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Three 8-hydroxyquinoline derivatives, assessed using an in vitro preformed dental plaque model system, were differentially inhibitory for four plaque-forming microorganisms.
Through broad screening of the compound library at Pharmacia, a naphthalene carboxamide was identified as a nonnucleoside inhibitor of human cytomegalovirus (HCMV) polymerase. Structure-activity relationship studies demonstrated that a quinoline ring could be substituted for naphthalene, resulting in the discovery of a 4-hydroxyquinoline-3-carboxamide (4-HQC) class of antiviral agents with unique biological properties. In vitro assays with the 4-HQCs have demonstrated potent inhibition of HCMV, herpes simplex virus type 1 (HSV-1), and varicella-zoster virus (VZV) polymerases but no inhibition of human alpha, delta, and gamma polymerases. Antiviral cell culture assays have further confirmed that these compounds are active against HCMV, HSV-1, HSV-2, VZV, and many animal herpesviruses. However, these compounds were not active against several nonherpesviruses representing different DNA and RNA virus families. A strong correlation between the viral DNA polymerase and antiviral activity for this class of compounds supports inhibition of the viral polymerase as the mechanism of antiviral activity. Northern blot analysis of immediate-early and late viral transcripts also pointed to a block in the viral life cycle consistent with inhibition of viral DNA replication. In vitro HCMV polymerase assays indicate that the 4-HQCs are competitive inhibitors of nucleoside binding. However, no cross-resistance could be detected with ganciclovir-resistant HCMV or acyclovir-resistant HSV-1 mutants. The unique, broad-spectrum activities of the 4-HQCs may offer new opportunities for treating many of the diseases caused by herpesviruses.
We describe the synthesis of two new substrates for the detection of beta-galactosidase and evaluate their performance in comparison with that of 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-Gal). Of 171 Enterobacteriaceae strains that were able to hydrolyze X-Gal, 166 (97.1%) also hydrolyzed cyclohexenoesculetin-beta-D-galactoside whereas only 96 (56.1%) showed evidence of hydrolysis of 8-hydroxyquinoline-beta-D-galactoside. No false-positive results were observed with either substrate.
The effects of the chelating agent 8-hydroxyquinoline (Hq) on Tetrahymena thermophila were examined. Cell division was completely inhibited by 5 micrograms of Hq per ml. At this concentration deoxyribonucleic acid, ribonucleic acid, and protein syntheses were also completely and nonselectively inhibited. The inhibition was reversible after 6 h of Hq treatment. At concentrations above 20 micrograms/ml a 10,000-fold decrease in survival as seen after 2 h in the drug. The sensitivity of Tetrahymena to Hq was found to be dependent upon cell concentration, wild-type strain, medium, and length of time the culture is at 38 degrees C before Hq is added. Mutants of Tetrahymena that are unable to divide at the restrictive temperature, but which continue macromolecular synthesis, were found to be resistant to Hq treatment. Conditions were obtained in which more than a 1,000-fold difference in survival was seen between this class of mutant and the wild type. The effect of Hq on three other classes of temperature-sensitive mutants was examined, and the results are discussed.
Of 72 clinical isolates of Pseudomonas aeruginosa examined for simultaneous production of secondary metabolites, 86% produced 2-alkyl-4-hydroxyquinolines, 75% produced rhamnolipids, and 58% produced phenazines, including pyocyanin. Whereas isolates producing two or one constituted smaller groups, 39% released all three metabolites. Metabolite production did not appear to influence site of infection.
8-Hydroxyquinolyl benzoate and 8-hydroxyquinolyl para-(fluorosulfonyl)benzoate have been synthesized and evaluated in vitro as antimicrobial and antiplaque agents. Both compounds inhibited the growth of cultures of the following genera: Streptococcus, Staphylococcus, Actinomyces, Lactobacillus, Veillonella, and Candida. Minimum inhibitory concentrations ranged from 0.98 to 62 microgram/ml. Extracted human teeth pretreated with 1% solutions of either compound and rinsed with distilled water exhibited reduced in vitro plaque formation for 48 hours. These results indicate that the in vitro antiplaque activity of 8-hydroxyquinolines can be enhanced by attaching the appropriate side chain in the 8-position.
