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PubMed2001

Activity of BMS284756 against 2,681 recent clinical isolates of Haemophilus influenzae and Moraxella catarrhalis: Report from The SENTRY Antimicrobial Surveillance Program (2000) in Europe, Canada and the United States.

Although the isolation and detection of fluoroquinolone-resistant Haemophilus influenzae and Moraxella catarrhalis has been a very rare occurrence, newer agents in the quinolone class must be evaluated to determine their comparative potencies and to develop in vitro testing methods. BMS284756 is an investigational desfluoro(6)-quinolone with a spectrum of activity most similar to recently introduced agents such as gatifloxacin and trovafloxacin. This compound was compared to levofloxacin, gatifloxacin, ciprofloxacin and moxifloxacin, as well as other orally administered antimicrobials against 1,872 H. influenzae and 810 M. catarrhalis isolates. Two Canadian H. influenzae strains had ciprofloxacin MICs elevated above the normal wild type susceptible MIC population (> 0.06 microg/mL). All other strains of H. influenzae and M catarrhalis were highly susceptible to the tested quinolones (MIC(90,) < or = 0.016 or 0.03 microg/mL). For the two H. influenzae isolates with elevated quinolone MICs the potency rank order was: gatifloxacin and BMS284756 (MICs, 0.25 and 1 microg/mL) > levofloxacin and moxifloxacin > ciprofloxacin (MICs, 0.5 and > 2 microg/mL). The comparison of Etest (AB BIODISK, Solna, Sweden) and disk diffusion results to the reference broth microdilution values produced acceptable intermethod accuracy when applied to BMS284756. This novel desfluoro compound possesses promising activity against fastidious Gram-negative respiratory tract pathogens and further clinical development is underway.

Anti-Infective Agents↗
PubMedDate not supplied

Analysis of the in vitro inhibition of murine and human tumor cell growth by pyrazole derivatives and a substituted azabicyclo [3.1.0] hexane-2,4-dione.

3-Ethoxycarbonyl-5-phenyl-1, 3a, 4, 5, 6, 6a-hexahydropyrrolo[3,4-c]pyrazole-4, 6-dione, 2, 2, 6, 6-tetraethyl-1H, 5H-pyrazole[1, 2-a]pyrazole-1, 3, 5, 7-[2H, 6H]-tetraone and 6-ethoxycarbonyl-3-phenyl-3-azabicyclo[3.1.0] hexane-2, 4-dione demonstrated potent cytotoxic activity in the human Tmolt3, Tmolt4 and HL-60 leukemia screens, HuT-78 lymphoma and HeLa suspended uterine carcinoma cell lines. Most notable was the finding that these compounds were significantly more active than the standard cytotoxic agents examined in the MCF-7 breast (ED50 0.2-1.0 microg/ml) and U87MG glioma (ED50 1.3-2. 6 microg/ml) tumor screens. The agents inhibited Tmolt4 leukemia DNA and RVA syntheses after 60 min at 100 microM Multiple enzymes involved with nucleic acid metabolism appeared to be targeted including inhibition of RNA polymerases, ribonucleotide reductase and nucleoside kinase activities, however, inhibition of de novo purine synthesis at the key regulatory enzyme IMP dehydrogenase appeared to be the primary target. The predominant IMPDH isoform (Type II) detected in a number of human cancers, such as leukemias, ovarian and breast, was inhibited by the compounds yielding IC50 values in the microM range. Furthermore, inhibition of IMP dehydrogenase activity led to the selective depletion of dGTP pool levels by two of the compounds. The DNA molecule was not a target of the agents since no alkylation of the bases, cross-linking of the DNA strands or intercalation between base pairs occurred. Yet, the compounds did cause DNA fragmentation after incubating at 100 microuM for 24 h which was consistent with the observed decrease in ct-DNA viscosity.

Animals↗
PubMed2001

Synthesis and antimicrobial properties of N-substituted derivatives of (E)-4-azachalcones.

Syntheses of 11 new N-bromoalkyl substituted bromides of (E)-4-azachalcone and N-o-(m- and p-) halobenzyl substituted halides of (E)-3'-hydroxy-4-azachalcone of antimicrobial activity are reported. Compounds 3d, 3e, 6b, 6c, and 6e reveal good antimicrobial activity against Staphylococcus aureus and Enterococcus faecalis as well as moderate activity against Escherichia coli and Klebsiella pneumoniae.

