[Research on substances with antineoplastic activity. LV. Synthesis and cytotoxic and cytostatic effect of heterocyclic azotate compounds related to the 6-aminochrysene].
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Amines↗
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Relation between induction of the mar operon and cyclohexane tolerance and reduction in fluoroquinolone susceptibility in Salmonella spp.
The relationship between cyclohexane tolerance and induction of the mar operon and a decrease in susceptibility to ciprofloxacin and moxifloxacin in isolates of Salmonella spp. from food and clinical isolates of Salmonella spp. was studied. We studied the influence of the mar operon using an inductor (acetylsalicylic acid) and we also studied the cyclohexane resistance. Induction was seen to produce an increase in the minimum inhibitory concentration (MIC) of these quinolones, which suggested that there was overexpression of the AcrAB type active efflux systems due to induction of the mar operon. Cyclohexane susceptibility was not shown to be a very sensitive method for studying this process, as only 3% (5/176) of the clinical isolates studied were cyclohexane-resistant; most of these belonged to the Hadar serotype. This study confirmed the participation of active efflux systems in the decrease in fluoroquinolone susceptibility in Salmonella spp. Furthermore, the study has indicated that these mechanisms (i.e., active efflux systems) are present in strains that are susceptible to the fluoroquinolone compounds, so their stimulation may be one of the mechanisms involved in the reduction in fluoroquinolone susceptibility. This suggests that the exposure of Salmonella spp. to antibiotics should be limited in order to prevent these active efflux systems from being activated. Consequently, the use of fluoroquinolones, both in the treatment of humans and in veterinary practice, should be controlled and rationalized in an attempt to curb the increase in the number of strains that are resistant to these compounds.
Anti-Bacterial Agents↗
Laboratory tests of 5-p-chlorophenyl silatrane as a rodenticide.
The properties of 5-p-chlorophenyl silatrane as a rodenticide against Rattus norvegicus and Mus musculus were investigated in the laboratory. The high oral toxicity of the compound was confirmed. When the compound was given to laboratory rats and mice by stomach tube at lethal dosages, signs of poisoning were observed within a minute. When caged wild rats and mice were given a choice between plain and poisoned baits the optimum rodenticidal concentration in the bait was about 0.5% for both species, producing 50% mortality in wild rats and 95% mortality in wild mice. The results are discussed in relation to safety in use and the probable effectiveness of the compound as a rodenticide in field conditions.
Administration, Oral↗
Synthesis and dopamine transporter affinity of 2-(methoxycarbonyl)-9-methyl-3-phenyl-9-azabicyclo[3.3.1]nonane derivatives.
A series of 9-methyl-3 beta-phenyl-2-substituted-9-azabicyclo[3.3.1]nonane derivatives were synthesized and evaluated as cocaine-binding site ligands at the dopamine transporter (DAT). The conformation of the bicyclic structures and the stereochemistry of the substituents were determined by NMR and X-ray crystallography. The in vitro binding affinity (Ki) of the 9-azabicyclo[3.3.1]nonane derivatives was measured in rat caudate-putamen tissue, and they were found to be 100-fold (Ki = 2-14 microM) less potent than cocaine and other tropane analogs. From these results it is evident that the cocaine-binding site at the DAT is very sensitive to structural modifications of the unsubstituted methylene bridge [C(6)-C(7)] of cocaine and cocaine-like compounds.
Animals↗
[Advances in the development of new antitubercular agents from orthocondensed heterocyclic compounds. Part 3. Substances containing several types of heteroatoms in the six-membered ring].
