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PubMed1975

Effect of activated nitrofurans on DNA.

Enzymically activated nitrofurazone reacts with co-valently closed circular DNA (derived from Escherichia coli minicells carrying lambdadv) to give at least two kinds of damage: breaks which are detected on neutral sucrose gradients and alkali-labile lesions in DNA which are converted to breaks when the DNA is subsequently Treated with alkali. DNA, isolated from nimicells exposed to the drug, also contains lesions which are converted to breaks upon treatment with endonuclease preparations obtained from Micrococcus luteus. Minicells repaired both breaks and nuclease-susceptible lesions within 2 h but did not repair alkali labile lesions within that time. Experiments with three other nitrofurans show that there are considerable differences in the degree to which DNA is damaged by activated metabolites of various derivatives and that the potency of the compounds as mutagens and carcinogens is correlated with the amount of damage caused to minicell DNA.

Binding Sites↗
PubMed1985

Antimicrobial activity of some heterocyclic derivatives of 1-methyl-1-nitroethyl sulphides.

The minimum inhibitory concentration values for a group of synthesized heterocyclic derivatives of 1-methyl-1-nitroethyl sulphide were determined for Gram-positive and Gram-negative bacteria, yeast, and fungi. The active compounds were further screened. The effect of these compounds on growth, morphology and incorporation of 3H-uridine was also tested. Comments on the possible model of action of such compounds is included.

Anti-Bacterial Agents↗
PubMed1974

Chemical carcinogens as frameshift mutagens: Salmonella DNA sequence sensitive to mutagenesis by polycyclic carcinogens.

Other investigators have shown that several polycyclic carcinogens are frameshift mutagens in Salmonella. Mutagenic potency of these compounds is assessed by ability to induce reversion of histidine-requiring frameshift mutants to prototrophy. One frameshift mutation in the histidinol dehydrogenase gene, hisD3052, is unusually sensitive to mutagenesis by certain polycyclic carcinogens. We find that the 3052 mutation is a - 1 deletion, probably loss of a G.C pair from a DNA repeat of [unk]. The polycyclic carcinogens tested (e.g., 2-nitroso-fluorene) revert 3052 by deleting a [unk] doublet from the DNA sequence [unk], which is close to the 3052 site. This rare mispairing-prone sequence represents the carcinogen-sensitive "hotspot" in 3052. The ICR compounds, noncarcinogenic intercalating agents, show a broader specificity of mutagenesis. Reversion with these mutagens occurs predominantly by two mechanisms: one identical to that of the polycyclic carcinogens, and the other by +1 additions in a third DNA tract narrowly separated from the 3052 site. The alkylating carcinogen N-methyl-N'-nitro-N-nitrosoguanidine appears to have a similar dual specificity. DNA base changes in 3052 revertants have been correlated with properties of histidinol dehydrogenase in crude extracts. This correlation of DNA base sequence with electrophoretic and other properties of the mutant proteins allows one to analyze easily the specificity of new mutagens that mutate this strain.

Acridines↗
PubMed2004

Comparative analysis of neonicotinoid binding to insect membranes: I. A structure-activity study of the mode of [3H]imidacloprid displacement in Myzus persicae and Aphis craccivora.

Neonicotinoids bind selectively to insect nicotinic acetylcholine receptors with nanomolar affinity to act as potent insecticides. While the members of the neonicotinoid class have many structural features in common, it is not known whether they also share the same mode of binding to the target receptor. Previous competition studies with [3H]imidacloprid, the first commercialised neonicotinoid, indicated that thiamethoxam, representing a novel structural sub-class, may bind in a different way from that of other neonicotinoids. In the present work we analysed the mode of [3H]imidacloprid displacement by established neonicotinoids and newly synthesized analogues in the aphids Myzus persicae Sulzer and Aphis craccivora Koch. We found two classes of neonicotinoids with distinct modes of interference with [3H]imidacloprid, described as direct competitive inhibition and non-competitive inhibition, respectively. Competitive neonicotinoids were acetamiprid, nitenpyram, thiacloprid, clothianidin and nithiazine, whereas thiamethoxam and the N-methyl analogues of imidacloprid and clothianidin showed non-competitive inhibition. The chloropyridine or chlorothiazole heterocycles, the polar pharmacophore parts, such as nitroimino, cyanoimino and nitromethylene, and the cyclic or acyclic structure of the pharmacophore were not relevant for the mode of inhibition. Consensus structural features of the neonicotinoids were defined for the two mechanisms of interaction with [3H]imidacloprid binding. Furthermore, two sub-classes of non-competitive inhibitors can be discriminated on the basis of their Hill coefficients for imidacloprid displacement. We conclude from the present data that the direct competitors share the binding site with imidacloprid, whereas non-competitive compounds, like thiamethoxam, bind to a different site or in a different mode.

Anabasine↗
PubMed2003

Nematocidal activity of nitazoxanide in laboratory models.

