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At least 433 records · Page 24Linked to original sources
PubMed1985

Enoxacin: a potent inducer of filamentous Escherichia coli cells (a note).

Enoxacin (CI-919; AT-2266), a new naphthyridine derivative was found to induce morphologic changes at very low concentrations in Escherichia coli but not in Staphylococcus aureus and Pseudomonas aeruginosa cells. The development of the long filamentous forms observed with nalidixic acid is most probably a consequence of inhibition of DNA synthesis. The phenomenon may, however, not be the sole mechanism of the broad-spectrum antimicrobial activity of enoxacin.

Anti-Bacterial Agents↗
PubMed1982

[Investigations on antibacterial activity of apalcillin].

In 201 clinical isolates the antibacterial activity of (2S,5R, 6R)-6-[(R)-2-(4-Hydroxy-1,5-naphthyridine-3-carboxamido) -2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]heptane-2-carbonic acid (apalcillin, PC-904) a new semisynthetic broad spectrum penicillin, was tested. The activity was almost equal to piperacillin, the at present optimal penicillin derivative, but against pseudomonas apalcillin was clearly superior. Lack of activity as compared to the acylureidopenicillins was found in proteus species whilst its activity against E. coli and klebsiella species was higher. Antagonism was observed in pseudomonas aeruginosa for the combination of apalcillin and cefoxitin which also existed with azlocillin or piperacillin and cefoxitin.

Ampicillin↗
PubMed1982

[Investigations on the pharmacokinetics of apalcillin in man].

Plasma levels and urinary excretion was studied after i.v. bolus of 1000 mg (2S,5R,6R)-6-[(R)-2-(4-hydroxy-1, 5-naphthyridine-3-carboxamido)-phenylacetamido]-3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (apalcillin, PC-904) and after long-term infusion of 3000 mg apalcillin in volunteers of both sexes. For measuring the concentrations a cylinder agar diffusion test was used. The plasma levels decreased from 150 microgram/ml 2 min after injection to 100 microgram/ml 15 min p.a. and to 37 microgram/ml after 90 min. For the terminal half-life of elimination from plasma a value of 1.0 was calculated. After termination of the long-term infusion concentrations of 70-80 microgram/ml were found in plasma. In this case a terminal half-life of 1.5 h was calculated. Due to the fast half-life of elimination no cumulation will occur in the case of repetitive dosing. This suggestion is supported by the finding, that the mean transit time of 1.4 h is very short. On the other hand the substance is distributed so rapidly that therapeutic levels are reached 30 min after infusion. Using data from literature, a proportionality between dose and area under the plasma curve could be demonstrated in the range 1000-3000 mg apalcillin. Our results show that about 20% of the dose administered is found in urine. 10 h after application the urinary excretion is finished. No side effects were observed during the acute assays.

Adult↗
PubMed1994

Combined factor and QSAR analysis for antibacterial and pharmacokinetic data from parallel biological measurements.

Antibacterial potency data for a variety of bacterial strains and pharmacokinetic parameters of naphthyridines taken from the literature were submitted to factor and QSAR analyses. Factor analysis of antibacterial potencies unraveled a distinct data structure. The information obtained about the internal relatedness of tests can be used in QSAR analyses and reflects itself in the QSAR results. Factor analysis of pharmacokinetic data also led to a clear grouping of measurements with a strong relationship of half life time and urinary recovery, respectively, with log D.

Animals↗
PubMed1993

Pharmacological properties of a new fluoroquinolone on the central nervous system in rodents.

The pharmacological effects of the novel fluoroquinolone 7-(1R,4R-2,5-diazebicyclo[2.2.1]heptan-2-yl)-1-(1,1-dimethyl )ethyl-6-fluoro - 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (BMY-40062, CAS 116143-32-9) on central nervous system were investigated in mice and rats, in comparison in some cases with those of reference quinolones. BMY-40062 showed no effect on general behavior, spontaneous activity, body temperature and neuromuscular coordination in rats at the doses of 1000 and 250 mg/kg. None of the quinolones tested including BMY-40062 modified the seizures induced by bicuculline, a specific GABA A antagonist. BMY-40062 and ciprofloxacin did not consistently influence the pentetrazol-induced convulsions. On the contrary, pefloxacin exhibited a marked convulsivant activity. In the fenbufen (non-steroidal anti-inflammatory drug)-induced seizure model, BMY-40062 showed no effect. Enoxacin, norfloxacin followed by ciprofloxacin elicited a convulsivant effect in presence of fenbufen. Under these experimental conditions, BMY-40062 had no effect on the central nervous system compared to the other tested quinolones in rodents.

