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PubMed2006

Thermodynamic characterization of the binding of naphthyridines to the AP site-containing DNA duplexes.

We here report on the thermodynamics of the hydrogen bond-mediated binding of 2-amino-7-methyl-1,8-naphthyridine (AMND) to a cytosine base opposite an abasic site (AP site) in a 21-meric DNA duplex (5'-GCA GCT CCC GXG GTC TCC TCG-3'/3'-CGT CGA GGG CCC CAG AGG AGC-5', X= AP site, C = target). The examination by fluorescence titration experiments shows a 1:1 binding constant of 2.7x10(6) M(-1) at 20 degrees C in solutions containing 110 mM Na(+) (pH 7.0). From the analysis of salt dependence of binding constants, polyelectrolyte (DeltaG(pe)) and non-polyelectrolyte (DeltaG(t)) contributions are calculated as -1.7 kcal/mol and -6.9 kcal/mol, respectively, at 110 mM Na(+) concentration. The binding enthalpy determined by isothermal titration calorimetry (ITC) is -18.5 kcal/mol in 110 mM Na(+) at 20 degrees C. We discuss these results with a view towards further development of our ligand-based fluorescence assay for SNPs (single nucleotide polymorphisms) typing.

Binding Sites↗
PubMed1992

Antibacterial activity of a 1,8-naphthyridine quinolone, PD 131628.

A new 1,8-naphthyridine quinolone antimicrobial, PD131628, was found to be as, or more active than ciprofloxacin or ofloxacin against Escherichia coli and considerably more active than the two 4-quinolone agents against staphylococci in terms of both MIC and OBC (the optimum bactericidal concentration, at which the rate of kill is greatest). In common with ciprofloxacin and ofloxacin, the rate of kill of PD131628 against Enterococcus faecalis was considerably slower than against the other three species tested. Bacterial protein synthesis, RNA synthesis and cell division were not required for the bactericidal activity of PD131628 against E. coli or the staphylococci, although the lethality of PD131628 in the absence of these activities was reduced.

Anti-Infective Agents↗
PubMed1991

In vitro antibacterial activities of PD 131628, a new 1,8-naphthyridine anti-infective agent.

PD 131628 is a new aminopyrrolidine-substituted fluorocyclopropyl naphthyridine quinolone which possesses high in vitro activity against a wide spectrum of bacterial species. The MICs for greater than or equal to 90% of strains were 0.125 to 0.25 microgram/ml for staphylococci, Streptococcus pyogenes, and S. pneumoniae; 0.5 micrograms/ml for S. agalactiae and Enterococcus faecalis; 0.125 micrograms/ml for members of the family Enterobacteriaceae and Acinetobacter spp.; 0.5 micrograms/ml for Pseudomonas aeruginosa; and less than or equal to 0.03 micrograms/ml for Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, and Neisseria gonorrhoeae. In these in vitro comparisons with ciprofloxacin, PD 131628 is more active against gram-positive organisms, approximately equivalent against gram-negative organisms, and, like most other quinolones, relatively inactive against gram-negative anaerobes. In most instances, the in vitro potency of PD 131628 exceeded those of widely used compounds: ciprofloxacin, imipenem, ampicillin, penicillin G, oxacillin, cefazolin, ceftazidime, cefoxitin, cefsulodin, aztreonam, piperacillin, amikacin, spectinomycin, doxycycline, erythromycin, metronidazole, and vancomycin.

Anti-Bacterial Agents↗
PubMed2005

Mechanism of action of a novel series of naphthyridine-type ribosome inhibitors: enhancement of tRNA footprinting at the decoding site of 16S rRNA.

