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PubMed2005

Identification of amino acids in HIV-1 and avian sarcoma virus integrase subsites required for specific recognition of the long terminal repeat Ends.

A tetramer model for HIV-1 integrase (IN) with DNA representing 20 bp of the U3 and U5 long terminal repeats (LTR) termini was assembled using structural and biochemical data and molecular dynamics simulations. It predicted amino acid residues on the enzyme surface that can interact with the LTR termini. A separate structural alignment of HIV-1, simian sarcoma virus (SIV), and avian sarcoma virus (ASV) INs predicted which of these residues were unique. To determine whether these residues were responsible for specific recognition of the LTR termini, the amino acids from ASV IN were substituted into the structurally equivalent positions of HIV-1 IN, and the ability of the chimeras to 3 ' process U5 HIV-1 or ASV duplex oligos was determined. This analysis demonstrated that there are multiple amino acid contacts with the LTRs and that substitution of ASV IN amino acids at many of the analogous positions in HIV-1 IN conferred partial ability to cleave ASV substrates with a concomitant loss in the ability to cleave the homologous HIV-1 substrate. HIV-1 IN residues that changed specificity include Val(72), Ser(153), Lys(160)-Ile(161), Gly(163)-Val(165), and His(171)-Leu(172). Because a chimera that combines several of these substitutions showed a specificity of cleavage of the U5 ASV substrate closer to wild type ASV IN compared with chimeras with individual amino acid substitutions, it appears that the sum of the IN interactions with the LTRs determines the specificity. Finally, residues Ser(153) and Val(72) in HIV-1 IN are among those that change in enzymes that develop resistance to naphthyridine carboxamide- and diketo acid-related inhibitors in cells. Thus, amino acid residues involved in recognition of the LTRs are among these positions that change in development of drug resistance.

Amino Acid Sequence↗
PubMed2003

Antibodies to the quinolones and fluoroquinolones for the development of generic and specific immunoassays for detection of these residues in animal products.

Several quinolone and fluoroquinolone haptens have been used to raise polyclonal antibodies exhibiting both specific and generic properties for these classes of antimicrobial compounds. The antisera have been assessed in rapid enzyme immunoassays (ELISAs) designed to exploit the specificities obtained. A direct generic ELISA for both the quinolones and fluoroquinolones has been developed that uses the cross-reactivity of an antibody raised against norfloxacin (1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid) linked to ovalbumin via a secondary amine group on the piperazinyl moiety to detect nine different drugs in these classes. Specific ELISAs to ciprofloxacin (1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid), enrofloxacin (1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid), flumequin (9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylic acid) and nalidixic acid (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid) have also been developed with a high degree of specificity to the individual compounds. The assays measure drug residues in bovine milk and ovine kidney with an interassay relative standard deviation (s(r)) of 10.5% or less and intra-assay s(r) of 11.2% or less. Sensitivity is less than 4 microg x kg(-1) for both the generic and specific assays for all but one of the compounds tested. (Pipemidic acid (8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido(2,3-d)pyrimidine-6-carboxylic acid) is detectable at 6 microg x kg(-1) in kidney.)

4-Quinolones↗
PubMed1997

Characteristics of quinolone-induced small colony variants in Staphylococcus aureus.

Exposure of Staphylococcus aureus to 1 x MIC of the quinolone antibiotic pazufloxacin for 24 h, followed by plating on drug-free media, led to the emergence of small colony variants (SCVs) in addition to large colony variants (LCVs). However, following incubation with 0.25 or 4 x MIC of pazufloxacin, only LCVs were obtained. The SCVs were half as susceptible to pazufloxacin or ciprofloxacin as wild-type S. aureus, while the susceptibilities of LCVs were essentially unchanged. The reduced susceptibilities of SCVs did not result from mutations in the quinolone-resistance-determining regions of DNA gyrase and topoisomerase IV, since the sequences of these genes were identical to those of the wild-type. However, the SCVs accumulated pazufloxacin and ciprofloxacin to a lesser degree than did wild-type. Furthermore, their susceptibility to quinolones was almost unaffected by reserpine or verapamil, suggesting that the reduced uptake resulted from decreased permeability, rather than from an active efflux pump. The ability of various quinolones to induce emergence of SCVs in S. aureus, correlated with the presence of carbon-bonded substituents at the C-7 position of a quinoline or naphthyridine nucleus, or with the presence of a benzoxazine nucleus. In conclusion, pazufloxacin-induced SCVs represent a mutant that one might expect to be rapidly eliminated in vivo and, hence, not to survive as a quinolone-resistant pathogen. This finding suggests a novel approach for development of future quinolones.

