been introduced recently for the fluorescence measurement of Cl concentration in biological preparations. The most Cl-sensitive compound was 6-methoxy-N-[3-sulfopropyl] quinolinium with peak excitation and emission wavelengths of 350 and 442 nm and a Stern-Volmer constant for quenching by Cl of 118 M-1. Six water-soluble quinoline derivatives were synthesized and characterized for the purposes of increasing Cl sensitivity, adding ester functions for cell trapping, and red-shifting the fluorescence peak wavelengths. Acetic acid ester functions were added at the N-, 2-, and 6-positions of the quinoline ring. The best ester compound, N-(6-methoxyquinolyl)acetoethyl ester (MQAE), was water soluble (270 g/liter at 23 degrees C; octanol:H2O partition coefficient of 0.009), had a high Cl sensitivity (Stern-Volmer constant 200 M-1), peak excitation and emission wavelengths of 355 and 460 nm, a fluorescence lifetime of 21.6 ns, and a molar absorbance of 4850 M-1 cm-1 (320 nm). MQAE fluorescence was not altered by the physiological anions HCO3, SO4, and PO4, by cations, or by pH. MQAE was used to measure chloride transport in liposome membranes and in cultured LLC-PK1 cells in monolayer; MQAE leaked out of cells less than 20% in 60 min at 37 degrees C. The physical, optical, and anion quenching properties for the series of ester compounds were determined to establish a set of structure-activity correlates.

Chemical Phenomena↗
PubMed1996

Discrimination between subtypes of apamin-sensitive Ca(2+)-activated K+ channels by gallamine and a novel bis-quaternary quinolinium cyclophane, UCL 1530.

1. Gallamine, dequalinium and a novel bis-quaternary cyclophane, UCL 1530 (8,19-diaza-3(1,4),5(1,4)-dibenzena-1 (1,4),7(1,4)-diquinolina-cyclononadecanephanedium) were tested for their ability to block actions mediated by the small conductance, apamin-sensitive Ca(2+)-activated K+ (SKCa) channels in rat cultured sympathetic neurones and guinea-pig isolated hepatocytes. 2. SKCa channel block was assessed in sympathetic neurones by the reduction in the slow afterhyperpolarization (AHP) that follows an action potential, and in hepatocytes by the inhibition of the SKCa mediated net loss of K+ that results from the application of angiotensin II. 3. The order of potency for inhibition of the AHP in sympathetic neurones was UCL 1530 > dequalinium > gallamine, with IC50 values of 0.08 +/- 0.02, 0.60 +/- 0.05 and 68.0 +/- 8.4 microM respectively, giving an equi-effective molar ratio between gallamine and UCL 1530 of 850. 4. The same three compounds inhibited angiotensin II-evoked K+ loss from guinea-pig hepatocytes in the order dequalinium > UCL 1530 > gallamine, with an equi-effective molar ratio for gallamine to UCL 1530 of 5.8, 150 fold less than in sympathetic neurones. 5. Dequalinium and UCL 1530 were as effective on guinea-pig as on rat sympathetic neurones. 6. UCL 1530 at 1 microM had no effect on the voltage-activated Ca2+ current in rat sympathetic neurones, but inhibited the hyperpolarization produced by direct elevation of cytosolic Ca2+. 7. Direct activation of SKCa channels by raising cytosolic Ca2+ in hepatocytes evoked an outward current which was reduced by the three blockers, with dequalinium being the most potent. 8. These results provide evidence that the SKCa channels present in guinea-pig hepatocytes and rat cultured sympathetic neurones are different, and that this is not attributable to species variation. UCL 1530 and gallamine should be useful tools for the investigation of subtypes of apamin-sensitive K+ channels.

Alkanes↗
PubMed1993

Reductive activation of benzazolo[3,2-a]-quinolinium chlorides.