Tuberculosis and other mycobacterial diseases are considered to be one of the most important problems of contemporary health service. Since 1985 and particularly in the 1990s and at present the search for new structures of antimycobacterial agents have ranked among the foremost areas of chemotherapeutic research. The present review paper is already the 18th communication in a group of review papers about substances with antituberculotic effects, and the third, final, communication devoted in this series about the development of new antimycobacterial agents to ortho-condensed heterocyclic compounds in recent 15 years. The classification of ortho-condensed compounds is based on six-membered heterocyclic substructural fragments and the present study deals with the substructural fragments containing a greater number of different heteroatoms. The literature search is based on the journal Chemical Abstracts, Current Awareness in Biomedicine, part Mycobacteria, and original papers. Current Awareness in Biomedicine is, however, a very imperfect literature search source, recording only a fraction of communications. Review papers about five-membered heterocyclic antituberculotic ortho-condensed compounds was published in the present journal in 1999.
Antitubercular Agents↗
Bioisosteric replacement strategy for the synthesis of 1-azacyclic compounds with high affinity for the central nicotinic cholinergic receptors.
Bioisosteric replacement of the isoxazole heterocycle in (3-methyl-5-isoxazolyl)methylene-azacyclic compounds with pyridine, oxadiazole, or an acyl group resulted in ligands with high to moderate affinity for the central nicotinic cholinergic receptors (IC50 = 2.0 to IC50 > 1000 nM) labeled by [3H]methylcarbamylcholine. Additionally, further support of an important distance parameter for high-affinity nicotinic compounds has been provided.
Aza Compounds↗
Electrochemical properties of polycyclic compounds studied by the polarographic method in anhydrous systems. VIII. The influence of proton-donor on reduction of carcinogenic nitrogen compounds in dimethylformamide.
The authors have studied the electrochemical behavior of a series of carcinogenic and inactive heterocyclic compounds in anhydrous medium in the presence of a proton-donor. As anhydrous medium the authors used anhydrous dimethylformamide as proton-donor phenol. In the presence of proton-donor there had occurred on polarographic reduction of the employed carcinogenic heterocyclic compounds changes in the number of polarographic waves. Between the two original waves in these compounds there arose in the presence of phenol a new wave. In non-carcinogenic heterocyclic compounds such an effect of phenol was not noted. In the present paper the authors discuss the possible mechanism of electroreduction of carcinogenic and inactive heterocyclic compounds in anhydrous medium in the presence of a proton-donor.
Aza Compounds↗
[Azabischalcones--a new class of potential antitubercular agents].
A series of substituted azabischalcones Ia-Ip, monochalcone II and dihydroxyderivative III has been prepared and examined for their in vitro activity against Mycobacterium tuberculosis, Mycobacterium kansasii, Mycobacterium avium, Mycobacterium fortuitum as well as INH-resistant strains. Several compounds under study have the same activity as INH and greater than PAS, Contebene, Ethionamide. The results are summarized in Table 1. In the case of compound Ie, its in vivo activity was studied against M. tuberculosis as well (see Table 2). The toxicity of compounds under study is very low--2000 mg/kg/mouse.
Animals↗
Inhibition of 2,3-oxidosqualene cyclases.
Monocyclic and tricyclic compounds possessing a nitrogen atom situated at a position corresponding to the carbenium ion of high energy intermediates or transition states involved during cyclization of 2,3-oxidosqualene to tetra- and pentacyclic triterpenes have been synthesized. These compounds were tested as inhibitors of 2,3-oxidosqualene cycloartenol, lanosterol-, and beta(alpha)-amyrin-cyclases in vitro and in vivo, and their affinity was compared to that of formerly synthesized 8-aza-bicyclic compounds [Taton et al. (1986) Biochem. Biophys. Res. Commun. 138, 764-770]. A monocyclic N-alkyl-hydroxypiperidine was shown to be the strongest inhibitor of the series upon cycloartenol-cyclase (I50 = 1 microM) from maize embryos but was much less effective on the beta(alpha)-amyrin-cyclases from Rubus fruticosus suspension cultures or pea cotyledons. In contrast, 13-aza-tricyclic derivatives displayed little inhibition on 2,3-oxidosqualene cycloartenol-, lanosterol-, and beta(alpha)-amyrin-cyclases. The obtained data exemplify the differences existing in the cyclization process between cycloartenol- (lanosterol-) cyclases on one hand and beta(alpha)-amyrin-cyclases on the other. The results are discussed with respect to current mechanisms postulated for 2,3-oxidosqualene cyclization. Because of its activity in vivo and in vitro the monocyclic N-alkyl-hydroxypiperidine appears to be a potent and promising tool to study sterol biosynthesis regulation.