Anti-Bacterial Agents↗
PubMed2000

Synthesis, molecular modeling, and opioid receptor affinity of 9, 10-diazatricyclo[4.2.1.1(2,5)]decanes and 2,7-diazatricyclo[4.4.0. 0(3,8)]decanes structurally related to 3,8-diazabicyclo[3.2. 1]octanes.

Various lines of evidence, including molecular modeling studies, imply that the endoethylenic bridge of 3,8-diazabicyclo[3.2. 1]octanes (DBO, 1) plays an essential role in modulating affinity toward mu opioid receptors. This hypothesis, together with the remarkable analgesic properties observed for N(3) propionyl, N(8) arylpropenyl derivatives (2) and of the reverted isomers (3), has prompted us to insert an additional endoethylenic bridge on the piperazine moiety in order to identify derivatives with increased potency toward this receptor class. In the present report, we describe the synthesis of the novel compounds 9,10-diazatricyclo[4.2. 1.1(2,5)]decane (4) and 2,7-diazatricyclo[4.4.0.0(3,8)]decane (5), as well as the representative derivatives functionalized at the two nitrogen atoms by propionyl and arylpropenyl groups (6a-e, 7a-d). Opioid receptor binding assays revealed that, among the compounds tested, the N-propionyl-N-cinnamyl derivatives 6a and 7a exhibited the highest mu-receptor affinity, and remarkably, compound 7a displayed in vivo (mice) an analgesic potency 6-fold that of morphine.

Analgesics↗
PubMed2001

A double ring closing metathesis reaction in the rapid, enantioselective synthesis of NK-1 receptor antagonists.

[structure: see text]. The NK-1 receptor antagonist 1 has been prepared in seven steps from phenylglycine methyl ester. The key steps are a double ring closing metathesis reaction of tetraene 7 to prepare spirocycle 6 and a reductive Heck reaction to introduce the aryl moiety. This latter reaction discriminates the olefins of compound 6 and proceeds in a highly regio- and stereoselective manner.

Aza Compounds↗
PubMed2002

Derivatives of benzotetrazine-1,3-dioxide are new NO-donors, activators of soluble guanylate cyclase, and inhibitors of platelet aggregation.

The ability of 5-nitro-, 7-nitro-, and 5,7-dinitrobenzotetrazine-1,3-dioxides to generate nitric oxide (NO) and activate soluble guanylate cyclase was investigated. All of these compounds were found to be thiol-dependent NO-donors and guanylate cyclase activators. The maximal stimulatory effect of 5-nitro-, 7-nitro-, and 5,7-dinitrobenzotetrazine-1,3-dioxides was observed at 10 microM concentration and the activity increase was 4.5-, 15.0-, and 8.2-fold in the presence of 20 microM dithiothreitol and 11.3-, 31.6-, and 20.5-fold, respectively, in the presence of added glutathione (100 microM). The NO-dependent mechanism of benzotetrazine-1,3-dioxide nitroderivative-induced activation of soluble guanylate cyclase (in the presence of 100 microM glutathione) was confirmed by the inhibition (by 78%) of 7-nitrobenzotetrazine-1,3-dioxide (10 microM)-stimulated guanylate cyclase activity in the presence of the NO-scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (Carboxy-PTIO, 50 microM) and by the inhibition with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 0.3 microM) of 5-nitro-, 7-nitro-, and 5,7-dinitrobenzotetrazine-1,3-dioxides (10 microM)-stimulated guanylate cyclase by 34, 69, and 39%, respectively. All compounds used inhibited ADP-induced aggregation of human platelets with IC50 of 10.0, 1.3, and 2.0 microM for 5-nitro-, 7-nitro-, and 5,7-dinitrobenzotetrazine-1,3-dioxides, respectively. A clearly defined correlation was established between the ability of the compounds to generate NO, activate soluble guanylate cyclase, and inhibit platelet aggregation.

Adenosine Diphosphate↗
PubMed2000

Intestinal anti-inflammatory activity of UR-12746, a novel 5-ASA conjugate, on acute and chronic experimental colitis in the rat.