Initial ferricytochrome c (Cyt(III)c) reduction rates occurring in aerobic or anaerobic solutions containing either 3-nitrobenzothiazolo[3,2-a]-(NBQCl), 1-ethyl-3-nitrobenzimidazolo[3,2-a]-(ENBIQCl), 7-ethylbenzimidazolo[3,2-a]quinolinium chloride (EHBIQCL), or nitrofurantoin (NFT) and xanthine/xanthine oxidase were measured. Maximum rates in nitrogen-saturated solutions follow the order NFT > NBQCL > ENBIQCL > EHBIQCL. These rates correlate linearly with the half-wave reduction potentials (E1/2) of these compounds. With the exception of EHBIQCl, smaller rates of Cyt(III)c reduction were obtained in air-saturated than in nitrogen-saturated solutions at the quinolinium salt concentrations used. Larger concentrations of superoxide dismutase (SOD) are needed for 50% inhibition of the Cyt(III)c reduction reaction for heterocyclic compounds with larger E1/2 values. Thus, measurement of the portion of the Cyt(III)c reduction rate under air that is inhibited by SOD does not account solely for the production of superoxide. These observations suggest that NBQCL, ENBIQCl, and less probably EHBIQCl may interfere with mitochondrial energy metabolism or induce DNA damage through reduced intermediates.

Chlorides↗
PubMed1990

Protection by inhibitors of multidrug resistance against mitochondrial mutagenesis in Saccharomyces cerevisiae.

A number of inhibitors thought to act on the drug efflux mechanism of multidrug-resistant cells have been tested for their ability to inhibit the induction of respiration-deficient (petite) colonies of the yeast Saccharomyces cerevisiae by mitochondrial mutagens. The mutagens tested were 3,6-diamino-9-(4-[(methylsulphonyl)aminophenyl]amino) acridine (an antitumour compound related to both amsacrine and proflavine), ethidium bromide, quinolinium dibromide (NSC 176319, a non-intercalative DNA binding antileukaemia agent) and rhodamine 123. The inhibitors tested included verapamil, perhexiline, chlorpromazine, trifluoperazine, reserpine, chloroquine, quinacrine, tamoxifen, clomiphene, cyclosporin A, valinomycin, amphotericin B and Tween 80. Several of these agents protected against mitochondrial mutagenesis, the most active being verapamil, reserpine, chloroquine, cyclosporin A and Tween 80. The correspondence between activity against multidrug resistance and activity in the yeast system strongly implies some degree of similarity in mechanisms for drug efflux from multidrug-resistant cells and drug uptake into the mitochondria of yeast. Agents protecting against the uptake of drugs into mitochondria of mammalian cells may have use in minimizing the long-term toxicity of anticancer drugs mediated by mitochondrial drug retention.

Aminoacridines↗
PubMed2006

QSAR modeling of mono- and bis-quaternary ammonium salts that act as antagonists at neuronal nicotinic acetylcholine receptors mediating dopamine release.

Back-propagation artificial neural networks (ANNs) were trained on a dataset of 42 molecules with quantitative IC50 values to model structure-activity relationships of mono- and bis-quaternary ammonium salts as antagonists at neuronal nicotinic acetylcholine receptors (nAChR) mediating nicotine-evoked dopamine release. The ANN QSAR models produced a reasonable level of correlation between experimental and calculated log(1/IC50) (r2=0.76, r(cv)2=0.64). An external test for the models was performed on a dataset of 18 molecules with IC50 values >1 microM. Fourteen of these were correctly classified. Classification ability of various models, including self-organizing maps (SOM), for all 60 molecules was also evaluated. A detailed analysis of the modeling results revealed the following relative contributions of the used descriptors to the trained ANN QSAR model: approximately 44.0% from the length of the N-alkyl chain attached to the quaternary ammonium head group, approximately 20.0% from Moriguchi octanol-water partition coefficient of the molecule, approximately 13.0% from molecular surface area, approximately 12.6% from the first component shape directional WHIM index/unweighted, approximately 7.8% from Ghose-Crippen molar refractivity, and 2.6% from the lowest unoccupied molecular orbital energy. The ANN QSAR models were also evaluated using a set of 13 newly synthesized compounds (11 biologically active antagonists and two biologically inactive compounds) whose structures had not been previously utilized in the training set. Twelve among 13 compounds were predicted to be active which further supports the robustness of the trained models. Other insights from modeling include a structural modification in the bis-quinolinium series that involved replacing the 5 and/or 8 as well as the 5' and/or 8' carbon atoms with nitrogen atoms, predicting inactive compounds. Such data can be effectively used to reduce synthetic and in vitro screening activities by eliminating compounds of predicted low activity from the pool of candidate molecules for synthesis. The application of the ANN QSAR model has led to the successful discovery of six new compounds in this study with experimental IC50 values of less than 0.1 microM at nAChR subtypes responsible for mediating nicotine-evoked dopamine release, demonstrating that the ANN QSAR model is a valuable aid to drug discovery.