Animals↗
Cycloalkane spiroheterocyclic compounds. 9. 8-(1,2,3,4-Tetrahydro-2-naphthyl)-2-oxo-1-oxa-3,8-diazaspiro(4.5)decanes and related compounds.
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Analgesics↗
Novel high energy intermediate analogues with a triazasterol structure as potential ergosterol biosynthesis inhibitors IV: antimicrobial activity of mono-, bi-, and tricyclic 8, 13, 15-triazasteroid analogues including the synthesis of novel 4-alkylamino- and 4-alkenylamino-9-hydroxypyrimidoisoquinolines.
4-alkylamino-and 4-alkenylamino-9-hydroxy-1, 6, 7, 11b-tetrahydro-2H-pyrimido[4, 3-a]isoquinolines were designed as inhibitory tricyclic triaza-analogues of carbocationic high energy intermediates (HEI) of enzymes involved in fungal ergosterol biosynthesis. Various routes for effective synthesis of 9-hydroxypyrimidoisoquinolines from 9-methoxythiones were investigated. The ether cleavage of 9-methoxy-pyrimidoisoquinolines, a key step in the synthesis, was carried out using various protocols. The structures of the obtained 9-hydroxy compounds were confirmed using homo- and hetero-nuclear correlated 1D and 2D NMR experiments. In vitro antifungal susceptibility tests of the alkylaminohydroxypyrimidoisoquinolines revealed weak to good antimycotic effects. The maximum antifungal efficacy was found for 4-[(3R)-6-isopropyl-3-methyl-6-heptenylamino]-9-hydroxypyrimidoisoquinoline. Furthermore, the in vitro activities of the newly synthesized 9-hydroxypyrimidoisoquinolines and of a series of prepared 8, 13, 15-triazasteroid analogues (N-alkyl-N'-(phenethyl- and cyclohexenylethyl)guanidines, N(2) -and N(2), 4-substituted imidazolin-2-amines, and N(4)-alkylaminopyrimidoisoquinolines) against representatives of gram-positive and gram-negative bacteria were investigated. The compounds showed significant antibacterial effects against gram-positive bacteria.
Anti-Infective Agents↗
In vitro activity of four fluoroquinolones against Mycobacterium tuberculosis.
The in vitro activity of ciprofloxacin, ofloxacin, levofloxacin and moxifloxacin against strains of Mycobacterium tuberculosis was studied. Moxifloxacin and levofloxacin showed the greatest activity having an MIC(90) of 1 mg/l. The MIC(90) for ofloxacin was 2 mg/l and for ciprofloxacin 4 mg/l. Further studies should be made to determine the role played by these compounds in the treatment of tuberculosis.
Anti-Infective Agents↗
Synthesis of 2-azaindolizines by using an iodine-mediated oxidative desulfurization promoted cyclization of N-2-pyridylmethyl thioamides and an investigation of their photophysical properties.
Iodine-mediated, oxidative desulfurization promoted cyclization of N-2-pyridylmethyl thioamides serves as an efficient and versatile method for the preparation of 2-azaindolizines (imidazo[1,5-a]pyridines) and rare 2-azaindolizine sulfur-bridged dimers. The 2-azaindolizines prepared in this manner are readily converted to a variety of fluorescent compounds by using transition-metal-catalyzed cross-coupling reactions. [reaction: see text].
Aza Compounds↗
Thrombin inhibitors built on an azaphenylalanine scaffold.
A series of azaphenylalanine derivatives were investigated as novel thrombin inhibitors based on the prodrug principle. By systematic structural modifications we have identified optimal groups for this series that led us to potent inhibitors of thrombin incorporating the benzamidine fragment at the P1 position, and their potentially orally active benzamidoxime prodrugs. The binding modes in the thrombin active site of two representative compounds were identified by X-ray crystallographic analysis.