The present study was undertaken to investigate the intestinal anti-inflammatory effects of UR-12746 on the acute and chronic stages of a trinitrobenzene sulphonic acid (TNBS) experimental model of inflammatory bowel disease (IBD) in the rat. UR-12746 is a novel, locally-acting compound which combines, through an azo bond, 5-aminosalicylic (5-ASA) and UR-12715, a potent platelet activating factor (PAF)-antagonist. UR-12746 oral pretreatment of colitic rats (50 and 100 mg kg(-1)) reduced acute colonic damage when evaluated 2 days after colonic insult. Postreatment for 4 weeks with UR-12746 (50 and 100 mg kg(-1)) resulted in a faster recovery of the damaged colonic mucosa, which was macroscopically significant from the third week. The intestinal anti-inflammatory effect of UR-12746 was associated with a decrease in leukocyte infiltration in the colonic mucosa, which was evidenced both biochemically, by a reduction in myeloperoxidase activity, and histologically, by a lower leukocyte count after morphometric analysis. This effect was higher than that seen with sulphasalazine, when assayed at the same doses and in the same experimental conditions. Several mechanisms can be involved in the beneficial effects showed by UR-12746: inhibition of leukotriene B(4) synthesis in the inflamed colon, improvement of the altered colonic oxidative status, and reduction of colonic interleukin-1beta production. The results suggest that the intestinal anti-inflammatory activity of UR-12746 can be attributed to the additive effects exerted by 5-ASA and UR-12715, the PAF antagonist compound, that are released in the colonic lumen after reduction of the azo bond by the intestinal bacteria.

Acute Disease↗
PubMed2001

Moxifloxacin: a review of the microbiological, pharmacological, clinical and safety features.

Antimicrobial agents are used to treat patients with infectious diseases. Initial antimicrobial compounds originated from natural sources and were generally deemed to be narrow in spectrum. Today, we are in the era of designer drugs that have been specifically developed with current issues in infectious diseases in mind. For example, some new compounds require once daily dosing, have minimal side effects, are active against resistant pathogens and, for some, have a lower propensity for selecting for antimicrobial resistance during patient therapy.

Anti-Infective Agents↗
PubMedDate not supplied

Synthesis and cardiotonic evaluation of R-sulfonyl derivatives of azaheterocycles.

A series of alpha-sulfonyl-2-(3-chloro)hetarylacetonitriles was prepared by the interaction of dichlorodiazines and R-sulfonylacetonitriles. Reaction of nucleophilic substitution of chlorine by different N-H-azoles has been studied. The compounds obtained showed 3 types of activity on cardiac papillary muscles: 1. a biphasic activity with increase in cardiac contractility at low concentration and inhibition in high concentration (1, 2, 4, 12-15), 2. a monophasic inhibitory activity (3, 5, 8-10), 3. non-active compounds (6, 7, 11). The preliminary SAR studies indicate the importance of chlorine atom at position 3 in diazine nucleus and of alkyl substituents in benzimidazole moiety for positive inotropic effects.

Acetonitriles↗
PubMed2005

Synthesis of 3'-deoxy-3'-difluoromethyl azanucleosides from trans-4-hydroxy-l-proline.

[reaction: see text] Two strategies were tried to synthesize 3'-deoxy-3'-difluoromethyl azanucleosides. After the failure of the first route, the key intermediate 12 from trans-4-hydroxyproline 7 in 8 steps was stereoselectively prepared. The alcohol 12 was subjected to selective protection, oxidation, and difluoromethylenation to afford the fluorinated compound 18, whose hydrogenation was then systematically investigated. After a series of transformations of protecting groups, the resultant compounds 22 and 23 were oxidized to the desired lactams 24 and 25, which were successfully utilized to synthesize our target molecules, 3'-deoxy-3'-difluoromethyl azanucleosides 33, 34a, 34b, and 35.

Aza Compounds↗
PubMed2003

In vitro susceptibility of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis: a European multicenter study during 2000-2001.

