Synthesis of some 1-(2-naphthyl)-2-(imidazole-1-yl)ethanone oxime and oxime ether derivatives and their anticonvulsant and antimicrobial activities.

In this study, oxime and oxime ether derivatives of anticonvulsant nafimidone [1-(2-naphthyl)-2-(imidozole-1-yl)ethanone] were prepared as potential anticonvulsant compounds. Nafimidone oxime was synthesized by the reaction of nafimidone and hydroxylamine hydrochloride. O-Alkylation of the oxime by various alkyl halides gave the oxime ether derivatives. Anticonvulsant activity of the compounds was determined by maximal electroshock (MES) and subcutaneous metrazole (scMet) tests in mice and rats according to procedures of the Antiepileptic Drug Development (ADD) program of the National Institutes of Health (NIH). In addition to anticonvulsant evaluation, compounds were also screened for possible antibacterial and antifungal activities because of the structural resemblance to the azole antifungals, especially to oxiconazole. All compounds were evaluated against three human pathogenic fungi and four bacteria using the microdilution method. Most of the compounds exhibited both anticonvulsant and antimicrobial activities; the O-alkyl substituted compounds (2, 3, 4 and 5) were found to be more active than the O-arylalkyl substituted compounds in both screening paradigms.

Effect of hypoxia alone or combined with inflammation and 3-methylcholanthrene on hepatic cytochrome P450 in conscious rabbits.

1 To investigate the effect of moderate hypoxia alone or combined with an inflammatory reaction or after 3-methylcholanthrene (3MC) pre-treatment on cytochrome P450 (P450), conscious rabbits were exposed for 24 h to a fractional concentration of inspired O2 of 10% (mean PaO2 of 34 mmHg). Hypoxia decreased theophylline metabolic clearance (ClM) from 1.73+/-0.43 to 1.48+/-0.13 ml min-1 kg-1 (P<0. 05), and reduced (P<0.05) the formation clearance of theophylline metabolites, 3-methylxanthine (3MX), 1-methyluric acid (1MU) and 1,3-dimethyluric acid (1,3DMU). Hypoxia reduced the amount of CYP1A1 and 1A2 but increased CYP3A6 proteins. 2 Turpentine-induced inflammatory reaction reduced (P<0.05) the formation clearance of 3MX, 1MU, and 1,3DMU, and diminished the amount of CYP1A1, 1A2 and 3A6 proteins. However, when combined with hypoxia, inflammation partially prevented the decrease in ClM, especially by impeding the reduction of 1,3DMU. The amount of CYP1A1 and 1A2 remained reduced but the amount of CYP3A6 protein returned to normal values. 3 Pre-treatment with 3MC augmented the ClM by 114% (P<0.05) due to the increase in the formation clearance of 3MX, 1MU and 1,3DMU. 3MC treatment increased the amount of CYP1A1 and 1A2 proteins. Pre-treatment with 3MC prevented the hypoxia-induced decrease in amount and activity of the P450. 4 It is concluded that acute moderate hypoxia and an inflammatory reaction individually reduce the amount and activity of selected apoproteins of the P450. However, the combination of hypoxia and the inflammatory reaction restores P450 activity to near normal values. On the other hand, pre-treatment with 3MC prevents the hypoxia-induced depression of the P450.

Disulfide cross-linked Fab-aggregates: preparation and biodistribution.

The high-molecular-weight soluble aggregates of Fab fragments of murine antibodies against cardiac myosin were prepared as a potential long-circulating and low immunogenic pharmaceutical carriers by conjugation of thiolated Fab and Fab modified with succinimidyl 3-(2-pyridyldithio)propionate. The clearance time and biodistribution of 111In-radiolabeled aggregates were studied in normal and nude-mice bearing human breast tumor implant and in rabbits with experimental myocardial infarction. The aggregates had a prolonged circulation time (half clearance time ca. 3-5 h) and ability to concentrate in the tumor and in the necrotic area of infarcted myocardium. Similar tumor-to-normal and infarct-to-normal accumulation ratios (ca. 3 h in both cases) suggest that combination of long circulation with impaired filtration in necrotic tissues is responsible for this accumulation rather than a specific interaction. The aggregates prepared may serve as long-circulating drug carriers able to deliver pharmaceuticals into areas with affected and leaky vasculature.

Synthesis of some N-arylazole acetamide derivatives and their anticonvulsant and antimicrobial activities.

Some new N-arylazole acetamide derivatives have been prepared by the reaction of alpha-bromo-N-arylacetamide with imidazole, pyrazole and 1,2,4-triazole. The structures of these compounds have been confirmed by UV, IR, 1H-NMR and elementary analysis. Their anticonvulsant activities were determined by maximal electroshock (MES) and subcutaneous metrazol (Scmet) tests. Most of the compounds showed anticonvulsant activity with significantly low neurotoxicity according to Phase I tests. Compound 6 carrying alpha-naphthyl and 1,2,4-triazole was found active in the MES test with ED50 = 64.9 mg/kg and TD50 = 221.0 mg/kg but it was not active in corneally stimulated rats. Antibacterial and antifungal activities of the compounds were determined against S. aureus, E. coli, P. aeruginosa, C. albicans, C. parapsilosis, C. pseudotropicalis and C. stellatoidea by using the microdilution broth method. Compounds 8 and 10 showed significant activity (MIC < 32 micrograms/ml) against various Candida species.

Synthesis and anticholinergic activity of some new N,N-disubstituted carbamodithioic acid 2-oxo-2-(diphenylamino) ethyl esters.

The synthesis of new N,N-disubstituted carbamodithioic acid 2-oxo-2-(diphenylamino) ethyl esters is reported. The structures of these compounds are supported by their UV, IR and 1H-NMR spectra, as well as by elemental analysis. The new compounds were tested for their anticholinergic activities.

Synthesis and anticonvulsant activity of some new 4-aryl-4-imidazoline-2-one derivatives.

In this study, some new 4-aryl-4-imidazoline-2-one derivatives have been prepared by the reaction of potassium cyanate with some aminoethanone hydrochlorides. The structure of these compounds have been confirmed by UV, IR, 1H-NMR and elementary analysis. Their anticonvulsant activities were determined by maximal electroshock (MES) and subcutaneous metrazol (ScMet) tests according to the ADD (Antiepileptic Drug Development) programme Phase I. Neurotoxicity of the compounds was evaluated by rotarod test. While 2 of the compounds showed protection against ScMet induced seizures at 30 and 300 mg/kg dose levels, 3 of the compounds showed neurotoxicity.