Aza Compounds↗
AM1 CI and ZINDO/S study of quaternary salts of diazaphenanthrenes with haloalkanes.
For quaternary salts of diazaphenanthrenes 1-3 with methyl iodide 4-6, diiodomethane 7-9 and 1,2-dibromoethane 10-12 UV spectral values have been calculated by AM1 CI, and in the case of 4-6 also with ZINDO/S method. Correlations of experimental and calculated wavenumber values of considered compounds show good compatibility. For geometry optimisation of 4-9 the AM1 CI method has been used.
Alkanes↗
In-vitro activity of moxifloxacin against fluoroquinolone-resistant strains of aerobic gram-negative bacilli and Enterococcus faecalis.
MICs of the new fluoroquinolone, moxifloxacin, and those of ciprofloxacin, ofloxacin and sparfloxacin for 19 genetically characterized fluoroquinolone-resistant strains were determined by the agar dilution method. The MICs of moxifloxacin for Escherichia isolates with one mutation in gyrA (corresponding to Ser83-->Leu or Asp87-->Gly substitution) were 0.25-0.5 mg/L, while those of ciprofloxacin, ofloxacin and sparfloxacin were 0.06-0.25, 1 and 0.12-0.5 mg/L, respectively. These values were four- to 16-fold higher than those of the same antibiotics for the wild-type strain, E. coli KL16. Similar results were observed with clinical isolates of Salmonella spp. harbouring one mutation in gyrA leading to the substitution of Ser83 by Phe or Tyr. In the presence of two mutations in the E. coli gyrA gene, the MICs of moxifloxacin ciprofloxacin, ofloxacin and sparfloxacin were 2, 0.5, 4 and 1 mg/L, respectively; these were 32 times higher than the MICs of these agents for E. coli KL16. The MICs of the four quinolones for triple mutants with two mutations in gyrA and one in parC were even higher, i.e. 8, 8, 16 and 8-16 mg/L, respectively. The MICs of moxifloxacin for Campylobacter coli and Campylobacter jejuni strains with a gyrA mutation leading to Thr86-->Ile substitution ranged from 1 to 2 mg/L, while the MICs of ciprofloxacin, ofloxacin and sparfloxacin were 16-32 mg/L, 8-16 and 4-8 mg/L, respectively. For high-level ciprofloxacin-resistant (MICs of 32 mg/L) clinical isolates of Enterococcus faecalis with one substitution at position 83 in GyrA (E. coli coordinates), the MICs of moxifloxacin, ofloxacin and sparfloxacin were 8-16, > or = 128 and 32 mg/L respectively. In conclusion, moxifloxacin and other fluoroquinolones exhibit cross-resistance against aerobic gram-negative bacilli and enterococci. The in-vitro activity of moxifloxacin was greater than that of ofloxacin and slightly less than that of ciprofloxacin and sparfloxacin against Enterobacteriaceae, but greater than those of the three other compounds tested against Campylobacter spp and E. faecalis.
Anti-Infective Agents↗
[Tumor suppressor gene p53 and molecular targeting therapy].
p53 is a molecule which is activated upon a DNA stress, such as gamma irradiation, UV, hypoxia, virus infection, and DNA damage, leading protection of cells by inducing target genes. The molecules activated by p53 induce apoptosis, cell cycle arrest, and DNA repair to conserve genome. In order to kill cancer cells, many strategies targeting p53 have been reported. Preclinical studies have demonstrated that overexpression of wt-p53 by adenovirus vector is capable of inducing apoptosis in cancers. Furthermore, restoration of mt-p53 into wild type by compound has been under development. In this review, clinical application of molecular targeting therapy for p53 is discussed.
Apoptosis↗
Predicting compound selectivity by self-organizing maps: cross-activities of metabotropic glutamate receptor antagonists.
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Algorithms↗