Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “NAPHTHYRIDINES”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources
PubMed2003

Nitro and amino substitution in the D-ring of 5-(2-dimethylaminoethyl)- 2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-ones: effect on topoisomerase-I targeting activity and cytotoxicity.

5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one exhibits potent TOP1-targeting activity and pronounced antitumor activity. It was hypothesized that replacement of the two methoxyl groups with a nitro substituent would allow for retention of similar activity. In this study 8-, 9-, and 10-nitro-5H-2,3-methylenedioxy-5-(2-N,N-dimethylaminoethyl)dibenzo[c,h][1,6]naphthyridin-6-one and their amino derivatives were synthesized and assessed for their relative TOP1-targeting activity and cytotoxicity. In the case of both the 8- and 9-nitro analogues, their TOP1-targeting activity and cytotoxicity are greater than that of camptothecin and comparable to that of 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one.

Amines↗
PubMed2006

Design, synthesis, and biological evaluation of new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives as CB2 selective agonists.

On the basis of docking studies carried out using the recently published cannabinoid receptor models,35 new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the cannabinoid CB1 and CB2 receptors. Compound 10, which presented p-fluorobenzyl and carboxycycloheptylamide substituents bound in the 1 and 3 positions of the 1,8-naphthyiridine-4-one nucleus, showed a high CB2 affinity with a Ki of 1.0 nM. The substitution of the naphthyridine-4-one nucleus with the quinoline-4-one system determined a general increase in CB2 affinity. In particular, the N-cyclohexyl-7-chloro-1-(2-morpholin-4-ylethyl)quinolin-4(1H)-on-3-carboxamide (40) possessed a remarkable affinity, with Ki of 3.3 nM, which was also accompanied by a high selectivity for the CB2 receptor (Ki(CB1)/Ki(CB2) ratio greater than 303). Moreover, the [35S]GTPgamma binding assay and functional studies on human basophils indicated that the 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives behaved as CB1 and CB2 receptor agonists.

Amides↗
PubMed1997

Antitumor agents. 178. Synthesis and biological evaluation of substituted 2-aryl-1,8-naphthyridin-4(1H)-ones as antitumor agents that inhibit tubulin polymerization.

As part of our continuing search for potential anticancer drug candidates in the 2-aryl-1,8-naphthyridin-4(1H)-one series, we have synthesized two series of 3'-substituted 2-phenyl-1,8-naphthyridin-4(1H)-ones and 2-naphthyl-1,8-naphthyridin-4(1H)-ones. All compounds showed significant cytotoxic effects (log GI50 < -4.0; log molar drug concentration required to cause 50% growth inhibition) against a variety of human tumor cell lines of the National Cancer Institute's in vitro screen, including cells derived from solid tumors such as non-small cell lung, colon, central nervous system, melanoma, ovarian, prostate, and breast cancers. All 3'-substituted compounds demonstrated strong cytotoxic effects in almost all tumor cell lines. Introduction of an aromatic ring at the 2'- and 3'-positions also generated compounds with potent antitumor activity. Incorporation of an aromatic ring at the 3'- and 4'-positions produced compounds with reduced activity. Interestingly, introduction of a halogen at the 3'-position yielded compounds with different selectivity for the tumor cell lines tested. All 3'-halogenated compounds (29-36) and compounds 38 and 42-44 were potent inhibitors of tubulin polymerization with activities nearly comparable to those of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. Active agents also inhibited the binding of [3H]colchicine to tubulin.

Antineoplastic Agents↗
PubMed2000

Synthesis of 6H-indolo[2,3-b][1,6]naphthyridines and related compounds as the 5-Aza analogues of ellipticine alkaloids.

Treatment of 2-(1-alkynyl)phenyl isocyanates 6 with the iminophosphorane 14 produced in situ the benzoenynyl carbodiimides 15. Thermolysis of 15 under refluxing p-xylene furnished the 6H-indolo[2,3-b][1,6]naphthyridines 5, which could be regarded as the 5-aza analogues of ellipticine alkaloids. Similarly, condensation of 6 with the iminophosphorane 20 led to the formation of the 6H-indolo[2,3-b][1,5]naphthyridines 25 as the major isomer and the 10H- indolo[2,3-b][1,7]naphthyridines 26 as the minor isomer. The indolonaphthyridines 32, 33, and 34 having a methoxyl substituent were likewise synthesized. Treatment of the diisocyanate 43 with 2 equiv of the iminophosphorane 7 furnished 45 having two indoloquinoline units incorporated in a seven-fused-ring system.

Antineoplastic Agents↗
PubMed2000

Synthesis of 8-methoxy-1-methyl-1H-benzo[de][1,6]naphthyridin-9-ol (Isoaaptamine) and analogues.