Animals↗
PubMed1998

Synthesis of some novel 2-oxo-pyrano(2,3-b)- and 2-oxo-pyrido(2,3-b)quinoline derivatives as potential antimalarial, diuretic, clastogenic and antimicrobial agents.

The 2-chloro-3-formyl quinoline derivatives (1a-e) on treatment with acetic anhydride and sodium acetate, afforded the corresponding novel 2-oxopyrano(2,3-b) quinoline derivatives (2a-e), and these were subjected to ammonia treatment to yield the corresponding naphthyridine derivatives (3a-e). The prepared compounds (2a-e) were tested for their antimalarial, diuretic, clastogenic and antimicrobial properties. Not all the compounds showed a diuretic effect and the significant increase in the frequency of micronuclei shows that they are non-clastogens, whereas the 7-chloro derivative (2e) was a very effective antimalarial agent against the mosquito species. All the compounds were found to have optimum antimicrobial activity against Staphylococcus aureus, Escherichia coli and Salmonella typhi. Compounds 2d and 2e were found to be most active against the bacteria tested.

Animals↗
PubMed2001

Molecular recognition of carbohydrates by artificial receptors: systematic studies towards recognition motifs for carbohydrates.

The synthesis and binding properties for carbohydrates of several artificial, acyclic receptors containing two or three heterocyclic recognition units covalently attached to a phenyl spacer is described. These host molecules having uncharged hydrogen-bonding sites were used in a systematic study towards the evaluation of recognition motifs for carbohydrates. A novel effective, acyclic hydrogen-bonding receptor possessing naphthyridine-amide moieties as heterocyclic recognition units has been developed.

Journal Article↗
PubMed1997

Adenosine A3 receptor agonists protect HL-60 and U-937 cells from apoptosis induced by A3 antagonists.

The effects of novel, selective adenosine (ADO) A3 receptor antagonists of diverse structure on cells of the human HL-60 leukemia and U-937 lymphoma cell lines were examined. Both 3-ethyl 5-benzyl 2-methyl-6-phenyl-4-phenylethynyl-1,4-(+/-)-dihydropyridine-3, 5-dicarboxylate (MRS 1191, 0.5 microM) and 6-carboxy-methyl-5, 9-dihydro-9-methyl-2-phenyl-[1,2,4]-triazolo [5,1-a][2,7]naphthyridine (L-249313, 0.5 microM) induced apoptotic cell death and expression of bak protein. Low concentrations of the A3 receptor agonist 2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA, 10 nM or 1 microM) protected against antagonist-induced cell death. At concentrations > or = 10 microM, the agonist alone produced apoptosis and bak expression in various cell lines. It is suggested that there exists a tonic low level of A3 receptor activation, possibly induced by release of endogenous adenosine, that results in cell protection.

Adenosine↗
PubMed1984

Forskolin and the release of noradrenaline in cerebrocortical slices.

The role of adenosine 3',5'-cyclic monophosphate (cAMP) in the release of noradrenaline from central neurones has been investigated by examining the effects of forskolin, 3-isobutyl-l-methylxanthine (IBMX), cis-6-(p-acetamidophenyl)-1,2,3,4,4a, 10b-hexahydro-8,9-dimethoxy-2-methyl-benzo[c] [1,6]-naphthyridine bis (+ +hydrogenmaleinate) (AH21-132; a new phosphodiesterase inhibitor) and N6,O2'-dibutyryl-adenosine 3',5'-cyclic monophosphate (dibutyryl-cAMP) on the outflow of tritiated compounds from rat and rabbit cerebral cortex slices preincubated with [3H]-noradrenaline. Forskolin, IBMX, AH21-132 and dibutyryl-cAMP produced a concentration-dependent increase in both basal and electrically-evoked efflux of tritium from rat and rabbit cortex slices. The increase in basal tritium efflux from rabbit cortex slices elicited by forskolin and IBMX could be attributed mainly to an increase in [3H]-DOPEG although a small increase in [3H]-noradrenaline was also observed. Forskolin and (when combined with noradrenaline) IBMX and AH21-132 increased the cAMP content of rat cortex slices at similar or somewhat higher concentrations that they increased tritium efflux. Neither forskolin nor IBMX or AH21-132 had any effect on the cocaine-sensitive uptake of [3H]-noradrenaline into synaptosomes prepared from rat or rabbit cortex. The effects of forskolin, IBMX and dibutyryl-cAMP on electrically-evoked overflow of tritium from rat and rabbit cortex slices were reduced when cocaine (10 microM) was present in the superfusion medium, although forskolin produced a similar increase in cAMP in the absence or presence of cocaine. It is suggested that cAMP may facilitate the normal process of noradrenaline release by nerve stimulation.

