4-Phenylselenyl-7-chloroquinoline, a new quinoline derivative containing selenium, has potential antinociceptive and anti-inflammatory actions.

The development of new drugs to treat painful and inflammatory clinical conditions continues to be of great interest. The present study evaluated the antinociceptive and anti-inflammatory effects of 4-phenylselenyl-7-chloroquinoline (4-PSQ). Mice were orally (p.o.) pretreated with 4-PSQ (0.1-25mg/kg), meloxicam (25mg/kg, a reference drug) or vehicle, 30min prior to the acetic acid, formalin, hot-plate and open-field tests. 4-PSQ reduced abdominal writhing induced by acetic acid and it caused an increase in latency time in the hot-plate test. 4-PSQ inhibited early and late phases of nociception and reduced the paw edema caused by formalin. Locomotor and exploratory activities in the open field test were not altered by treatments. In addition, a time-response curve was carried out by administration of 4-PSQ (25mg/kg; p.o.) at different times before the acetic acid injection. The antinociceptive effect in inhibiting acetic acid-induced abdominal writhing of 4-PSQ started at 0.5h and remained significant up to 4h after administration. Indeed, the anti-inflammatory and antioxidant properties of 4-PSQ were investigated. 4-PSQ diminished the edema formation and decreased the myeloperoxidase activity and reactive species levels induced by croton oil in the ear tissue. 4-PSQ partially protected against the decrease of the 2,2'-Azinobis-3-ethylbenzothiazoline 6-sulfonic acid (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) levels induced by croton oil. Meloxicam presented similar results for 4-PSQ in tests evaluated. These results demonstrated that 4-PSQ exerts acute anti-inflammatory and antinociceptive actions, suggesting that it may represent an alternative in the development of future new therapeutic strategies.

Understanding the molecular basis of agonist/antagonist mechanism of GPER1/GPR30 through structural and energetic analyses.

The G-protein coupled receptors (GPCRs) represent the largest superfamily of membrane proteins in charge to pass the cell signaling after binding with their cognate ligands to the cell interior. In breast cancer, a GPCR named GPER1 plays a key role in the process of growth and the proliferation of cancer cells. In a previous study, theoretical methods were applied to construct a model of GPER1, which later was submitted to molecular dynamics (MD) simulations to perform a docking calculation. Based on this preceding work, it is known that GPER1 is sensitive to structural differences in its binding site. However, due to the nature of that past study, conformational changes linked to the ligand binding were not observed. Therefore, in this study, in order to explore the conformational changes coupled to the agonist/antagonist binding, MD simulations of about 0.25µs were performed for the free and bound states, summarizing 0.75µs of MD simulation in total. For the bound states, one agonist (G-1) and antagonist (G-15) were chosen since is widely known that these two molecules cause an impact on GPER1 mobility. Based on the conformational ensemble generated through MD simulations, we found that despite G-1 and G-15 being stabilized by similar map of residues, the structural differences between both ligands impact the hydrogen bond pattern not only at the GPER1 binding site but also along the seven-helix bundle, causing significant differences in the conformational mobility along the extracellular and cytoplasmic domain, and to a lesser degree in the curvatures of helix 2, helix 3 and helix 7 between the free and bound states, which is in agreement with reported literature, and might be linked to microscopic characteristics of the activated-inactivated transition. Furthermore, binding free energy calculations using the MM/GBSA method for the bound states, followed by an alanine scanning analysis allowed us to identify some important residues for the complex stabilization.

Synthesis and evaluation of 2-(1H-indol-3-yl)-4-phenylquinolines as inhibitors of cholesterol esterase.

A series of 2-(substituted) phenyl and 2-indolyl quinoline derivatives (10a-l) was synthesized by an efficient microwave-assisted, trifluoroacetic acid-catalyzed, solvent-free method. Evaluation of the inhibitory activity led to the identification of two quinoline inhibitors of cholesterol esterase. 2-(1H-Indol-3-yl)-6-nitro-4-phenylquinoline (10l; IC50=1.98µM) was characterized as a mixed-type inhibitor with a pronounced competitive binding mode.

Molecules of the quinoline family block tau self-aggregation: implications toward a therapeutic approach for Alzheimer's disease.