Animals↗
PubMed1999

Comparison of the pharmacological properties of classical and novel BZ-omega receptor ligands.

The experiments in this study compared the pharmacological properties of several BZ-omega receptor ligands, including the imidazobenzodiazepine imidazenil, the beta-carboline abecarnil, the pyridazinone Y-23684, the pyrido [1,2-a]benzimidazole RWJ 46771 and the 1,6-naphthyridin-2(1H)-one derivative SX-3228, with the prototypical BZs diazepam, clobazam and bretazenil. In in vitro experiments diazepam, bretazenil, imidazenil and Y-23684 displaced [3H]flumazenil binding non-selectively in membranes from rat cerebellum and spinal cord, two brain areas enriched in the BZ-omega 1 and BZ-omega 2 receptor subtypes, respectively. In contrast, abecarnil, RWJ 46771 and SX-3228 were more potent in displacing [3H]flumazenil binding to membranes from rat cerebellum than from spinal cord or hippocampus, indicating selectivity for the BZ-omega 1 receptor subtype. The in vivo experiments showed that all compounds increased the latency to clonic seizures produced by isoniazid. However, the maximal increase in latency induced by diazepam, clobazam, abecarnil, RWJ 46771 and SX-3228 was greater than that of bretazenil, imidazenil and Y-23684, thereby indicating that these latter compounds have low intrinsic efficacy. In the punished drinking, the punished lever pressing and the elevated plus-maze tests in rats, three models of anxiety, diazepam, clobazam and imidazenil elicited clear anxiolytic-like effects but at doses which were close to those producing hypolocomotion, ataxia and myorelaxation as measured in activity cages, the rotarod and the loaded grid tests, respectively. In contrast, bretazenil and Y-23684 induced anxiolytic-like activity at much lower doses than those which impaired motor performances. The magnitude of the positive effects of Y-23684 was similar to that of the reference BZs, suggesting that it may become a valuable alternative to currently used agents for the treatment of anxiety disorders. Abecarnil, RWJ 46771 and SX-3228 produced weaker or non-specific anxiolytic-like effects as they decreased anxiety-related behaviours at doses similar or close to those impairing motor performance. However, unlike the other compounds they induced myorelaxation at doses which were 3-10 times higher than those needed to produce decrease in exploratory activity. It is suggested that the behavioural profiles of abecarnil, RWJ 46771 and SX-3228 may be attributed to their selectivity for the BZ-omega 1 receptor subtype which may account for their sedative activity, thereby masking other effects including anxiolytic-like activity. This suggests that BZ receptor modulation of anxiety may involve BZ receptor subtypes other than BZ-omega 1.

Animals↗
PubMed2004

Contribution of serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor subtypes to the hyperlocomotor effects of cocaine: acute and chronic pharmacological analyses.

The role of serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor subtypes (5-HT2AR, 5-HT2BR, and 5-HT2CR) in acute cocaine-evoked hyperactivity was compared with their contribution to the development and expression of locomotor sensitization upon repeated, intermittent treatment with cocaine (10 mg/kg/day for 5 days) in male Wistar rats. Cocaine-evoked hyperactivity was significantly enhanced by pretreatment with the preferential 5-HT2AR agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT2CR antagonist SDZ SER-082 [(+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7-BC)(2,6) naphthyridine fumarate]. The 5-HT2AR antagonist SR 46349B [1(Z)-[2-(dimethylamino)ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene] and the preferential 5-HT2CR agonist MK 212 [6-chloro-2-(1-piperazinyl)pyrazine HCl] (2 mg/kg) significantly attenuated acute cocaine-evoked hyperactivity; however, a lower dose of MK 212 (0.3 mg/kg) enhanced cocaine-evoked hyperactivity. The 5-HT2BR agonist BW 723C86 (1-[5-(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine HCl) and the 5-HT2BR antagonist SB 204741 [N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl) urea] had no effect on cocaine-evoked hyperactivity. Repeated treatment with cocaine alone resulted in a 2-fold increase in hyperactivity upon challenge with cocaine 5 days after termination of the cocaine regimen (sensitization). The 5-HT2AR antagonist SR 46349B also blocked cocaine-evoked hyperactivity following repeated cocaine treatment, whereas the other 5-HT2R ligands were ineffective. When any of the 5-HT2R ligands was coadministered with cocaine during the treatment regimen (10 mg/kg/day for 5 days), the development of sensitization was unchanged as measured by the level of cocaine-evoked hyperactivity upon challenge 5 days after termination of the treatment. The present study implies that 5-HT2AR and 5-HT2CR exert oppositional influence upon hyperactivity evoked by acute administration of cocaine; this balance is altered following repeated cocaine administration.