The nematocidal activity of a broad-spectrum antiparasitic agent, nitazoxanide [( N-(5-nitrothiazol-2-gammal)salicylamide; NTZ], was evaluated in both in vitro and in vivo models using Caenorhabditis elegans, Heligmosomoides polygyrus and Trichinella spiralis. In vitro, NTZ (100 muM) exhibited a low activity against C. elegans and had no effect on embryonation and hatching of H. polygyrus eggs. At concentrations of 100 and 50 muM, the inhibition of excretion/secretion of acetylcholinesterase and acid phosphatase of adult H. polygyrus by NTZ was variable. The in vitro effects of mebendazole (5 muM), albendazole (1 muM) and levamisole (10 muM) were superior to those of NTZ. In mice, NTZ at 1 g/kg proved to be inactive against preadults of T. spiralis whereas mebendazole at 10 mg/kg reduced the worm burden by up to 83%. NTZ at 1 g/kg per day for 3 consecutive days showed a low activity against adults of H. polygyrus (21% reduction). Levamisole, at a single dose of 10 mg/kg, reduced the worm burden by up to 89.9%. The results of this study suggest that NTZ would not have met criteria of a candidate compound.

Animals↗
PubMed2006

Synthesis and evaluation of alpha-hydroxymethylated conjugated nitroalkenes for their anticancer activity: inhibition of cell proliferation by targeting microtubules.

The Morita-Baylis-Hillman (MBH) type reaction of a variety of aromatic and heteroaromatic conjugated nitroalkenes with formaldehyde in the presence of stoichiometric amounts of imidazole and catalytic amounts (10 mol %) of anthranilic acid at room temperature provided the corresponding hydroxymethylated derivatives in moderate to good yield. The parent nitroalkenes and their MBH adducts were subsequently screened for their anticancer activity. Some of the MBH adducts were found to inhibit cervical cancer (HeLa) cell proliferation at low micromolar concentrations with half-maximal inhibitory concentrations in the range of 1-2 microM. The antiproliferative activity of 3-((E)-2-nitrovinyl)furan and three potent MBH adducts, namely, hydroxymethylated derivatives of 3-((E)-2-nitrovinyl)thiophene, 1-methoxy-4-((E)-2-nitrovinyl)benzene, and 1,2-dimethoxy-4-((E)-2-nitrovinyl)benzene was correlated well with their antimicrotubule activity. At their effective concentration range, the tested compounds perturbed the organization of mitotic spindle microtubules and chromosomes. In the presence of hydroxymethylated nitroalkenes, abnormal bipolar or multipolar mitotic spindles were apparent. Interphase microtubules were found to be significantly depolymerized at relatively higher concentrations of the tested compounds. These compounds inhibited tubulin assembly into microtubules in vitro by binding to tubulin at a site distinct from the vinblastine and colchicine binding sites. The compounds reduced the intrinsic tryptophan fluorescence of tubulin and the fluorescence of tubulin-1-anilinonaphthalene-8-sulfonic acid (ANS) complex indicating that they induced conformational changes in the tubulin. The results suggest that hydroxymethylated nitroalkenes exert their antiproliferative activity at least in part by depolymerizing cellular microtubules through tubulin binding and indicate that hydroxymethylated nitroalkenes are promising lead compounds for cancer therapy.

Alkenes↗
PubMed1975

[Research in antitumoral chemotherapy. X. Cytotoxic and antitumoral activity of beta-nitrostyrenes and of composed nitrovinyl derivatives].

In previous work the antitumoral cytotoxicity of beta-nitrostyrenes obtained by simplification of the aristolochic acid molecule was demonstrated. The effect of modifying the three characteristic parts of the beta-nitrostyrene molecule has now been investigated. The results obtained in vitro and in vivo allow hypothesis of a mechanism of action for the various beta-nitrostyrene and nitrovinyl compounds studied and definition of the maximum simplification compatible with retention of biological activity.

Animals↗
PubMed1975

Azulene analogs of pharmacological agents III: acute toxicity and local anesthetic activity of azulylamides and azulenecarboxamides.

This paper describes the acute toxicity of two azulylamides and six azulenecarboxamides and the nerve conduction-inhibiting properties of some of these compounds. The azulene derivatives are compared to their benzenoid prototypes, lidocaine and procainamide, as part of a continuing investigation of the biological properties of nonbenzenoid aromatic compounds.

Acetamides↗
PubMed1989

Release of iron from ferritin by semiquinone, anthracycline, bipyridyl, and nitroaromatic radicals.

The cytotoxicity of many xenobiotics is related to their ability to undergo redox reactions and iron dependent free radical reactions. We have measured the ability of a number of redox active compounds to release iron from the cellular iron storage protein, ferritin. Compounds were reduced to their corresponding radicals with xanthine oxidase/hypoxanthine under N2 and the release of Fe2+ was monitored by complexation with ferrozine. Ferritin iron was released by a number of bipyridyl radicals including those derived from diquat and paraquat, the anthracycline radicals of adriamycin, daunorubicin and epirubicin, the semiquinones of anthraquinone-2-sulphonate, 1,5 and 2,6-dihydroxyanthraquinone, 1-hydroxyanthraquinone, purpurin, and plumbagin, and the nitroaromatic radicals of nitrofurantoin and metronidazole. In each case, iron release was more efficient than with an equivalent flux of superoxide. Introduction of air decreased the rate of iron release, presumably because the organic radicals reacted with O2 to form superoxide. In air, iron release was inhibited by superoxide dismutase. Semiquinones of menadione, benzoquinone, duroquinone, anthraquinone 1,5 and 2.6-disulphonate, 1,4 naphthoquinone-2-sulphonate and naphthoquinone, when formed under N2, were unable to release ferrin iron. In air, these systems gave low rates of superoxide dismutase-inhibitible iron release. Of the compounds investigated, those with a single electron reduction potential less than that of ferritin were able to release ferritin iron.