Dopamine↗
PubMed2006

Synthesis and evaluation of isosteres of N-methyl indolo[3,2-b]-quinoline (cryptolepine) as new antiinfective agents.

Isosteres of cryptolepine (1) were synthesized and evaluated for their antiinfective activities. Overall, the sulfur isostere, 5-methyl benzothieno[3,2-b]quinolinium salt (5b), was equipotent to 1 and has shown no cytotoxicity at 23.8 microg/mL. Compound 5b was also found to have a broad spectrum of activity. Both the carbon and oxygen isosteres were less potent than cryptolepine. A limited library of 2-substituted analogs of 5b has been synthesized and evaluated in antifungal screens but did not show increase in potency compared to the unsubstituted 5b. Similarly, evaluation of tricyclic benzothieno[3,2-b]pyridines while showing promise in individual screens did not produce an overall increase in potency. Overall, the evaluation of the activities of 5b compared with standard antifungal/anti-protozoal agents suggests that the benzothienoquinoline scaffold could serve as a lead for optimization.

Alkaloids↗
PubMed1994

In vitro studies of the antibacterial and antifungal activity of oxine and its derivatives.

Twenty-one derivatives of 8-hydroxyquinoline (oxine, 8H, CAS 148-24-3) were prepared and characterized by UV, IR, MS and NMR spectroscopy. Four of these derivatives, N-butyl, 8-butyloxyquinolinium bromide (HBD), 8-pentyloxyquinoline (HPEM), N-pentyl, 8-pentyloxyquinolinium bromide (HPED) and N-benzyl, 8-benzyloxy quinolinium chloride (HBED) are new and reported for the first time. The antimicrobial activity of these compounds was carried out in vitro against 11 Gram positive and 18 Gram negative bacteria, and 18 fungi including 9 dermatophytes, 7 other filamentous fungi and 2 Candida species. Three compounds namely, HPRD, HPED and HBED were found to possess significant antibacterial activity in order of HPED > HPRD > HBED, whereas 4 were found to possess significant antifungal activity in order of 8H > HT > HPEM > 8B.

Anti-Bacterial Agents↗
PubMed1996

Quinolinium Dichromate Oxidation of Diols: A Kinetic Study.

Quinolinium dichromate (QDC) in water oxidizes vicinal and nonvicinal diols to the corresponding alpha-hydroxy carbonyl compound. The rate is proportional to the concentrations of diol, oxidant and hydrogen ions, and the reactions proceed almost twice as fast in D(2)O than in H(2)O. These data can be correlated with a mechanistic pathway involving the intermediate formation of a chromate ester, which undergoes decomposition to give the product.

Journal Article↗
PubMed2006

Three 4-aminoquinolines of antimalarial interest.