Amphetamines↗
PubMed2005

Orexin 1 receptor activation attenuates neurogenic dural vasodilation in an animal model of trigeminovascular nociception.

The pathophysiology underlying the pulsating quality of the pain of a migraine attack is not fully understood, although trigeminal vascular afferents containing the sensory neuropeptide calcitonin gene-related peptide (CGRP) must have a role. Antimigraine drugs, such as triptans, serotonin 5-hydroxytryptamine(1B/1D) receptor agonists, reproducibly block neurogenic vasodilation associated with CGRP release. We examined the effects of the hypothalamic neuropeptides orexin A and orexin B on neurogenic dural vasodilation, dissecting out the receptor pharmacology with the novel orexin 1 (OX1) receptor antagonist N-(2-methyl-6-benzoxazolyl)-N''-1,5-naphthyridin-4-yl urea (SB-334867). Electrical stimulation of dural afferents (50-300 microA) resulted in reproducible dural vasodilation of 136 +/- 9%. Orexin A 30 microg kg(-1), but not 3 and 10 microg kg(-1), inhibited the dilation brought about by electrical stimulation over 60 min and maximally after 15 min by 60% (t7= 7.138; P < 0.001; n = 8). This response was reversed by pretreatment with the OX1 receptor antagonist SB-334867. Addition of CGRP(8-37) at the point of maximal effect of orexin A produced a further significant decrease in neurogenic dural vasodilation compared with orexin A only. CGRP administration (1 microg kg(-1)) produced a reproducible dural blood vessel dilation of 145 +/- 7% that was not inhibited by intravenous administration of orexin A (30 microg kg(-1)). Orexin B had no significant effect even at the highest dose. The current study demonstrates that orexin A is able to inhibit neurogenic dural vasodilation via activation of the OX1 receptor, resulting in inhibition of prejunctional release of CGRP from trigeminal neurons.

Animals↗
PubMed2003

[3H]sildenafil binding to phosphodiesterase-5 is specific, kinetically heterogeneous, and stimulated by cGMP.

Sildenafil (Viagra) potentiates penile erection by acting as a nonhydrolyzable analog of cGMP and competing with this nucleotide for catalysis by phosphodiesterase-5 (PDE5), but the characteristics of direct binding of radiolabeled sildenafil to PDE5 have not been determined. [3H]Sildenafil binding to PDE5 was retained when filtered through nitrocellulose or glass-fiber membranes. Binding was inhibited by excess sildenafil, 2-(2-methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2-yl)methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride (T-0156), 3-isobutyl-1-methylxanthine, EDTA, or cGMP, but not by cAMP or 5'-GMP. PDE5 was the only [3H]sildenafil binding protein detected in human lung extract. Using purified recombinant PDE5, [3H]sildenafil exchange dissociation yielded two components with t1/2 values of 1 and 14 min and corresponding calculated KD values of 12 and 0.83 nM, respectively. This implied the existence of two conformers of the PDE5 catalytic site. [3H]Sildenafil binding isotherm of PDE5 indicated KD was 8.3 to 13.3 nM, and low cGMP decreased the KD to 4.8 nM but only slightly increased Bmax to a maximum of 0.61 mol/mol-subunit. Results suggest that these effects occur via cGMP binding to the allosteric cGMP binding sites of PDE5. Results imply that by inhibiting PDE5 and thereby increasing cGMP, sildenafil accentuates its own binding affinity for PDE5, which further elevates cGMP. The data also indicate that after physiological elevation, cGMP may directly stimulate the catalytic site by binding to the allosteric cGMP-binding sites of PDE5, thus causing negative feedback on this pathway.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1996

Structure-related inhibitory effect of antimicrobial enoxacin and derivatives on theophylline metabolism by rat liver microsomes.