Antibiotics, Antineoplastic↗
PubMed2005

Pharmacokinetic studies of a novel 1,2,4-thiadiazole derivative, inhibitor of Factor XIIIa, in the rabbit by a validated HPLC method.

Activated Factor XIII (FXIIIa) stabilizes fibrin clot by covalent cross-linking of fibrin strands in the fibrin, making it resistant to physiological and pharmacologically induced fibrinolysis. Inhibition of Factor XIIIa offers a novel approach to treatment of thrombosis. Selected derivatives of 1,2,4-thiadiazoles, presently in discovery and development, may offer new treatment strategies as inhibitors of Factor XIIIa. In order to evaluate its pharmacokinetic (PK) profile and to facilitate the selection of drug candidates for drug discovery and development process, we developed and validated a simple and selective reversed-phase high-performance liquid chromatographic method (RP-HPLC) with UV detection for the determination of N-[6-(imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino)hexyl]-2-nitrobenzensulfonamide (5624) in rabbit plasma. The plasma protein precipitation and sample preparation was achieved by using acetonitrile, followed by organic phase evaporation to dryness and the residue reconstitution in the mobile phase. The 5624 recovery from the plasma was about 90%. Chromatography was performed on a C18 column using a gradient of acetonitrile in water as a mobile phase. A chemically related compound, N-[6-(imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino)hexyl]naphthalene-1-sulfonamide (5422), was used as an internal standard. Limit of detection (LOD), based on signal to noise ratio>3, was 0.2 microM (on-column amount of about 7 ng), while limit of quantification (LOQ), based on signal to noise ratio>10, was 0.5 microM (on-column amount of about 20 ng). The plasma samples for the PK study were collected at defined time points during and after 5624 slow intravenous infusion (25 mg/kg) to male White New Zealand rabbits and analyzed by RP-HPLC method. The PK parameters, such as half-life, volume of distribution, total clearance, elimination rate constant etc., were determined. The PK profile of 5624 offered insights in the design and development of additional new compounds, derivatives of 1,2,4-thiadiazole, with desired PK properties.

Animals↗
PubMed1973

Functional groups in the activity and regulation of Escherichia coli citrate synthase.

1. Citrate synthase has been purified from Escherichia coli and shown to exist at an equilibrium between three forms: monomer (mol.wt. 57000), tetramer (mol.wt. 230000) and, possibly, octamer. Modification of the enzyme by photo-oxidation and by treatment with specific chemical reagents has been carried out to gain information on the amino acid residues involved in enzymic activity and in the inhibition of activity by NADH and alpha-oxoglutarate. 2. Several photo-oxidizable amino acids appear to be involved in activity. The nature of the pH-dependence of their rates of photo-oxidation with Methylene Blue suggests that these are histidines, a conclusion supported by the greater rate of photo-inactivation with Rose Bengal and the destruction of activity by diethyl pyrocarbonate. 3. The participation of histidine at the alpha-oxoglutarate effector site is indicated by photo-oxidation and the participation of cysteine at the NADH effector site suggested by photo-oxidation is confirmed by the desensitization to NADH produced by treatment with 5,5'-dithiobis-(2-nitrobenzoate). Inactivation of the enzyme after modification with this reagent suggests the additional involvement of cysteine in catalytic activity. 4. Amino acid analyses of native and photo-oxidized enzyme are consistent with these conclusions. 5. Modification with 2-hydroxy-5-nitrobenzyl bromide indicates the participation of tryptophan in the activity of the enzyme.

Amino Acids↗
PubMed1977

[Method of the spectrophotometric analysis of polyene antibiotics].

The method of quantitative spectrophotometric analysis of several substances in the presence of admixtures is described. The method is based on presentation of an unknown spectrum of the admixture absorption by the polyen of the 3rd or 4th power depending on the wave length. The optical density of the mixture of any wave length is expressed by the linear equation, including the Firord equation for the known components and the given polynome. The system of such equations for 10-15 analytical wave lengths may be solved with the method of the least squares using an electronic computer. The system solvations are the concentrations of the mixture components to be determined and the polynome coefficients. The method was tested on model mixtures composed of amphotercin B, myocheptin, nystatin and griseofulvin, as well as of isomeric nitroanilines playing the role of the admixture. The analysis error for the compounds of the polyenic structure having not less than 2 absorption maxima in the given spectral ranges did not exceed 1-3 per cent. As for the compounds with a single maximum or when the admixture included also polyenic compounds the analysis error increased up to 6--50 per cent.

Amphotericin B↗