The neurofibrillary tangles (NFTs) generated by self-aggregation of anomalous forms of tau represent a neuropathological hallmark of Alzheimer's disease (AD). These lesions begin to form long before the clinical manifestation of AD, and its severity is correlated with cognitive impairment in patients. We focused on the search for molecules that interact with aggregated tau of the Alzheimer's type and that may block its aggregation before the formation of NFTs. We show that molecules from a family of quinolines interact specifically with oligomeric forms of tau, inhibiting their assembly into AD filaments. The quinolines 2-(4-methylphenyl)-6-methyl quinoline (THQ-4S) and 2-(4-aminophenyl)-6-methylquinoline (THQ-55) inhibited in vitro aggregation of heparin-induced polymers of purified brain tau and aggregates of human recombinant tau. They also interact with paired helical filaments (PHFs) purified from AD postmortem brains. In vitro studies indicated a significantly lower inhibitory effect of amyloid-ß42 on the aggregation, suggesting that tau aggregates are specific targets for quinoline interactions. These compounds showed highly lipophilic properties as corroborated with the analysis of total polar surface areas, and evaluation of their molecular properties. Moreover, these quinolines exhibit physical chemical properties similar to drugs able to penetrate the human brain blood barrier. Docking studies based on tau modeling, as a structural approach to the analysis of the interaction of tau-binding ligands, indicated that a C-terminal tau moiety, involved in the formation of PHFs, seems to be a site for binding of quinolines. Studies suggest the potential clinical use of these quinolines and of their derivatives to inhibit tau aggregation and possible therapeutic routes for AD.

Docking studies on the binding of quinoline derivatives and hematin to Plasmodium falciparum lactate dehydrogenase.

The literature has reported that ferriprotoporphyrin IX (hematin) intoxicates the malarial parasite through competition with NADH for the active site of the enzyme lactate dehydrogenase (LDH). In order to avoid this, the parasite polymerizes hematin to hemozoin. The quinoline derivatives are believed to form complexes with dimeric hematin, avoiding the formation of hemozoin and still inhibiting LDH. In order to investigate this hypothesis we calculated the docking energies of NADH and some quinoline derivatives (in the free forms and in complex with dimeric hematin) in the active site of the Plasmodium falciparum LDH (PfLDH). Ours results showed better docking score values to the complexes when compared to the free compounds, pointing them as more efficient inhibitors of Pf_LDH. Further we performed Molecular Dynamics (MD) simulations studies on the best docking conformation of the complex chloroquine-dimeric hematin with PfLDH. Our in silico results corroborate experimental data suggesting a possible action route for the quinoline derivatives in the inhibition of PfLDH.

Membrane potential and pH-dependent accumulation of decynium-22 (1,1'-diethyl-2,2'-cyanine iodide) flourencence through OCT transporters in astrocytes.

1,1 '-Diethyl-2,2'-cyanine iodide (decynium22; D22) is a potent blocker of the organic cation family of transporters (EMT/OCT) known to move endogenous monoamines like dopamine and norepinephrine across cell membranes. Decynium22 is a cation with a relatively high affinity for all members of the OCT family in both human and rat cells. The mechanism through which decynium22 blocks OCT transporters are poorly understood. We tested the hypothesis that denynium22 may compete with monoamines utilizing OCT to permeate the cells. Using the ability of D22 to aggregate and produce fluorescence at 570 nm, we measured D22 uptake in cultured astrocytes. The rate of D22 uptake was strongly depressed by acid pH and by elevated external K+. The rate of uptake was similar to that displayed by 4-(4-(dimethylamino)-styryl)-N-methylpyridinium (ASP+), a well established substrate for OCT and high-affinity Na+-dependent monoamine transporters. These data were supported by measurement of electrogenic uptake using whole cell voltage clamp recording. Decynium22 depressed norepinephrine, but not glutamate uptake. These data are also consistent with the described OCT transporter characteristics. Taken together, our results suggest that decynium22 accumulation might be a useful instrument to study monoamine transport in the brain, and particularly in astrocytes, where they may play a prominent role in monoamine uptake during brain dysfunction related to monoamines (like Parkinson disease) and drug addiction.

Synthesis and biotransformation of tetrahydroquinoline by Mortierella isabelina.

Tetrahydroquinoline (1), prepared by a traditional synthetic method, the imino Diels-Alder reaction, was biotransformed by Mortierella isabelina to afford a new compound, 2, characterized by spectroscopic methods.