Enoxacin, an antimicrobial fluoroquinolone with a 7-piperazinyl-1, 8-naphthyridine skeleton, is a potent inhibitor of cytochrome P-450-mediated theophylline metabolism. The present study was designed to clarify, using seven enoxacin derivatives, the molecular characteristics of the fluoroquinolone responsible for the inhibition. Three derivatives with methyl-substituted 7-piperazine rings inhibited rat liver microsomal theophylline metabolism to 1,3-dimethyluric acid to an extent similar to that of enoxacin (50% inhibitory concentrations [IC50s] = 0.39 to 0.48 mM). 7-Piperazinyl-quinoline derivatives, 8-hydroenoxacin (8-Hy) and 1-cyclopropyl-8-fluoroenoxacin (8-F1), which have a hydrogen and a fluorine at position 8, respectively, more weakly inhibited metabolite formation (IC50s = 0.88 and 1.29 mM, respectively). Little inhibition (IC50 > 2 mM) was observed in those with 3'-carbonyl and 4'-N-acetyl groups on the piperazine rings. The substrate-induced difference spectra demonstrated that the affinities of enoxacin, 8-Hy, and 8-F1 to cytochrome P-450 were parallel with their inhibitory activities. The substituent at position 8 was found to determine the molecular conformations of the fluoroquinolones, and the planarity in molecular shape decreased in the same order as the inhibitory activity (enoxacin > 8-Hy > 8-F1). Moreover, the 3'-carbonyl and 4'-N-acetyl groups decreased the basicity of their vicinal 4'-nitrogen atoms when judged from their electrostatic potentials, which showed a remarkably broadened negative charge around the nitrogens. As a result, the planarity of the whole molecule and the basicity of the 4'-nitrogen atom of enoxacin are likely to be dominant factors in the inhibition of theophylline metabolism by cytochrome P-450.

Animals↗
PubMed2002

Discovery of a novel and potent class of FabI-directed antibacterial agents.

Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elongation cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. High-throughput screening of the Staphylococcus aureus FabI enzyme identified a novel, weak inhibitor with no detectable antibacterial activity against S. aureus. Iterative medicinal chemistry and X-ray crystal structure-based design led to the identification of compound 4 [(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide], which is 350-fold more potent than the original lead compound obtained by high-throughput screening in the FabI inhibition assay. Compound 4 has exquisite antistaphylococci activity, achieving MICs at which 90% of isolates are inhibited more than 500 times lower than those of nine currently available antibiotics against a panel of multidrug-resistant strains of S. aureus and Staphylococcus epidermidis. Furthermore, compound 4 exhibits excellent in vivo efficacy in an S. aureus infection model in rats. Biochemical and genetic approaches have confirmed that the mode of antibacterial action of compound 4 and related compounds is via inhibition of FabI. Compound 4 also exhibits weak FabK inhibitory activity, which may explain its antibacterial activity against Streptococcus pneumoniae and Enterococcus faecalis, which depend on FabK and both FabK and FabI, respectively, for their enoyl-ACP reductase function. These results show that compound 4 is representative of a new, totally synthetic series of antibacterial agents that has the potential to provide novel alternatives for the treatment of S. aureus infections that are resistant to our present armory of antibiotics.

Animals↗
PubMed1996

Structure-antibacterial activity and cytotoxicity relationships of thiazolo and thiazetoquinolone derivatives.

In the course of our search for derivatives with potent antibacterial activity and low cytotoxicity, we have studied the relationships among the structure, antibacterial activity and cytotoxicity of thiazoloquinolone and thiazetoquinolone derivatives (the term quinolone as used in this paper includes the quinolone, 1,8-naphthyridine and pyridopyrimidine nuclei). The antibacterial activities and cytotoxicity of these derivatives were compared with those of norfloxacin, ofloxacin, enoxacin and ciprofloxacin. The antibacterial activities of the thiazoloquinolone derivatives were more potent than those of the dihyrothiazoloquinolone derivatives, and comparable to that of ciprofloxacin. All of the thiazoloquinolone derivatives were highly cytotoxic against mammalian cells, but some of the dihyrothiazoloquinolone derivatives were less cytotoxic, being comparable in cytotoxicity to the reference drugs. The thiazetoquinolone derivatives were less cytotoxic than the thiazoloquinolone derivatives, and one of them, 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a] quinoline-3-carboxylic acid, showed the most potent antibacterial activity of all compounds tested in this study, as well as a very low cytotoxicity. The antibacterial activity and cytotoxicity of this compound were similar to that of ciprofloxacin.