8-Hydroxyquinoline (HQ) chelates Mg2+ and Mn2+ and, secondarily, affects the activities of DNA and RNA polymerases. The in vivo effect of HQ has been estimated in Allium cepa L. meristems growing under new growth kinetics in the presence of this agent. HQ (at both 5 X 10(-5) M and 10(-4) M) depressed incorporation of [3H]uridine much more effectively than that of [3H]-thymidine. Cycle kinetics in meristems behaved as if they were independent of the rates of synthesis or accumulation of RNA since, under HQ, cycle time was only moderately modified and the new cycle kinetics achieved could be explained by the new rates of [3H]thymidine incorporation. Lengthened S periods were partially compensated for by shortened G2 phases, suggesting that, in these cells, both the growth cycle and its coupling with the DNA-division cycle were not disturbed by a decreased amount of RNA. Finally, the nucleolar cycle during mitosis, but not the interphase nucleolus, was modified under the new rates of RNA synthesis.
A new antibiotic, korormicin, isolated from a marine bacterium Pseudoalteromonas sp. F-420, was found to strongly inhibit the respiratory chain-linked Na+-translocating NADH-quinone reductase (NQR) from the marine Vibrio alginolyticus. Similar to 2-n-heptyl-4-hydroxyquinoline N-oxide (HQNO), korormicin specifically inhibited the Na+-dependent reaction in the NQR complex that is directly coupled to the extrusion of Na+ from the cells. Both korormicin and HQNO acted as purely noncompetitive inhibitors with regard to Q-1, and the inhibitor constants were estimated to be 82 pM and 0.3 microM, respectively. Mutual exclusiveness of korormicin and HQNO was analyzed by kinetic methods, which indicated that a part of the binding site of korormicin and HQNO overlapped, preventing a simultaneous binding of the two inhibitors to the NQR complex. The site of Ag+ inhibition was the initial reaction of the NQR complex catalyzed by Nqr6 subunit. The time courses of Ag+ inhibition and the release of FAD indicate that the Ag+-denatured Nqr6 subunit gradually releases FAD.
The bromine atoms of the title compound, 5,7-dibromo-2-methyl-8-hydroxyquinoline were replaced by the requisite amino compound to afford 6 amino derivatives viz: bis(diethylamino)-, bis(dibutylamino)-, bis(dicyclohexylamino)-, dipyrolidino-, dipiperidino- and dipiperazino derivatives. The antimicrobial activity of these compounds were investigated against selected gram positive (Staphylococcus aureus and Bacillus subtilis), gram negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and yeast (Candida albicans). All the compounds showed significant activity against the test microorganisms, from 5-30 times compared to the title compound. It was observed that all derivatives were more effective against gram positive bacteria. No correlation has been established between the minimum inhibitory (MIC) concentrations of the derivatives and the structural modifications.
Many derivatives of 2,3-dimethoxy-4-hydroxypyridine, which were designed from examination of the structure-activity relationship of piericidins, were tested for inhibition of NADH-UQ reductase. The lipophilic side chain of those compounds was indicated to be a key part for activity and its optimal length was conjectured. By the use of two different phases of assay material, intact mitochondria and submitochondria, the size of a membrane effect was shown to depend on the structure of the side chain. 4-Hydroxyquinoline derivatives were also tested for an analogous role in relation to the electron transport function of menaquinone, and they were proven to be inhibitors of NADH-UQ reductase as good as the pyridine derivatives.
Streptomyces griseoflavus subsp. (Gö 3592) was investigated by chemical screening methods. The mycelium contained gilvocarcin V (1). The culture filtrate contained the calcium salt of 3-hydroxyquinoline-2-carboxylic acid (2) confirmed by spectroscopic methods and by a 5-step partial synthesis of the free acid (3).
Proton-ligand dissociation constant of 5-(p-aminophenylazo)-8-hydroxyquinoline (HL) and metal-ligand stability constants of their complexes with bivalent (Mn2+, Co2+, Ni2+ and Cu2+) metal ions have been determined potentiometrically in 0.1 M KCl and 30% (v/v) dimethyl formamide (DMF)-water mixture. The order of the stability constants of the formed complexes was found to be Mn2+ < Co2+ < Ni2+ < Cu2+. The effect of temperature was studied and the corresponding thermodynamic parameters (delta G, delta H and delta S) were derived and discussed. The dissociation process is nonspontaneous, endothermic and entropically unfavorable. The formation of the metal complexes has been found to be spontaneous, endothermic and entropically favorable.