The novel ribosome inhibitors (NRIs) are a broad-spectrum naphthyridine class that selectively inhibits bacterial protein synthesis (P. J. Dandliker et al., Antimicrob. Agents Chemother. 47:3831-3839, 2003). Footprinting experiments, using a range of NRIs and chemical modification agents on Escherichia coli ribosomes, revealed no evidence for direct protection of rRNA. In the presence of tRNA, however, we found that NRIs enhanced the known ribosomal footprinting pattern of tRNA in a dose-dependent manner. The most prominent increase in protection, at A1492/3 and A1413 in helix-44 of 16S RNA, strictly required the presence of tRNA and poly(U), and the effect was correlated with the potency of the inhibitor. Radioligand binding studies with inhibitor [(3)H]A-424902 showed that the compound binds to tRNA, either in its charged or uncharged form. The dissociation constant for [(3)H]A-424902 binding to Phe-tRNA(Phe) was determined to be 1.8 microM, near its translation inhibition potency of 1.6 muM in a cell-free S. pneumoniae extract assay. The compound did not change the binding of radiolabeled tRNA to the 30S ribosomal subunit. Taken together, these results imply that the NRIs exert their effects on protein synthesis by structurally perturbing the tRNA/30S complex at the decoding site.

Autoradiography↗
PubMed1999

Biochemical and pharmacological characteristics of a newly synthesized H+/K+-ATPase inhibitor, YJA20379-8, 3-butyryl-4-[R-1-methylbenzylamino]-8-ethoxy-1,7-naphthyridine, in pigs and rats.

We have investigated the effect of the newly synthesized proton-pump inhibitor YJA20379-8, 3-butyryl-4-[R-1-methylbenzylamino]-8-ethoxy-1,7-naphthyridine, on gastric mucosal proton pump (H+/K+-ATPase) activity, gastric acid secretion and gastric lesions in experimental animals. In lyophilized pig gastric microsomes, YJA20379-8 was shown to inhibit H+/K+-ATPase activity; the inhibitory effect was not affected by pH, the IC50 (dose resulting in 50% inhibition) being 28.0 microM and 30.0 microM at pH 6.4 and pH 7.4, respectively. The effect was fully reversed by dilution and subsequent washing of the incubation mixtures of H+/K+-ATPase and YJA20379-8, suggesting the reversible nature of the enzyme inhibition. In pylorus-ligated rats, YJA20379-8 administered by different routes (intraduodenal, subcutaneous, intravenous or oral) resulted in dose-dependent suppression of basal gastric acid secretion. The duration of antisecretory action of 30 mg kg(-1) YJA20379-8 given intraduodenally was very brief (less than 7 h). Pretreatment with YJA20379-8 also dose-dependently prevented gastric lesions induced by absolute ethanol and water-immersion stress in rats. These results suggest that YJA20379-8 might exert its antiulcer activity partly by reversible suppression of acid secretion and partly by protecting the gastric mucosa against ulcerative stimuli.

Animals↗
PubMed1994

Substituted 1,8-naphthyridin-2(1H)-ones as selective phosphodiesterase IV inhibitors.

New substituted 1,8-naphthyridin-2(1H)-ones have been found to exhibit highly selective phosphodiesterase (PDE) IV inhibition. These compounds inhibited polymorphonuclear leukocyte activation induced by N-formylmethionyl-leucyl-phenylalanine and caused relaxation of isolated guinea pig trachea precontracted by histamine or leukotriene D4. In anesthetized guinea pigs, presensitized with the antigen, these compounds also alleviated airway constriction induced by the antigen. Since these compounds differ in their chemical structure compared with theophylline and other PDE IV inhibitors so far reported and some of them have been shown to be well tolerated in acute toxicity studies, they will provide a new tool for investigating the possible relationship between PDE IV inhibition and anti-asthmatic activity.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2002

Synthetic studies on selective type 4 phosphodiesterase (PDE 4) inhibitors. 1. Structure-activity relationships and pharmacological evaluation of 1,8-naphthyridin-2(1H)-one derivatives.