1-Methyl-3-isobutylxanthine↗
PubMed1988

4-quinolones inhibit biotransformation of caffeine.

The pharmacokinetics of caffeine, including formation of its major metabolite paraxanthine in plasma, has been investigated in 12 healthy males (age 20-40 years) alone and during co-administration of the 4-quinolones ofloxacin, norfloxacin, pipemidic acid, ciprofloxacin, and enoxacin; ciprofloxacin and enoxacin were given in 3 different dose levels. The naphthyridine derivative enoxacin and the pyrido-pyrimidine derivative pipemidic acid had caused marked inhibition of caffeine and paraxanthine metabolism, whereas the genuine quinolone derivatives norfloxacin and ciprofloxacin had little effect, and the pyrido-benzoxacine derivative ofloxacin had no detectable effect. The different molecular and spatial structures of the compounds appear to be responsible for the differences in inhibitory potency.

Adult↗
PubMed2001

Evidence that orexin-A-evoked grooming in the rat is mediated by orexin-1 (OX1) receptors, with downstream 5-HT2C receptor involvement.

RATIONALE: Orexins A and B have recently been discovered and shown to be derived from preproorexin, primarily expressed in the rat hypothalamus. Orexin-A has been ascribed a number of in vivo functions in the rat after intracerebroventricular (ICV) administration, including hyperphagia, neuroendocrine modulation and, most recently, evidence for a behavioural response characterised by an increase in grooming. OBJECTIVES: Here, we have investigated the orexin-receptor subtypes involved in the grooming response to orexin-A (3 microg, ICV) in the rat. METHODS: Male rats, habituated to clear Perspex behavioural observation boxes, were pretreated with antagonists with mixed selectivity for OX1, OX2, 5-HT2B and 5-HT2C receptor subtypes prior to the administration of orexin-A and the intense grooming response elicited by this peptide assessed. RESULTS: Pretreatment of rats with a mixed OX1/5-HT2B/2C receptor antagonist 1-(4-methylsulfanylphenyl)-3-quinolin-4-ylurea (SB-284422), revealed a significant, but incomplete, blockade of orexin-A-induced grooming. Despite the low potency of orexin-A at 5-HT2B and 5-HT2C receptors in vitro (pKi<5), studies were undertaken to determine whether downstream 5-HT2B or 5-HT2C receptors mediate in the grooming-elicited by orexin-A. Whilst the selective 5-HT2B receptor antagonist, SB-215505 (3 mg/kg, PO, 5-HT2B, pKi=8.58; OX1, pKB < 5.15) failed to effect orexin-A-induced grooming, the selective 5-HT2C receptor antagonist, SB-242084 (1 mg/kg, IP, 5-HT2C, pKi = 8.95; OX1, pKB < 5.1) potently antagonised the grooming response to this peptide. This suggested that the partial blockade of orexin-A-induced grooming obtained with SB-284422 might be attributable to its 5-HT2C and/or OX1 receptor blocking activity. However, complete blockade of orexin-A-induced grooming by the subsequently identified selective OX1 receptor antagonist 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea hydrochloride, SB-334867-A (OX1, pKB = 7.4; OX2, pKB = 5.7), devoid of appreciable affinity for either 5-HT2B (pKi < 5.3) or 5-HT2C (pKi < 5.4) receptors, provides the first definitive evidence that a central behavioural effect of orexin-A (grooming) is mediated by OX1 receptors. CONCLUSIONS: This data suggests that orexin-A indirectly activates 5-HT2C receptors downstream from OX1 receptors to elicit grooming in the rat. The use of SB-334867-A in vivo will enable the role of OX,1 receptors within the rat central nervous system to be further characterised.

Animals↗
PubMed1995

Effect of vinconate on the extracellular levels of dopamine and its metabolites in the rat striatum: microdialysis studies.

The effects of (+/-)-methyl-3-ethyl-2,3,3 alpha, 4-tetrahydro-1H- indolo[3,2,1-de][1,5]naphthyridine-6-carboxylate hydrochloride (vinconate), an indolonaphthyridine derivative, on the extracellular levels of dopamine and its metabolites in the rat striatum were examined using brain microdialysis. Single administration of vinconate (10, 100 mg/kg i.p.) increased the extracellular level of dopamine and its metabolites. This enhancing effect of vinconate was antagonized by scopolamine (10 microM), a muscarinic receptor antagonist, which was added to the perfusate from 30 min before vinconate treatment. These findings suggest that vinconate, even when systemically administered, enhances the endogenous release of dopamine in the striatum, probably via the stimulation of presynaptic muscarinic receptors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Effect of vinconate, an indolonaphthyridine derivative, on metabolism and function of cerebral cholinergic neurons in rat.