8-Methoxy-1-methyl-1H-benzo[de][1,6]naphthyridin-9-ol, isoaaptamine, a PKC inhibitor isolated from sponge was synthesized. The synthesis parallels a synthesis of 8,9-dimethoxybenzo[de][1,6]naphthyridine, aaptamine, but uses a nitromethyl substituent as a precursor of the key 5-(2-aminoethyl)-1H-quinolin-4-one intermediate. The quinolone intermediates were prepared by thermolysis (220-240 degrees C) of anilinomethylene derivatives of Meldrum's acid. The quinolone intermediates were N-methylated prior to cyclization to the benzo[de][1,6]naphthyridine derivatives. Aaptamine and several analogues of aaptamine and isoaaptamine were prepared including 9-demethylaaptamine, 1-methyl-8-demethylaaptamine, 1-methylaaptamine, and the 8,9-methylenedioxy analogues of aaptamine and 1-methylaaptamine.

Enzyme Inhibitors↗
PubMed2004

A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase.

The increasing incidence of resistance to current HIV-1 therapy underscores the need to develop antiretroviral agents with new mechanisms of action. Integrase, one of three viral enzymes essential for HIV-1 replication, presents an important yet unexploited opportunity for drug development. We describe here the identification and characterization of L-870,810, a small-molecule inhibitor of HIV-1 integrase with potent antiviral activity in cell culture and good pharmacokinetic properties. L-870,810 is an inhibitor with an 8-hydroxy-(1,6)-naphthyridine-7-carboxamide pharmacophore. The compound inhibits HIV-1 integrase-mediated strand transfer, and its antiviral activity in vitro is a direct consequence of this ascribed effect on integration. L-870,810 is mechanistically identical to previously described inhibitors from the diketo acid series; however, viruses selected for resistance to L-870,810 contain mutations (integrase residues 72, 121, and 125) that uniquely confer resistance to the naphthyridine. Conversely, mutations associated with resistance to the diketo acid do not engender naphthyridine resistance. Importantly, the mutations associated with resistance to each of these inhibitors map to distinct regions within the integrase active site. Therefore, we propose a model of the two inhibitors that is consistent with this observation and suggests specific interactions with discrete binding sites for each ligand. These studies provide a structural basis and rationale for developing integrase inhibitors with the potential for unique and nonoverlapping resistance profiles.

Animals↗
PubMed2003

The binding of naphthyridine tetramer to guanine-rich sequences.

A dimeric form of 2-amino-1,8-naphthyridine derivative ND binds to human telomeric sequence d(TTAGGG)n by strong stabilization of G-G mismatches in the hypothetical duplex of the sequence, and inhibits the elongation of the sequence by telomerase. To gain higher affinity to the telomeric sequence, we have synthesized naphthyridine tetramer NT which contains four naphthyridine chromophores. Tm measurements of the telomeric sequence in the presence of NT and ND indicated that NT binds more strongly to the telomeric sequence than ND. Electrospray ionization mass spectorometry of the complex between NT and 15-mer telomeric sequence clearly showed that one molecule of NT bound to the 15-mer sequence. This suggested that the 15-mer forms hairpin-like structure in the complex, and the resultant of the G-G mismatches were stabilized by NT.

Base Sequence↗
PubMed2000

New method for scanning of single-nucleotide polymorphisms (SNPs): recognition of guanine-guanine mismatches by dimeric naphthyridine.

Dimeric naphthyridine was designed and synthesized as a novel ligand that specifically binds to G-G mismatch, one of four SNP types. In the presence of dimeric naphthyridine, CD spectra of the G-G mismatch containing duplex noticeably changed, being accompanied by the induced CD at 300-350 nm, whereas no CD spectral change was observed for normal duplex. DNaseI footprinting titration indicated a selective binding of dimeric naphthyridine to the G-G mismatch with a dissociation constant of 53 nM.

Base Pair Mismatch↗
PubMed1969

Microbiological metabolism of naphthyridines.

Penicillium adametzi and seven other species convert nalidixic acid, 1,4-dihydro-1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid, to 1,4-dihydro-1-ethyl-7-hydroxymethyl-4-oxo-1,8-naphthyridine-3-carboxylic acid. Forty-seven other species from six orders of fungi seem to achieve the same conversion as judged by chromatographic and spectral evidence. Under special conditions, P. adametzi also produces a second metabolite which was identified as the corresponding 7-carboxylic acid. The metabolic attack on the ring substituent is identical with the pathway previously established with humans. No evidence was obtained for metabolic attack on the naphthyridine nucleus itself.

Ascomycota↗
PubMed1994

Synthesis and pharmacological evaluation of new esters of 2- and 4-alkylamino-1,8-naphthyridine-3-carboxylic acids endowed with positive inotropic properties.