The structures of three compounds with potential antimalarial activity are reported. In N,N-diethyl-N'-(7-iodoquinolin-4-yl)ethane-1,2-diamine, C15H20IN3, (I), the molecules are linked into ribbons by N-H...N and C-H...N hydrogen bonds. In N-(7-bromoquinolin-4-yl)-N',N'-diethylethane-1,2-diamine dihydrate, C15H20BrN3.2H2O, (II), two aminoquinoline molecules and four water molecules form an R5(4)(13) hydrogen-bonded ring which links to its neighbours to form a T5(2) one-dimensional infinite tape with pendant hydrogen bonds to the aminoquinolines. The phosphate salt 7-chloro-4-[2-(diethylammonio)ethylamino]quinolinium bis(dihydrogenphosphate) phosphoric acid, C15H22ClN3(2+).2H2PO4-.H3PO4, (III), was prepared in order to establish the protonation sites of these compounds. The phosphate ions form a two-dimensional hydrogen-bonded sheet, while the aminoquinoline cations are linked to the phosphates by N-H...O hydrogen bonds from each of their three N atoms. While the conformation of the quinoline region hardly varies between (I), (II) and (III), the amino side chain is much more flexible and adopts a significantly different conformation in each case. Aromatic pi-pi stacking interactions are the only supramolecular interactions seen in all three structures.

Aminoquinolines↗
PubMed1987

Antiradiation compounds. XXII. Methyl 3-amino-2-phenyldithiopropenoates and 1,1-bis(methylthio)-3-amino-2-phenyl-1-propenes.

The title compounds were prepared in the attempt to provide methylthio and bis(methylthio) analogues of the radioprotective pyridinium- and quinolinium-2-dithioacetic acid derivatives in which the methylthio function is attached to an amino group through an aliphatic chain. The methyl 3-amino-2-phenyldithiopropenoates were obtained by the reaction of amines with 4-phenyl-3-methylthio-1,2-dithiolium iodide, and the 1,1-bis(methylthio)-3-amino-2-phenyl-1-propenes were obtained by methylation and reduction of the dithiopropenoates. The methyl dithiopropenoates with aliphatic substituents on the nitrogen gave only fair or poor radiation protection in mice, and one example of the reduced bis(methylthio) derivatives tested was inactive. The precursor 1,2-dithiole-3-thione and its methiodide, predicted to be radiation protective, were found inactive in this test.

Alkenes↗
PubMed1988

The relationship between lipophilic-hydrophilic balance, uptake and anti-bacteriophage lambda activity of experimental anti-tumour bisquaternary salts.

The uptake by Escherichia coli of a series of bisquaternary experimental anti-tumour agents (quinolinium 4-[p-9(-pyridylamino)phenylcarbamoyl]-aniline-bisalkyl dibromides) has been measured both by association of radiolabelled compounds and their inhibition of the vegetative replication of bacteriophage lambda (after heat inactivation of the phage repressor) as a measure of biologically effective intracellular drug concentration. Uptake of these compounds was correlated with biological effect, and was a function of both incubation temperature and the lipophilic-hydrophilic balance of the compound. At 30 degrees C uptake was drug concentration-dependent and was not readily reversible. No saturation of uptake was apparent over the concentration range tested. Preliminary experiments indicated that time-dependent drug uptake was also related to growth inhibition in cultured L1210 murine leukaemia cells. These results are consistent with the hypothesis that uptake occurs by diffusion across the plasma membrane followed by strong binding to cell constituents such as DNA. The approximate range of uptake of the most active compounds, using an external drug concentration of 1 microM, are 100 and 2400 molecules/s respectively for bacteria and murine leukemia cells. For bacteria, the uptake of approx. 2 X 10(5) molecules of drug/cell inhibits the yield of phage lambda by 90%.

Animals↗
PubMed2000

Pharmacological characterization of small-conductance Ca(2+)-activated K(+) channels stably expressed in HEK 293 cells.