OBJECTIVE: To assess the current (2001) activity of respiratory fluoroquinolones and comparator agents against respiratory pathogens isolated in European countries. METHODS: During 2000-2001, we prospectively collected 1995 isolates of Haemophilus influenzae, 1870 isolates of Streptococcus pneumoniae and 649 isolates of Moraxella catarrhalis from hospital laboratories in France, Germany, Greece, Italy, Spain and the UK. National Committee for Clinical Laboratory Standards (NCCLS)-approved broth microdilution antimicrobial susceptibility testing methods and interpretive criteria were used throughout. RESULTS: Of the S. pneumoniae isolates, 99.6% were susceptible to moxifloxacin, gatifloxacin and levofloxacin; the corresponding figure for H. influenzae was 100%. All M. catarrhalis isolates had moxifloxacin MICs </= 0.12 mg/L. For all three pathogens, fluoroquinolone susceptibility remained unchanged from the previous 1997-98 study. The incidence of penicillin non-susceptibility in the S. pneumoniae isolates tested remained similar to or higher than that recorded in previous studies: France, 165/291 (56.7%); Germany, 46/506 (9.1%); Greece, 20/55 (36.4%); Italy, 45/364 (12.4%); Spain, 146/268 (54.5%); and the UK, 26/386 (6.7%). Significant levels of resistance to oral compounds (cefuroxime, cefaclor, cefdinir, clarithromycin, azithromycin, tetracycline, and trimethoprim-sulfamethoxazole) were detected among S. pneumoniae isolates. beta-Lactamase production among H. influenzae isolates ranged from 6.2% to 33.1% per country, and ampicillin, clarithromycin or trimethoprim-sulfamethoxazole resistance were the most common phenotypes detected. beta-Lactamase production among M. catarrhalis isolates ranged from 94.1% to 100% per country. CONCLUSIONS: With the exception of a few localized reports, resistance to moxifloxacin and other new fluoroquinolones in common respiratory pathogens is a rare occurrence, despite significant resistance to other compound classes. Surveillance will play a key role in tracking changes in fluoroquinolone susceptibility in European countries.

Anti-Infective Agents↗
PubMed2006

In vitro degradation of hexanitrohexaazaisowurtzitane (CL-20) by cytosolic enzymes of Japanese quail and the rabbit.

Hexanitrohexaazaisowurtzitane (CL-20) is a polycyclic nitramine explosive and propellant, currently being considered as a potential replacement for existing cyclic nitramine explosives. Earlier studies have provided evidence suggestive of adverse liver effects in adult Coturnix spp. exposed to CL-20, yet analysis of tissue samples (plasma, liver, brain, heart, or spleen) indicated that CL-20 was not detectable in these treated animals. The present study was conducted to identify and purify the enzymes capable of CL-20 biotransformation. Results indicate that the hepatic biotransformation of CL-20 in vitro was inhibited by ethacrynic acid (93%) and by the glutathione (GSH) analogue S-octylglutathione (80%), suggesting the involvement of glutathione-S-transferase (GST). Partially purified cytosolic alpha- and mu-type GST (requiring presence of GSH as a cofactor) from quail and rabbit liver was capable of CL-20 biotransformation. The degradation of CL-20 (0.30 +/- 0.05 and 0.40 +/- 0.02 nmol/min/mg protein for quail and rabbit, respectively) was accompanied with the formation of nitrite and consumption of GSH. Using liquid chromatography/mass spectrometry, we detected two intermediates, that is, open-ring, monodenitrated GSH-conjugated CL-20 biotransformation product with the same deprotonated molecular mass ion at 699 Da, suggesting isomeric forms of the intermediate metabolites. Identity of the conjugated metabolites was confirmed by using ring-labeled [15N]CL-20 and the nitro group-labeled [15NO2]CL-20. These data suggest that the in vitro biotransformation of CL-20 by GST under the conditions tested may be a key initial step in the in vivo degradation of CL-20 in the quail and resulted in the formation of more biologically reactive intermediates than the parent compound. These data will aid in our understanding of the biotransformation processes of CL-20 in vivo.

Amino Acid Sequence↗
PubMed2000

Clathculins A and B, two novel nitrogen-containing metabolites from the sponge Clathrina aff. reticulum.

Two novel acyclic diaza alkenynes, clathculins A and B (1 and 2), were isolated from the Indo-Pacific sponge Clathrina aff. reticulum collected in Sodwana Bay, South Africa. The structure of the mixture of the two unstable inseparable compounds was established by spectroscopic analysis, mainly 1D and 2D NMR measurements and two chemical transformations. Clathculins A and B are the first reported linear marine metabolites containing a 1,2-diaminoethane moiety.