In order to gain insight into structure-activity relationships concerning the positive inotropic effect of N-heterocycles, a series of 1,8-naphthyridines was synthesized by two different methods. First, 4-hydroxy substituted derivatives were accessible by cyclization of 2-vinylamino-1,8-naphthyridines using diphenyl-ether followed by chlorination and nucleophilic reactions with various amino compounds. Second, 2-amino-nicotinic acid was transformed to 2-alkylamino-1,8-naphthyridines involving a variation of the Friedländer synthesis as well as many subsequent steps. The effect of the compounds on myocardial contractility was assessed in guinea pig left atria paced at 3 Hz. In general, the concentrations for positive inotropism ranged in between 10(-6)-10(-4) mol/l. The compounds differed considerably with respect to the efficacy of the increase in contractile force. The pharmacological investigations appear to demonstrate the following requirements for the pharmacophoric structure. In connection with a lipophilic ester function in 3-position the target compounds have to contain an alkylamino side chain at C-4 bearing a pi-electron-rich center in a definite distance to the NH-function.

Animals↗
PubMed1996

Synthesis and Reactivity of (Pentafluorophenyl)platinate(II) Complexes with Bridging 1,8-Naphthyridine (napy) and X Ligands (X = C(6)F(5), OH, Cl, Br, I, SPh). Crystal Structure of [NBu(4)][Pt(2)(&mgr;-napy)(&mgr;-OH)(C(6)F(5))(4)].CHCl(3).

By reaction of [NBu(4)](2)[Pt(2)(&mgr;-C(6)F(5))(2)(C(6)F(5))(4)] with 1,8-naphthyridine (napy), [NBu(4)][Pt(C(6)F(5))(3)(napy)] (1) is obtained. This compound reacts with cis-[Pt(C(6)F(5))(2)(THF)(2)] to give the dinuclear derivative [NBu(4)][Pt(2)(&mgr;-napy)(&mgr;-C(6)F(5))(C(6)F(5))(4)] (2). The reaction of several HX species with 2 results in the substitution of the bridging C(6)F(5) by other ligands (X) such as OH (3), Cl (4), Br (5), I (6), and SPh (7), maintaining in all cases the naphthyridine bridging ligand. The structure of 3 was determined by single-crystal X-ray diffraction. The compound crystallizes in the monoclinic system, space group P2(1)/n, with a = 12.022(2) Å, b = 16.677(3) Å, c = 27.154(5) Å, beta = 98.58(3) degrees, V = 5383.2(16) Å(3), and Z = 4. The structure was refined to residuals of R = 0.0488 and R(w) = 0.0547. The complex consists of two square-planar platinum(II) fragments sharing a naphthyridine and OH bridging ligands, which are in cis positions. The short Pt-Pt distance [3.008(1) Å] seems to be a consequence of the bridging ligands.

Journal Article↗
PubMed2003

Highly regioselective Friedländer annulations with unmodified ketones employing novel amine catalysts: syntheses of 2-substituted quinolines, 1,8-naphthyridines, and related heterocycles.

Catalysts were evaluated on the preparation of 2-substituted quinolines, 1,8-naphthyridines, and chromone derivatives from unmodified methyl ketones and o-aminoaromatic aldehydes. While oxide catalysts yielded the 2,3-dialkyl substituted products, cyclic secondary amines provided the 2-alkylsubstutited products regioselectively. In particular, pyrrolidine derivatives provided the highest regioselectivity favoring the 2-substituted products. The most reactive and regioselective catalyst was the bicyclic pyrrolidine derivative, TABO (1,3,3-trimethyl-6-azabicyclo[3.2.1]octane), yielding 1,8-naphthyridines with as high as 96:4 regioselectivity. Regioselectivity increased with slow addition of the methyl ketone substrate to the reaction mixture, and was positively related to temperature. Isolated yields of single regioisomers were typically 65-84%, while observed regioselectivities were > or =90:10 for 1,8-naphthyridines and > or =84:16 for quinolines.

Journal Article↗
PubMed2006

Pd-catalyzed amidation of 2-chloro- and 2,7-dichloro-1,8-naphthyridines.

[reactions: see text] The catalytic amidation between 2-chloro- and 2,7-dichloro-1,8-naphthyridines and primary amides bearing functional groups is reported. When Pd(OAc)2, xantphos, and K2CO3 are used, it is possible to obtain symmetric as well as nonsymmetric 2,7-diamido-1,8-naphthyridines in 50-90% yield with good functional-group tolerance. Monoamidation of 2,7-dichloro-1,8-naphthyridine using 0.9 equiv of the amide proceeded with good selectivity compared to the formation of the diamide, but as a result of the difficult isolation of the product, isolated yields were poor to moderate (22-42%).