Effects of (+/-)-methyl 3-ethyl-2,3,3a,4-tetrahydro-1H-indolo [3,2,1,-de] [1,5] naphthyridine-6-carboxylate hydrochloride (vinconate), an indolonaphthyridine derivative, on the metabolism and function of cerebral cholinergic neurons were investigated using male Wistar rats. Single administration of vinconate (5, 50 and 200 mg/kg) decreased acetylcholine content in the striatum but not those in the cerebral cortex and hippocampus. The same treatment with vinconate (5, 50 and 200 mg/kg, p.o.) had no effect on the activities of choline acetyltransferase and acetylcholinesterase in these brain areas. Although the addition of vinconate (10(-7) - 10(-4) M) had no effect on the high affinity uptake of [3H]choline into striatal slices, it induced a concentration-dependent increase of a KCl(2 x 10(-2) M)-evoked endogenous acetylcholine release. The addition of (-)-sulpiride (10(-8) - 10(-6) M), a dopamine D2 receptor antagonist, also accentuated the KCl(2 x 10(-2) M)-evoked endogenous acetylcholine release form striatal slices. Furthermore, it was found that this (-)-sulpiride (10(-7) M)-induced increase of endogenous acetylcholine release was further augmented by the addition of vinconate (10(-5) M). These results suggest that vinconate may enhance the release of endogenous acetylcholine via the modulation of presynaptic dopamine heteroreceptor in the striatum.

Acetylcholine↗
PubMed1992

In vitro activity of various antimicrobial agents against Staphylococcus aureus isolates including fluoroquinolone- and oxacillin-resistant strains.

To determine susceptibility to 31 old and new antimicrobials, 44 strains of Staphylococcus aureus, most resistant to oxacillin and ciprofloxacin and isolated in a community hospital, were tested in vitro. For the peptide/peptide-derivative compounds, with the exception of mersacidin, all strains were inhibited by less than or equal to 2 micrograms/ml. Minimum inhibitory concentration (MIC)90 values indicated mupirocin, teicoplanin, and MDL 62211 to be fourfold more active than vancomycin, ramoplanin, and decaplanin. For fluoroquinolones, ciprofloxacin-resistant S. aureus exhibited high-level cross-resistance to ofloxacin, norfloxacin, fleroxacin, enoxacin, and Ro 23-9424. WIN 57253, a new fluorinated naphthyridine, showed good activity against these strains. Among the beta-lactams, the penem-derivative compounds (imipenem, meropenem, FCE 22101, and HRE 664) had the greatest activity, although resistance to each compound was detected among oxacillin-resistant S. aureus. The presence of tazobactam reduced the piperacillin MIC90 fourfold. Oxacillin-susceptible strains were susceptible to cephalosporins/cephamycins, whereas most oxacillin-resistant strains exhibited resistance. This study has shown that certain old and new quinolones and peptide-derivative compounds have good in vitro activity against multiply resistant strains of S. aureus.

Aminoglycosides↗
PubMed2005

Part 3: synthesis and biological evaluation of some analogs of the antitumor agents, 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid, and 2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid.

2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (X469) and 2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic Acid (SH80) are among the most highly and broadly active antitumor agents to have been developed in our laboratories. However, the mechanism(s) of action of these agents remain to be elucidated, which prompted our continued endeavor to delineate a pharmacophoric pattern, from which a putative target might be deduced. Herein, we provide additional evidence that intact quinoxaline and quinoline rings in XK469 and SH80, respectively, are fundamental to the activities of these structures against transplanted tumors in mice. The consequence of further modification of the heterocyclic ring system in XK469 and SH80, leading to [1,8]naphthyridine; pyrrolo[1,2-a]; imidazo[1,2-a]; and imidazo[1,5-a] derivatives, all deprive the parent structures of antitumor activity. Introduction of CH3, CF3, CH3O, CO2H, or C6H5 substituents at C4 of the quinoline ring of SH80 led to weakly active antitumor agents. Similarly, the phenanthridine analog of SH80 manifested only modest cytotoxicity. Lastly, XK469 and SH80 are both significantly more active than the corresponding regioisomeric structures, 2-{4-[(7-halo-4-quinolinyl)oxy]phenoxy)propionic acids.