4-Quinolones↗
PubMed1989

Kinetic interaction between theophylline and a newly developed quinolone, NY-198.

The effect of a newly developed quinolone, NY-198, on the pharmacokinetics and metabolism of theophylline was investigated under steady-state conditions in six male healthy volunteers, in a crossover fashion. A sustained-release theophylline formulation (200 mg twice daily at 12 h intervals) was received as monotherapy or coadministration with NY-198 (200 mg twice daily at 12 h intervals). No significant change in the pharmacokinetic parameters of theophylline was observed during coadministration of NY-198. No significant change in urinary excretion of theophylline and its metabolites was also observed. These findings indicate that NY-198 does not influence the pharmacokinetics of theophylline and we can suggest that quinoline derivatives have less effect on theophylline disposition than 1,8-naphthyridine derivatives among quinolones.

4-Quinolones↗
PubMed1989

Synthesis and antiallergic activity of N-[4-(4-diphenylmethyl-1-piperazinyl)butyl]-1,4-dihydro-4-oxopyridine-3 - carboxamides.

A new series of oxopyridinecarboxamide derivatives 3a--g and 5a were synthesized and evaluated for their antiallergic activity. 1,4-Dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxamides 3a and 5a exhibited potent antiallergic activity (inhibitory rates of 80.7 and 88.3%, respectively, at 20 mg/kg, p.o.) in the rat passive cutaneous anaphylaxis (PCA) test and also exhibited much more potent in vitro inhibitory activity than caffeic acid against the enzyme 5-lipoxygenase (5-LO). Their in vitro antihistamine activity, however, was weaker than that of ketotifen. Compounds 3a and 5a are viewed as promising candidates for antiallergic agents.

Animals↗
PubMed1990

Fluorinated pyrido[2,3-c]pyridazines. II. Synthesis and antibacterial activity of 1,7-disubstituted 6-fluoro-4(1H)-oxopyrido[2,3-c]pyridazine-3- carboxylic acids.

Chemical modification of pyridonecarboxylic acid antibacterials with a 1,8-naphthyridine ring, such as enoxacin and tosufloxacin, to their 2-aza derivatives was studied. A new series of 1,7-disubstituted 6-fluoro-4(1H)-oxopyrido[2,3-c]pridazine-3-carboxylic acids (25-27) was prepared by a route involving either alkylation of ethyl 6-fluoro-4(1H)-oxo-7-(p-tolylthio)pyrido[2,3-c]pyridazine-3-carbox ylate (7) or intramolecular cyclization of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-2-[2-(p-fluorophenyl)hydraz ono]acetate, (20), followed by displacement reaction with cyclic amines at C-7; the N-1 substituent in these compounds included of ethyl, 2-fluoroethyl and p-fluorophenyl groups, and the C-7 functional group comprised variously-substituted piperazines and pyrrolidines. Antibacterial activities of these compounds were markedly inferior to those of enoxacin and tosufloxacin.

4-Quinolones↗
PubMed1992

Fluorometric assay of rat tissue N-methyltransferases with nicotinamide and four isomeric methylnicotinamides.

Nicotinamide (NA) and its four isomeric methyl analogs [2-, 4-, 5- and 6-methylnicotinamides (MNs)] were tested as substrates for nicotinamide N-methyltransferase (NNMT) and amine N-methyltransferase (ANMT) using rat liver, kidney, spleen and brain 9000 x g supernatant fluids as model enzyme preparations. The N-methylated products were determined fluorometrically by their reaction with acetophenone or 4-methoxybenzaldehyde to form fluorescent 2,7-naphthyridine derivatives, and the lower limits of the determination were 8-30 pmol/100 microliters. N-Methyltransferase activities were detected in the liver with NA, 4-MN and 5-MN, and in the brain and spleen with 4-MN. On this basis, 5-MN is considered to be a selective substrate for NNMT in addition to NA, which is a known methyl acceptor for this enzyme. Although 4-MN appears to serve as a methyl acceptor for both ANMT and NNMT, it seems to be essentially a selective substrate for brain ANMT because of the absence of NNMT in brain. The fluorometric methods used here are also very useful because of their simplicity, sensitivity and selectivity.