In order to develop novel and orally active phosphodiesterase (PDE) 4 inhibitors, random screening was performed using our chemical library to find YM-10335 possessing the 1,8-naphthyridin-2(1H)-one skeleton which is a completely different structure from rolipram. In this report, the syntheses and structure-activity relationships of the YM-10335 derivatives were described. Some compounds showed selective inhibitory activities for PDE 4 derived from human peripheral blood cells and no effect on the other PDE types (1, 2, 3, 5). The inhibition of the tumor necrosis factor-alpha (TNF-alpha) release in vitro and the carrageenan-induced pleurisy in rats were also described.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMedDate not supplied

Synthesis and evaluation of antihypertensive activity of 1,8-naphthyridine derivatives. Part X.

A series of 4-(N-methylencycloalkylamino)-1,8-naphthyridine derivatives variously substituted in positions 2 and 7 were synthesized and pharmacologically investigated for possible antihypertensive activity. These compounds were tested to determine a possible vasodilator mechanism of action. Compounds 22, 23, 27-29, 47 and 48 showed satisfactory levels of potency (pIC(50)>5), which in one case (compound 23) reached a really interesting value (pIC(50) 6.92). Furthermore, for some selected compounds (19, 22, 23, 26, 28, 29, 47), the vasorelaxing activity was also evaluated in the presence of the guanylate cyclase blocker ODQ or of the adenylate cyclase blocker SQ 22536, and some of these can be considered as possible guanylate-cyclase inhibitors. Finally, compounds 19, 22 and 23 were also tested in the presence of the ATP-sensitive potassium channel blocker glybenclamide and seem to possess activating properties on these potassium channels.

Animals↗
PubMed1975

Histogenesis and growing patterns of lung tumors induced by potassium 1-methyl-1,4-dihydro-7-(2-(5-nitrofuryl)vinyl)-4-oxo-1,8-naphthyridine-3-carboxylate in ICR mice.

The oral administration of 0.01% potassium 1-methyl-1,4-dihydro-7-(2-(5-nitrofuryl)vinyl)-4-oxo-1,8-naphthyridine-3-carboxylate (NFN) in ICR/JCL mice resulted in the development of tumors in the lung, forestomach, thymus, and other areas. Special attention was directed to the incidence and growing processes of the pulmonary tumors, which usually exhibited multicentric occurrence. Adenomatous hyperplasia and adenoma were observed in 22.2% of group A (15 approximately 30 weeks), 81.3% of group B (30 approximately 38 weeks), and 91.2% of group C (38 approximately 54 weeks). One case of carcinoma in group B and 5 cases in group C were also found. Most of adenomatous hyperplasia and adenomas developed around 30 weeks after the beginning of administration, whereas the carcinomas developed after 36 weeks. The incidence of tumors was much earlier in females than in males. Further, the tumors were observed to have originated from type B alveolar epithelial cells. The growth of type B alveolar epithelial cells was first noted as an adenomatous hyperplasia along the original alveolar walls, disintegrating and virtually replacing type A alveolar epithelial cells. Accordingly adenoma noduli was formed by these proliferated type B alveolar epithelial cells. Atypical, basophilic cell clusters were found to be present within the adenomas. It was suggested that carcinomas might have originated from these atypical type B alveolar epithelial cells.

Adenoma↗
PubMed1975

[Reaction of 1,8-naphthyridine azides with ethyl acrylate].

The reaction of 1,8-naphthyridine azides with ethyl acrylate leads to the formation of 2-pyrazolines instead of 1,2,3-triazolines. Some of the compounds obtained have undergone pharmacological and microbiological (antibacterial) testing.

Acrylates↗
PubMedDate not supplied

Benzo[b]-1,8-naphthyridine derivatives: synthesis and reversal activity on multidrug resistance.