Alkyl, aryl, alkylarylquinoline, and related alkaloids.

The Rutaceae continues to be the primary source of new alkyl-, aryl-, and alkylarylquinolin/ones. In the past 17 years, the overall distribution of these alkaloid types within the family has changed little since the chemosystematics reviews by Waterman (270), Mester (40), and da Silva et al. (279). Alkylquinolones dominate the reported isolations with about 51% of the total, with arylquinolones (16%), alkylquinolines (15%), alkylarylquinolines (11%), arylquinolines (3%), alkylarylquinolones (2%), and quinolines (2%) as the significant structural groups contributing to the remainder of this class of alkaloids. The alkyl-, aryl-, and alkylarylquinolin/one alkaloids occur in 50 species belonging to 24 genera and 6 subfamilies. Despite the intensive chemical exploration of many species from other plants in the Rutales family, but not in the family Rutaceae, the first alkaloid alkylquinolone from a simaroubaceous plant (160) was not reported until 1997. Although many additional alkaloids have been reported, some of new structural types (Bo.4), substantial biosynthetic work on plant-derived alkylquinolin/ones has not yet been carried out. The biosynthesis of some of these alkaloids in bacteria was firmly established as being derived from anthranilic acid. Outside of the Rutales, alkyl-, aryl-, and alkylarylquinolin/ones have not been found, except for simple quinoline (A.1; only one) and 2-methylquinoline derivatives in the Zygophyllaceae, and only an atypical quinolone derivative (Ao.1) in the Asteraceae family. A few 3-phenylquinolines (2), 3-(1H-indol-3-yl)quinoline (1), and quinoline-quinazoline (1) alkaloids have been reported from only a single genus in the Zygophyllaceae. Tryptophan-derived quinolines in higher plants are confined to a few 2-carboxylicquinolin/ones (6) and 4-carbaldehydequinolines (5); the former found in the Ephedraceae (5), Boraginaceae (1), Fagaceae (1), Ginkgoaceae (1), Plumbaginaceae (1), Solanaceae (1), and Apiaceae (1), and the latter in the Moraceae (3), Alliaceae (1), and Pontederiacae (1). The number of quinolones derived from glycine and a polyketide is also limited. 5-Alkyl-2-methylquinolin-4(1H)-ones (8) occur in the Euphorbiaceae, and 5-alkyaryl-2-methylquinolin-4(1H)-ones ((3) in the Sterculiaceae. Alkylquinolin/ones are well-known as typical alkaloids of three Proteobacteria and three Actinobacteria; the genus Pseudomonas yielded the majority (46%) of the total number of alkaloids reported (39). 2-Carboxylicquinolin/ones (4) and 4-carbaldehydequinolines (6) are minor constituents in both divisions of bacteria. More interesting are the quinolactacins (7), in which the second nitrogen is derived from L-valine or L-isoleucine, recently reported to occur only in the fungus Penicillium. Many of these diverse alkaloids have served directly as medicines or as lead compounds for the synthesis (258) of derivatives with an improved biological profile. It is apparent from the summary view of the alkyl-, aryl-, and alkylarylquinolin/ones reported in the Rutaceae that they help to confirm the affinity between Rutoideae tribes and provide firm support for placing the Spathelioideae and the Dictyolomatoideae close to the more primitive Zanthoxyleae tribe. On the other hand, the bacteria and fungi are needed for more substantial chemical studies. When more data become available, it is likely that useful systematic correlations will emerge. More detailed studies regarding the biosynthetic pathways of the alkyl-, aryl-, and alkylarylquinolin/ones in the Rutaceae and in bacteria are needed. Such studies would clarify the differences in the pathways based on their derivation from anthranilic acid in bacteria and in rutaceous plants. Finally, this survey indicates that the Rutaceae, and various bacterial and fungal species offer considerable potential for the discovery of new or known alkaloids with significant and possibly valuable biological activities.

Growth and production of laccases by the ligninolytic fungi, Pleurotus ostreatus and Botryosphaeria rhodina , cultured on basal medium containing the herbicide, Scepter (imazaquin).