Alkynes↗
PubMed1999

Comparative susceptibility to penicillin and quinolones of 1385 Streptococcus pneumoniae isolates. Austrian Bacterial Surveillance Network.

Antibiotic resistance among Streptococcus pneumoniae isolates has spread rapidly throughout the world since the first description of a strain with diminished susceptibility to penicillin in Australia in 1967. A total of 1385 strains of S. pneumoniae, collected in several centres throughout Austria, were assessed for their sensitivity to moxifloxacin, trovafloxacin, ciprofloxacin, ofloxacin, levofloxacin and lomefloxacin. The MICs were determined using the agar dilution method, according to NCCLS guidelines. Both moxlfloxacin and trovafloxacin showed good anti-pneumococcal activity in terms of MIC50 (both 0.125 mg/L) and MIC90 (both 0.25 mg/L). Less active, but with similar activity to each other, were ciprofloxacin and levofloxacin, each with an MIC50 of 1 mg/L and an MIC90 of 2 mg/L. Ofloxacin showed only moderate activity (MIC50, 1 mg/L; MIC90, 2 mg/L) and lomefloxacin was the least active compound (MIC50, 4 mg/L; MIC90, 8 mg/L). Both moxifloxacin and trovafloxacin at a concentration of < or = 0.5 mg/L inhibited all of the S. pneumoniae strains tested.

Anti-Infective Agents↗
PubMed2004

Design and synthesis of methyl 2-methyl-7,7-dihalo-5-phenyl-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates with calcium channel antagonist activity.

A group of methyl 2-methyl-7,7-dihalo-5-(substituted-phenyl)-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates were prepared by reaction of dihalocarbenes (:CX2, X = Br, Cl) with methyl 1-methyl-4-(substituted-phenyl)-1,4-dihydropyridine-3-carboxylates. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. The title compounds exhibited weaker CC antagonist activity (10(-5)-10(-6)M range) than the reference drug nifedipine (1.4 x 10(-8)M). Structure-activity relationship studies showed that the position of a nitro substituent on the C-5 phenyl ring where the relative potency order was ortho > meta > para, and the size and/or electronegativity of the C-7 geminal-dihalo substituents (Br > Cl), were determinants of calcium channel antagonist activity. This class of compounds did not exhibit any inotropic effect on guinea pig left atria. A dihalocyclopropyl moiety is a potential bioisostere for the 2-methyl-3-methoxycarbonylvinyl moiety present in the calcium channel antagonist nifedipine.

Animals↗
PubMed2005

Synthesis, spectral and thermal studies of some organotin(IV) derivatives of 5-amino-3H-1,3,4-thiadiazole-2-thione.

Some tri- and diorganotin(IV) compounds of the general formula, RnSnL4-n (where n=2, R=Me, n-Bu and Ph; n=3, R=Me, n-Bu, n-Pr and Ph; HL=5-amino-3H-1,3,4-thiadiazole-2-thione) have been synthesized by the reaction of RnSnCl4-n (where n=2 or 3, R=Me, n-Bu, n-Pr and Ph) and the sodium salt of the ligand. Oct2SnL2 was obtained by the reaction of Oct2SnO with HL in a 1:2 molar ratio under azeotropic removal of water. The bonding and coordination behavior in these derivatives are discussed on the basis of IR, Far-IR, multinuclear (1H, 13C and 119Sn) NMR and 119Sn Mössbauer spectroscopic studies. These investigations suggest that in all the compounds the ligand acts as monoanionic bidentate coordinating through ring N(3) and exocyclic S. Thermal studies of five compounds, viz., Ph3SnL, Me2SnL2, n-Bu2SnL2, Oct2SnL2 and Ph2SnL2 have been carried out in the temperature range 25-1000 degrees C using TG, DTG and DTA techniques under an atmosphere of dry nitrogen.

Alkenes↗
PubMed2003

Design, synthesis and evaluation of novel azasugar-based MMP/ADAM inhibitors.

In order to verify whether azasugar would be a useful scaffold for inhibitory activity against metalloproteinases, we synthesized some azasugar-based compounds. As a result, it is clarified that azasugar moiety could function as successful inhibitor of matrix metalloproteinase-1, -3 and -9 and TACE.

ADAM Proteins↗