Synthesis and structure-activity relationships of novel arylfluoroquinolone antibacterial agents.

A series of novel arylfluoroquinolones has been prepared. These derivatives are characterized by having a fluorine atom at the 6-position, substituted amino groups at the 7-position, and substituted phenyl groups at the 1-position. Structure-activity relationship (SAR) studies indicate that the in vitro antibacterial potency is greatest when the 1-substituent is either p-fluorophenyl or p-hydroxyphenyl and the 7-substituent is either 1-piperazinyl, 4-methyl-1-piperazinyl, or 3-amino-1-pyrrolidinyl. The electronic and spatial properties of the 1-substituent, as well as the steric bulk, play important roles in the antimicrobial potency in this class of antibacterials. As a result of this study, compounds 45 and 41 were found to possess excellent in vitro potency and in vivo efficacy.

Synthesis and evaluation of 19F labeled sulfonyl fluorides as probes of protease structure: alpha-chymotrypsin.

Active site Ser-195-fluorine-labeled derivatives of alpha-chymotrypsin were prepared from a series of N-(trifluoromethylphenyl)-fluorosulfonylphenyl carboxamides whose synthesis is described. The six new 19F spin labels varied in the position of the -CF3 substituent (o-, m-, and p-) and the fluorosulfonyl substituent (m- or p-). The chemical shifts of these covalently bound analogs of "tosyl-chymotrypsin" were each uniquely sensitive to their environment in the catalytic center as evidenced by differences in resonance line position for each label. Upon titrating these derivatives with the reversible competitive inhibitor, indole, a downfield shift was observed (with all but one label), which could be fit in each case to an apparent dissociation constant for indole binding. Indole binding to the p-sulfonyl derivatives was essentially unaltered from that for the native enzyme, while the m-sulfonyl derivatives required some additional free energy of binding to saturate the enzyme. The results are consistent with a partial embedding of the phenylsulfonyl moiety in the aromatic specificity pocket.

Studies of potential organo-fluorine antibacterial agents. Part 5: Synthesis and antibacterial activity of some new fluorine-containing indole-2,3-dione derivatives.

A series of new 1-dialkylaminoacetyl-5/6-fluoroindole-2,3-diones and 3-arylhydrazino-5/6-fluoro-1-morpholinomethylindol-2-ones have been synthesized; the former by the reaction of different secondary amines with N-chloro-acetyl-5/6-fluoroindole-2,3-diones and the latter, by the condensation of substituted phenylhydrazines with 5/6-fluoro-1-morpholinomethylindole-2,3-diones. All synthesized compounds have been characterized by their IR, 1H-NMR and elemental analysis. These compounds have been screened for their antibacterial activity against the Gram positive bacterium Staphylococcus albus and the Gram negative bacterium Escherichia coli.

Catalytic versatility of Bacillus pumilus beta-xylosidase: glycosyl transfer and hydrolysis promoted with alpha- and beta-D-xylosyl fluoride.

Bacillus pumilus beta-xylosidase, an enzyme considered restricted to hydrolyzing a narrow range of beta-D-xylosidic substrates with inversion of configuration, was found to catalyze different stereochemical, essentially irreversible, glycosylation reactions with alpha- and beta-D-xylopyranosyl fluoride. The enzyme promoted the hydrolysis of beta-D-xylopyranosyl fluoride at a high rate, V = 6.25 mumol min-1 mg-1 at 0 degrees C, in a reaction that obeyed Michaelis-Menten kinetics. In contrast, its action upon alpha-D-xylopyranosyl fluoride was slow and characterized by an unusual relation between the rate of fluoride release and the substrate concentration, suggesting the possible need for two substrate molecules to be bound at the active center in order for reaction to occur. Moreover, 1H NMR spectra of a digest of alpha-D-xylosyl fluoride showed the substrate to be specifically converted to alpha-D-xylose by the enzyme. The observed retention of configuration is not consistent with direct hydrolysis by this "inverting" enzyme but is strongly indicative of the occurrence of two successive inverting reactions: xylosyl transfer from alpha-D-xylosyl fluoride to form a beta-D-xylosidic product, followed by hydrolysis of the latter to produce alpha-D-xylose. The transient intermediate product formed enzymically from alpha-D-xylosyl fluoride in the presence of [14C]xylose was isolated and shown by its specific radioactivity and 1H NMR spectrum as well as by methylation and enzymic analyses to be 4-O-beta-D-xylopyranosyl-D-xylopyranose containing one [14C]xylose residue.(ABSTRACT TRUNCATED AT 250 WORDS)

N-trifluoroacetyl derivatives as pharmacological agents. III. Analgesic, antipyretic activities and physicochemical features of some antiinflammatory trifluoroacetanilides.

Further pharmacological (antipyretic and analgesic activities) and physicochemical (pka and relative lipophilicity) studies are reported on some trifluoroacetanilides which have preliminary revealed promising activities in the animal models of acute and chronic inflammation, in analogy with the known antiinflammatory trifluoromethanesulfonanilides.

[Phenylethylamine fluorides. II. Synthesis and neurobiochemistry in the rat]. / Phényléthylamines fluorées. II. Synthèse et étude neurobiochimique chez le rat.

Sixteen fluorinated phenylethylamines analogous to catecholamine were obtained by fluoration from the corresponding amino-alcohols. The biological activity of the compounds was evaluated by determining their affinity for the central adrenergic receptors of rat brain membranes and by measuring the monoamine synaptosomal uptake. These compounds significantly inhibited serotonine uptake, but they showed no affinity for amphetaminergic binding sites.