The herbicide, Scepter, whose active principle is imazaquin, is commonly used in soybean farming to combat wide-leaf weeds. The basidiomycete, Pleurotus ostreatus , and the ascomycete, Botryosphaeria rhodina , were evaluated for their growth and laccase production when cultured on basal media containing Scepter. Both fungi could grow on the herbicide when cultivated in solid and submerged liquid culture in the presence of Scepter at concentrations of 0-6% (v/v) for P. ostreatus , and up to 0-50% (v/v) for B. rhodina , and in each case produced laccases when assayed against ABTS [2,2(1)-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)] and 2,6-dimethoxyphenol. P . ostreatus could tolerate up to 6% of Scepter before it became toxic to the fungus, while in the case of B. rhodina , 50% (v/v) Scepter was the highest amount that supported grow, and laccase activity was detectable up to 25% (v/v). An inverse relationship existed between the level of Scepter in the culture medium that supported fungal growth and laccase production. Analysis of the results showed that the fungi studied presented different behaviour towards Scepter in the culture environment.

Sorption of imazaquin in soils with positive balance of charges.

The herbicide imazaquin has both an acid and a basic ionizable groups, and its sorption depends upon the pH, the electric potential (psi0), and the oxide and the organic carbon (OC) contents of the soil. Sorption and extraction experiments using 14C-imazaquin were performed in surface and subsurface samples of two acric oxisols (an anionic "rhodic" acrudox and an anionic "xanthic" acrudox) and one non-acric alfisol (a rhodic kandiudalf), treated at four different pH values. Imazaquin showed low to moderate sorption to the soils. Sorption decreased and aqueous extraction increased as pH increased. Up to pH 5.8, sorption was higher in subsurface than in surface layers of the acric soils, due to the positive balance of charges resulted from the high Fe and Al oxide and the low OC contents. It favored electrostatic interactions with anionic molecules of imazaquin. For the subsurface samples of these highly weathered soils, where psi0 was positive and OC was low, it was not possible to predict sorption just by considering imazaquin speciation and its hydrophobic partition to the organic domains of the soil. Moreover, if Koc measured for thesurface samples were assumed to represent the whole profile in predictive models for leaching potential, then it would result in underestimation of sorption potential in subsurface, and consequently result in overestimation of the leaching potential.

Microsomal metabolism of quinifuryl--a nitrofuryl-ethenyl-quinolone antiseptic possessing antitumor activity in vitro.

Quinifuryl, 2-(5'-nitro-2'-furanyl)ethenyl-4-[N-[4'-(N,N-diethylamino)-1'-methylbuty l] carbamoyl] quinoline, is a representative of a family of nitrofuran-ethenyl-quinoline antibiotics synthesized in the USSR by Dr N.M. Sukhova. The drug has been shown to be an effective cytostatic and radiosensitizer towards cancer cells in culture. While rapid metabolic consumption of these drugs by liver tissue has been shown, none of the drug metabolites have been isolated and characterized. Here, we present the results of experiments focusing on the isolation and characterization of quinifuryl metabolites. A pyridine derivative was the sole product detected and characterized by GC-MS analysis. An alteration of quinifuryl metabolism by peroxynitrite formed during the metabolism of the drug was assumed to be responsible for an unexpectedly high drug decomposition.

Concentraçöes inibitórias mínimas de ciprofloxacin (BAY-9867) para bactérias isoladas no Rio de Janeiro, RJ / Minimal inhibitory concentrations of ciprofloxacin (BAY-9867) for isolated bacteria isolated in Rio de Janeiro, RJ

Foi determinada a concentraçäo inibitória mínima in vitro do ciprofloxacin para cepas de enterobactérias, enterecocos, staphylococcus, Pseudomonas e bactérias anaeróbias estritas isoladas de diversos processos infecciosos de pacientes do Rio de Janeiro, RJ. A maioria das cepas de Escherichia coli e Klebsiella pneumoniae foi inibida com 0,25microng/ml do antimicrobiano, enquanto 1,0microng/ml foi necessário para inibir 90% das cepas de Proteus e Staphylococcus. A CIM90 para cepas de Pseudomonas aeruginosa e Streptococcus faecalis atingiu 2,0microng/ml; no entanto, para bactérias anaeróbias estritas (Bacteroides fragilis e Clostridium perfringens) elevou-se para 16 e 18micron/ml, respectivamente. A análise da curva de morte empregando amostra-padräo de Escherichia coli (ATCC-25922) revelou o efeito bactericida do ciprofloxacin