Animals↗
PubMed2005

Esters and amides of 2,3-dimethoxy-8,9-methylenedioxy-benzo[i]phenanthridine-12-carboxylic acid: potent cytotoxic and topoisomerase I-targeting agents.

The exceptional topoisomerase I-targeting activity and antitumor activity of 5-(2-N,N-dimethylamino)ethyl-8,9-dimethoxy-2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-one (ARC-111, topovale) prompted studies on similarly substituted benzo[i]phenanthridine-12-carboxylic ester and amide derivatives. Among the benzo[i]phenanthridine-12-carboxylic esters evaluated, the 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)-1-methylethyl, and 2-(N,N-dimethylamino)-1,1-dimethylethyl esters possessed similar cytotoxicity, ranging from 30 to 55 nM in RPMI8402 and KB3-1 cells. Several of the carboxamide derivatives possess potent topoisomerase I-targeting activity and cytotoxicity. The 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, and 2-(pyrrolidin-1-yl)ethyl amides were among the more cytotoxic benzo[i]phenanthridine-12-carboxylic derivatives, with IC50 values ranging from 0.4 to 5.0 nM in RPMI8402 and KB3-1 cells.

Amides↗
PubMed2004

Synthesis of novel 2-nitroimidazole-tethered tricyclic quinolines, bearing a second heteroatom, and their in vitro evaluation as hypoxia-selective cytotoxins and radiosensitizers.

Two novel nitroimidazole-based bioreductive compounds, 10-[3-(2-nitroimidazolyl)-propylamino]-3,4-dihydro-1H-thiopyrano[4,3-b]quinoline hydrochloride (8a) and 10-[3-(2-nitroimidazolyl)propylamino]-2-methyl-1,2,3,4-tetrahydro-benzo[b]-1,6-naphthyridine hydrochloride (8b) have been synthesized and evaluated in V79 cells as hypoxia-selective cytotoxins and radiosensitizers that target DNA through weak intercalation. Both compounds were relatively good radiosensitizers (C(1.6) values of 40.0+/-0.8 and 59.0+/-0.4 microM for 8a and 8b, respectively) but neither of the compounds was superior to 2 which does not carry a second heteroatom in the DNA-intercalating chromophore.

Animals↗
PubMed2006

Novel potent and selective alphavbeta3/alphavbeta5 integrin dual antagonists with reduced binding affinity for human serum albumin.

The binding of lead compounds and drugs to human serum albumin (HSA) is a ubiquitous problem in drug discovery since it modulates the availability of the leads and drugs to their intended target, which is linked to biological efficacy. In our continuing efforts to identify small molecule alpha(V)beta(3) and alpha(V)beta(5) dual antagonists, we recently reported indoles 2-4 as potent and selective alpha(V)beta(3)/alpha(V)beta(5) antagonists with good oral bioavailability profile. In spite of subnanomolar binding affinity of these compounds to human alpha(V)beta(3) and alpha(V)beta(5) integrins, high HSA binding (96.5-97.3%) emerged as a limiting feature for these leads. Structure-activity HSA binding data of organic acids reported in the literature have demonstrated that the incorporation of polar groups into a given molecule can dramatically decrease the affinity toward HSA. We sought to apply this strategy by examining the effects of such modifications in both the central core constrain and the substituent beta to the carboxylate. Most of these derivatives were prepared in good yields through a cesium fluoride-catalyzed coupling reaction. This reaction was successful with a variety of nitrogen-containing scaffolds (20, 33, and 43) and selected acetylenic derivatives (16, 19, and 34). Among the compounds synthesized, the 3-[5-[2-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)ethoxy]indol-1-yl]-3-[5-(N,N-dimethylaminomethyl)-3-pyridyl]propionic acid (25) was found to be the most promising derivative within this novel series with a subnanomolar affinity for both alpha(v)beta(3) and alpha(v)beta(5) (IC(50) = 0.29 and 0.16 nM, respectively), similar to our initial lead receptor antagonists 2-4, and exhibiting a low HSA protein binding (40% bound, K(d) = 1.1+/-0.4 x 10(3) microM) and an improved in vitro stability profile toward human and mouse microsomes (99.9% and 98.7% remaining after 10 min). Moreover, the selectivity of 25 toward alpha(5)beta(1) and IIbIIIa integrins was perfectly maintained when compared to the parent leads 2-4. Thus, compound 25 was selected as a new lead with improved drug-like properties for further evaluations in the field of oncology and osteoporosis.

Alkynes↗