Journal Article↗
PubMed2006

Hybridization properties and enzymatic recognitions of naphthyridine:imidazopyridopyrimidine base pairs.

We describe the synthesis of 1,8-naphthyridine C-nucleosides, Na-N(O) and Na-O(N), and full details of hybridization properties of the duplexes containing naphthyridine:imidazopyridopyrimidine pairs. The desired compounds were obtained from Na-O(N) derivative 1 via conversions of the substituents of 2- and 7-positions, respectively. The 17mer duplex containing one Na-O(O):Im-N(N) pair in the center was stabilized by +11.4 degrees C relative to that containing a T:A pair, and this value was highest among the naphthyridine:imidazopyridopyrimidine pairs.

Base Pairing↗
PubMed1994

Pharmacological characterization of positive inotropic derivatives of 4-amino-7-methyl-1,8-naphthyridine-3-carboxylic acid.

The positive inotropic effect of a series of 4-amino-7-methyl-1,8-naphthyridine-3-carboxylic acid derivatives was compared with the effects of known inotropic agents (ouabain, dihydroouabain, isoproterenol, adrenaline, histamine and isobutylmethylxanthine) in guinea-pig atrial and ventricular myocardial preparations. With respect to their functional effects, the 1,8-naphthyridine compounds are clearly different from drugs acting on the cAMP system, whereas several similarities with cardiac glycoside effects were found. Their ability to inhibit [3H]ouabain binding in guinea-pig cardiac membranes correlates well with their effects on myocardial contractile force. However, the latter effect was exerted by tenfold lower concentrations. The dissimilarities found between the 1,8-naphthyridines and digitalis may be due to a different type of interaction with the binding site on the (Na(+) + K+)-ATPase.

Animals↗
PubMed1999

Synthesis and antitumor activity of some new substituted quinolin-4-one and 1,7-naphthyridin-4-one analogs.

The synthesis of some new analogs of quinolin-4-one and 1,7-naphthyridin-4-one is described. The prepared compounds were tested for their in vitro antitumor and cdc2 kinase or cdc25 phosphatase inhibitory activity. Compound ethyl 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][2,3-b]pyrido-1,4-thiazine-6-carboxylate (6b) showed antitumor activity against CNS SNB-75, breast T-47D, and lung NCI-H522 cancer cell lines with GI50 values of 8.3, 17.6, and 22.7 microM, respectively. Meanwhile, the compounds ethyl 4-oxo-8-phenylthio-1H,4H-quinoline-3-carboxylate (11a) and 4-oxo-8-phenylthio-1H,4H-1,7-naphthyridine-3-carboxylic acid (12b) have proved to be cdc25 phosphatase inhibitors at IC50 values of 11 and 5 microM, respectively.

Antineoplastic Agents↗
PubMed2004

Synthesis and cytostatic properties of some 6H-Indolo[2, 3-b][1, 8]naphthyridine derivatives.

The new and efficient synthesis of the title heterocyclic ring system is described starting from suitable 2-chloro-1, 8-naphthyridines. The synthesized 6H-indolo[2, 3-b][1, 8]naphthyridine derivatives were tested in vitro on 55 tumor cell lines for their anticancer properties. The presence of the acetylamino moiety at position 3 in the main ring system proved to be crucial for the cytostatic activity of this class of compounds.

Antineoplastic Agents↗
PubMed2004

Synthesis and biological evaluation of 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives as new ligands of cannabinoid receptors.

Cannabinoid receptors have been studied extensively in view of their potential functional role in several physiological and pathological processes. For this reason, the search for new potent, selective ligands for subtype CB receptors, CB(1) and CB(2), is still of great importance, in order to investigate their role in various physiological functions. The present study describes the synthesis and the biological properties of a series of 1,8-naphthyridine derivatives, characterised by the presence of some important structural requirements exhibited by other classes of cannabinoid ligands, such as an aliphatic or aromatic carboxamide group in position 3, and an alkyl or arylalkyl substituent in position 1. These compounds were assayed for binding both to the brain and to peripheral cannabinoid receptors (CB(1) and CB(2)). The results obtained indicate that the naphthyridine derivatives examined possess a greater affinity for the CB(2) receptor than for the CB(1) receptor. In particular, derivatives 6a and 7a possess an appreciable affinity for the CB(2) receptor, with K(i) values of 5.5 and 8.0 nM respectively; also compounds 4a, 5a and 8a exhibit a good CB(2) affinity, with K(i) values in the range of 10-44 nM. Furthermore, compounds 3g-i and 18 revealed a good CB(2) selectivity, with a CB(1)/CB(2) ratio >20.

Animals↗