Three genes encode the small-conductance Ca(2+)-activated K(+) channels (SK channels). We have stably expressed hSK1 and rSK2 in HEK 293 cells and addressed the pharmacology of these subtypes using whole-cell patch clamp recordings. The bee venom peptide apamin blocked hSK1 as well as rSK2 with IC(50) values of 3.3 nM and 83 pM, respectively. The pharmacological separation between the subtypes was even more prominent when applying the scorpion peptide blocker scyllatoxin, which blocked hSK1 with an IC(50) value of 80 nM and rSK2 at 287 pM. The potent small molecule blockers showed little differentiation between the channel subtypes. The bis-quinolinium cyclophane UCL 1684 blocked hSK1 with an IC(50) value of 762 pM and rSK2 at 364 pM. The antiseptic compound dequalinium chloride blocked hSK1 and rSK2 with IC(50) values of 444 nM and 162 nM, respectively. The nicotinic acetylcholine receptor antagonist d-tubocurarine was found to block hSK1 and rSK2 with IC(50) values of 27 microM and 17 microM when measured at +80 mV. The inhibition by d-tubocurarine was voltage-dependent with increasing affinities at more hyperpolarized potentials. The GABA(A) receptor antagonist bicuculline methiodide also blocked hSK1 and rSK2 in a voltage-dependent manner with IC(50) values of 15 and 25 microM when measured at +80 mV. In conclusion, the pharmacological separation between SK channel subtypes expressed in mammalian cells is too small to support the notion that the apamin-insensitive afterhyperpolarization of neurones is mediated by hSK1.

Amino Acid Sequence↗
PubMed1996

Synthesis, molecular modeling, and K+ channel-blocking activity of dequalinium analogues having semirigid linkers.

Dequalinium [1,1'-(decane-1, 10-diyl)bis(2-methyl-4-aminoquinolinium)] is an effective blocker of the small conductance Ca2(+)-activated K+ channel. It has been shown that the number of methylene groups in the alkyl chain linking the two quinolinium rings of this type of molecule is not critical for activity. To further investigate the role of the linker, analogues of dequalinium have been synthesized, in which the alkyl chain has been replaced by CH2XCH2 where X is a rigid or semirigid group containing aromatic rings. The compounds have been tested for blockade of the slow after-hyperpolarization on rat sympathetic neurons. The most potent compounds have X = phenanthryl, fluorenyl, cis-stilbene, and C6H4(CH2)nC6H4, where n = 0-4. The conformational preferences of the compounds were investigated using the XED/COSMIC molecular modeling system. Although there is some dependence of the potency of the analogue on the conformational properties of the linker (X), overall, X groups having substantial structural differences are tolerated. It seems that X provides a support for the two quinolinium groups and does not interact with the channel directly. The intramolecular separation between the quinolinium rings, which is provided by rigid groups X, is not critical for activity; this may be attributed to the residual conformational mobility of the heterocycles and to the extensive delocalization of the positive charge. These two factors may permit favorable contacts between the quinolinium groups and the channel over a range of intramolecular separations.

Animals↗
PubMed1987

Antiradiation compounds. 20. 1-Methylquinolinium(and pyridinium)-2-dithioacetic acid derivatives.

A new class of radiation-protective compounds has been found in the bis(methylthio) and methylthio amino derivatives of 1-methylquinolinium- and 1-methylpyridinium-2-dithioacetic acids. The compounds gave good protection to mice vs. 1000-rad gamma-radiation in ip doses of 10 mg/kg or less, much lower than those required for the aminoalkyl thiols (approximately 150-600 mg/kg). The dithioacetic acid zwitterions were prepared from the base-catalyzed reaction of carbon disulfide with quinaldine and picoline methiodides, and the bis(methylthio) derivatives resulted from reaction with methyl iodide at room temperature. Replacement of one methylthio moiety took place readily on reaction of the bis(methylthio) derivatives with 1 molar equiv of an amine. The best protective activity was found with the methylthio piperidino derivative in both the quinolinium and pyridinium series.

Animals↗