In this paper, the absorption and fluorescence spectra of 7-Hydroxyquinoline (7HQ) in the copolymer of methyl methacrylate (MMA) and methacrylic acid (MAA) monomers were observed. The influence of different matrices on the species of 7HQ and the excited state proton transfer effect were investigated. The results showed that, as the number of carboxylic group in the matrix was increased, the relative contents of different species of 7HQ should be changed and the excited state proton transfer effect of 7HQ was enhanced.
7-hydroxyquinoline (7-HQ) is a kind of organic molecule with excited-state proton transfer (ESPT) effect. 7-HQ in ethanol solution causes ESPT reaction under the excitation of ultraviolet light. The fluorescence spectrum of the sample exhibits two bands. In contrast, 7-HQ in dimethyl sulfoxide (DMS) solution does not cause ESPT reaction. The fluorescence spectrum of the sample exhibits a single band. But after the sample was irradiated with a strong UV light, its fluorescence spectrum also exhibits two bands. This phenomenon is reported for the first time in the present paper, and its cause is investigated through the study on the absorption spectra and fluorescence spectra of 7-HQ in ethanol, dimethyl sulfoxide and N, N-dimethyl formamide solution. The conclusion is that the change in the fluorescence spectrum of 7-HQ in DMS solution is due to the fact that 7-HQ causes ESPT reaction which results from the photodecomposition of DMS and the product of water after the solution was irradiated with strong UV light.
Inhibition of photosystem II (PS II) activity by 8-hydroxyquinoline (8-HQ) has been investigated in case of spinach chloroplasts and isolated photosystem II particles using the thermoluminescence technique. In presence of 8-HQ, water to methylviologen (MV) photoreduction in isolated chloroplasts is inhibited while the reduction of dichlorophenol indophenol is inhibited in both chloroplasts as well as in photosystem II particles. The activity can be restored fully by addition of diphenylcarbazide (DPC), suggesting that the donor side of water oxidation complex is affected. The changes in the thermoluminescence peaks indicate that the charge recombination processes involving S2 or S3 states of the Kok's cycle are probably affected by 8-HQ treatment.
Zinc is able to form complexes with 8-hydroxyquinoline (HC). Therefore the penetration of HC from topical formulations into the ear of guinea-pigs and into a multilayer membrane system was decreased by Zi. Using the AUC a suitable in vitro-in vivo correlation was obtained. An exception was observed when there were interactions between the ointment base and the in vitro model system. Furthermore, it was found that also zincoxinate is able to penetrate into the skin of guinea-pigs.
The cellular respiratory inhibition activity of 7-substituted 4-hydroxyquinoline-3-carboxylic acids recently designed by Shah and Coats is found by regression analysis to be significantly correlated with van der Waals volume (V(w)). A parabolic correlation is obtained in case of ascites cell inhibition and a linear correlation in case of malate dehydrogenase inhibition. The correlation of both types of inhibition with a single parameter, V(w), makes the process of substituent selection in designing more potent inhibitors of whole respiratory cell much simpler.
It has been shown that quinozole (aqueous solution), enteroseptol and nitroxoline (suspension with Tween-80) in a concentration of 0.2 X 10(-6)-1.10(-5) decrease the tone of the rat and guinea-pig ileum and diminish their peristalsis. When administered in the same concentrations quinozole removes or prevents the spasmogenic effects of barium chloride (1 X 10(-5)-4.10(-5), of histamine (2 X 10(-5) and -6) but not of acetylcholine (1 X 10(-6)). When administered orally in a dose 50 mg/kg to rats enteroseptol and nitroxoline inhibit the serotonin-, agar- and carrageenin-induced edemas of the rat paws without changing the response to subplantar injection of histamine. The data obtained should be taken into consideration during the use of 8-hydroxyquinolines as antimicrobial substances.