Animals↗
PubMed1998

7-(2-Aminomethyl-1-azetidinyl)-4-oxoquinoline-3-carboxylic acids as potent antibacterial agents: design, synthesis, and antibacterial activity.

2-Aminomethyl-1-azetidinyl, -1-pyrrolidinyl, and -1-piperidinyl groups were designed as novel C-7 substituents for potential antibacterial quinolone agents. Of the three substituents, the 2-aminomethyl-1-azetidinyl group (compound 12a) was found to be the most favorable for enhancing the activity of the 6,8-difluoroquinoline molecule 12. Therefore the 2-aminomethyl-1-azetidinyl group was introduced into a variety of quinolines (giving 24-26a, and 28a) and naphthyridines (giving 31a and 32a). Through optical resolution of 1-benzylazetidine-2-carboxamide (19) and chiral synthesis of its R-isomer, both enantiomers of 2-aminomethyl-1-azetidinyl quinolines 12a and 24-26a were also prepared. The most active of all the compounds was 5-amino-6,8-difluoroquinoline (R)-26a. The activity of (R)-26a was more potent than those of the corresponding 1-piperazinyl derivative (3) and sparfloxacin (1), and was comparable to those of the corresponding 3-amino-1-pyrrolidinyl (4), 3-aminomethyl-1-pyrrolidinyl (5), and 3-amino-1-azetidinyl (6) derivatives.

4-Quinolones↗
PubMed2000

Studies on the 1,4-oxazepine ring formation reaction using the molecular orbital method.

1,4-Oxazepine formation reactions of 1,8-naphthyridine derivatives (1-4) with peroxy acid have been studied using a semiempirical MO method (AM1) and an ab initio molecular orbital method (Gaussian 94). The energies of molecules involved in the reaction paths were calculated and the transition states related to experimental products were obtained. For the reactions of 1-3, the calculated energies of the transition states predicted the previously obtained products. However, the calculated values for the reaction of 4 suggested a different type of oxazepine compound, which was verified in further experiments.

Chemical Phenomena↗
PubMed2001

Microbial synthesis of three metabolites of a tachykinin receptor antagonist, TAK-637.

The compound TAK-637 ((aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione), a tachykinin receptor antagonist, has been shown to be converted into three metabolites in rats and guinea pigs. It was difficult to isolate the metabolites from rats and guinea pigs administered TAK-637 and elucidate the structures. A total of 100 actinomycete strains were screened for the ability to convert TAK-637 into its metabolites. Three strains, Streptomyces subrutilus IFO13388, Streptomyces tanashiensis subsp. cephalomyceticus IFO13929 and Streptomyces lavenduligriseus IFO13405, were found to convert TAK-637 into the metabolites consistent with the metabolites formed in rats and guinea pigs as determined by HPLC analyses. The metabolites were synthesized by microbial conversion using the actinomycetes. The structures of the metabolites were elucidated by spectral analyses. It was found that the methyl group at the C(5)-phenyl group of TAK-637 was hydroxylated and the resulting alcohol was converted to carboxylic acid via aldehyde. One of the metabolites (hydroxylated TAK-637) was obtained using a 200-l fermentor in a large-scale cultivation to evaluate its biological activity.

Journal Article↗
PubMed1998

pH effects on the spectroscopic and photochemical behavior of enoxacin: a steady-state and time-resolved study.

The spectroscopic and photochemical behavior of Enoxacin (ENX), 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)- 1,8-naphthyridine-3-carboxylic acid, has been investigated in aqueous solutions between pH 3.5 and pH 12. The absorption and emission properties of ENX are strongly affected by pH. The fluorescence quantum yield, 4 x 10(-3) at pH 3.5, increases by a factor of two on going to neutral pH while a strong reduction is observed at alkaline pH. The photodegradation quantum yield also depends on pH, being maximum in neutral conditions (ca 0.04). Nanosecond flash photolysis experiments confirm that the yield of absorbing transients is maximum at neutral pH while it decreases to zero at acid and alkaline pH. These results indicate that both the dissociation of the carboxylic group and the protonation of the piperazinyl residues are key steps for the formation of the photochemically active form of ENX. Loss of F by heterolytic cleavage of the C-F bond is proposed to occur from the triplet state of the zwitterion with formation of a carbocation. A path for the evolution of this intermediate to the final product is also proposed.

Anti-Infective Agents↗