A series of benzo[b]-1,8-naphthyridine derivatives branched with various side-chains and substituents were prepared with the aim of being investigated as multidrug resistance (MDR) modulators. The syntheses were achieved from 2-halonicotinic acid and suitable aryl-amines according to a three-step procedure. All the derivatives were tested in vitro on mouse T-Lymphoma cell line L5178 transfected by MDR1 gene and the chemosensitizing properties of the compounds were compared to those of verapamil and propranolol, as well as to several other tricyclic derivatives like phenothiazines and acridines. Most of the compounds tested reversed the MDR of tumour cells more effectively than the reference drugs did and they showed more potent chemosensitizing activity than phenothiazine and acridine derivatives have.

Animals↗
PubMed2005

[Benzo[h][1 ,6]naphthyridines from dimethyl 1,2-dihydro-2-(2-nitrophenyl)-pyridine-3,5-dicarboxylate].

The reaction of 2-nitrobenzaldehyde with methyl propiolate and ammonium acetate in acetic acid yields 2,6-dinor-nifedipine (1a) and as a by-product not the dimethyl 2,5-dicarboxylate isomer, but the rac. 1,2-dihydropyridine (DHP) 1b, as proven by X-ray analysis. The benzo[h][1,6]naphthyridines 4-6 are synthesized from the oxidation product 2b and the photo-product 3b. The compounds 6 represent starting materials for potential anti-malarial agents.

Antimalarials↗
PubMed1989

Study of inhibition of platelet aggregation of 1,8-naphthyridine derivatives.

The antiplatelet activity of some 1,8-naphthyridine derivatives was studied. The compounds displayed different abilities in blocking the effects of ADP, collagen and arachidonic acid. Four of them showed an in vitro remarkable activity similar to that of dipyridamole and papaverine.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1989

[Study on metabolism of pyridonecarboxylic acid II. Determination of metabolites of (+-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate hydrate (T-3262) in blood, urine, bile, and feces].

The fate of (+-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl-1,4- dihyro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate hydrate (T-3262) was studied using T-3262 and 14C-T-3262 in various animals. 1. Metabolites in serum and urine were assayed for mouse, rat, rabbit, dog and monkey following oral administration of T-3262. In serum, besides unchanged T-3262 base, T-3262A (N-acetylated) was detected in rat, rabbit and monkey; T-3262B (deamino-hydroxylated) was detected in monkey. In urine, unchanged T-3262 base was excreted mainly. But a few of metabolites (T-3262A, T-3262B, T-3262 glucuronide, T-3262A glucuronide, T-3262B glucuronide, and unknown compound M-1) were detected, and species difference existed in types of metabolites. 2. Metabolites in bile and feces were assayed for mouse and rat following oral administration of T-3262 and 14C-T-3262. Metabolites in bile were similar to the urine, but the volume of T-3262A and T-3262A glucuronide was larger than in urine. In feces, the excreted compounds mainly consisted of unchanged T-3262 base. 3. p-Toluenesulfonic acid, which is the counter acid for T-3262 base, was absorbed following the oral administration of T-3262, and excreted in urine in the unchanged form.

4-Quinolones↗
PubMed1987

Synthesis and binding study on pyrazolo[4,5-c] [1,8]naphthyridines.

Following our previous reports on pyrazolo[4,5-c]quinoline derivatives some isosteric pyrazolo[4,5-c] [1,8]naphthyridines were synthesized and tested for their ability to displace [3H]flunitrazepam from rat brain membranes. The lack of activity of the synthesized compounds and structure-activity relationships for the whole series are discussed.

Animals↗
PubMed1986

Synthesis of new 6H-indolo[2,3-b] [1,8]naphthyridines and their specific inhibition of benzodiazepine receptor.

Some 3-amino- and 3-hydroxy-8-halosubstituted 6H-indolo[2,3-b] [1,8]naphthyridines were synthesized and tested for their affinity for the benzodiazepine receptor in bovine cortical membranes. All prepared compounds were more active than the corresponding 8-unsubstituted derivatives. Moreover, among these compounds the 8-chloroindolonaphthyridines were clearly the most potent.

Animals↗