New S-benzylisothiosemicarbazones with antimycobacterial activity.

Benzaldehyde- and salicylaldehyde-S-benzylisothiosemicarbazones show a moderate to high in vitro activity against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii. Benzaldehyde-S-4-bromobenzylisothiosemicarbazone and salicylaldehyde-S-4-chlorobenzylisothiosemicarbazone have the most promising antimycobacterial properties.

New antimycobacterial 2,3-dihydro-1-alkylindole-2-thiones.

A series of 2,3-dihydroindole-2-thiones was evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. kansasii, M. fortuitum, two strains of M. intracellulare and three strains of M. avium. 2,3-Dihydro-1-methyl-2-thioxoindole-3-one and 2,3-dihydro-1-butyl-2-thioxoindole-3-one were the most active substances against potentially pathogenic strains, being more active than isoniazide.

New antimycobacterial S-alkylisothiosemicarbazones.

In connection with a systematic study of antimycobacterial agents against potentially pathogenic strains the series of 12 S-alkylisothiosemicarbazones was evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. kansasii, M. fortuitum, two strains of M. intracellulare and three strains of M. avium. Quinoline-4-carbaldehyde-S-hexyl-isothiohydrazone was found to be more active against potentially pathogenic strains than isoniazide.

New synthetic siderophores and their beta-lactam conjugates based on diamino acids and dipeptides.

Linking of siderophores to antibiotics improves the penetration and therefore increases the antibacterial activity of the antibiotics. We synthesized the acylated catecholates and hydroxamates as siderophore components for antibiotic conjugates to reduce side effects of unprotected catecholate and hydroxamate moieties. In this paper, we report on bis- and tris-catecholates and mixed catecholate hydroxamates based on diamino acids or dipeptides. These compounds were active as siderophores in a growth promotion assay under iron limitation. Most of the conjugates with beta-lactams showed high in vitro activity against Gram-negative bacteria especially Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens and Stenotrophomonas maltophilia. The compounds with enhanced antibacterial activity use active iron uptake routes to penetrate the bacterial outer membrane barrier, demonstrated by assays with mutants deficient in components of the iron transport system. Correlation between chemical structure and biological activity was studied.

New artificial siderophores based on a monosaccharide scaffold.

New artificial catecholate siderophores with methyl alpha-D-glucopyranoside as scaffold were synthesized. The dihydroxy- or di(acetoxy)benzoyl moieties were attached either directly or via aminopropyl spacer groups, to the carbohydrate scaffold. The siderophore activity of the prepared siderophore analogs was examined by a growth promotion assay using various Gram-negative bacteria and mycobacteria and by the CAS-assay.

Fe(III) coordination properties of two new saccharide-based enterobactin analogues: methyl 2,3,4-tris-O-[N-[2,3-di(hydroxy)benzoyl-glycyl]-aminopropyl]-alpha-D-glucopyranoside and methyl 2,3,4-tris-O-[N-[2,3-di-(hydroxy)-benzoyl]-aminopropyl]-alpha-D-glucopyranoside.

The synthesis of two saccharide-based enterobactin analogues, methyl 2,3,4-tris-O[-N[2,3-di(hydroxy)benzoyl-glycyl]-aminopropyl]-alpha-D-glucopyranoside (H(6)L(A)) and methyl 2,3,4-tris-O-[N-[2,3-di(hydroxy)benzoyl]-aminopropyl]-alpha-D-glucopyranoside (H(6)L(B)), are reported along with their pK(a) values, Fe(III) binding constants, and aqueous solution speciation as determined by spectrophotometric and potentiometric titration techniques. Use of a saccharide platform to synthesize a hexadentate triscatechol chelator provides some advantages over other approaches to enterobactin models, including significant water solubility, resistance to hydrolysis, and backbone chirality which may provide favorable recognition and availability to cells. The protonation constants for the catechol ligand hydroxyl moieties were determined for both ligands and found to be significantly different, which is attributed to the differences in the spacer chain of the two triscatechols. Proton dependent Fe(III)-ligand equilibrium constants were determined using a model involving the sequential protonation of the Fe(III)-ligand complex. These results were used to calculate the formation constants, log beta(110) = 41.38 for Fe(III)-H(6)L(A) and log beta(110) = 46.38 for Fe(III)-H(6)L(B). The calculated pM values of 28.6 for H(6)L(A) and 28.3 for H(6)L(B) indicate that these ligands possess Fe(III) affinities comparable to or greater than other enterobactin models and are thermodynamically capable of removing Fe(III) from transferrin.

Frequency of headache in the medical students of Santa Catarina's Federal University.

Studies in well-defined populations are useful in identifying factors that influence frequency and severity of headache and in understanding its impact on people. The aims of this study were to determine the frequency of headache in the medical students of Santa Catarina's Federal University, examine associated factors, verify the diagnostic impressions of the different types of headache, and describe the self-medication level. This study included 408 medical students who were interviewed by a questionnaire from October 1997 to August 1998. The frequency of headache in this group was 33%, with women and students in the five last semesters of the medical course experiencing increased headache frequency. The diagnostic impressions of the different types of headache were migraine without aura (31.3%), migraine with aura (8.2%), episodic tension-type headache (32.1%), chronic tension-type headache (7.5%), and tension-type headache combined with migraine without aura (3%). Self-medication was reported by 51.8% of the medical students with headache; 34.4% used prescribed medications. The most common self-help techniques used by students during a headache were to lie down or isolate themselves from their surroundings.

8-Acyloxy-1,3-benzoxazine-2,4-diones as siderophore components for antibiotics.

8-Acyloxy-1,3-benzoxazine-2,4-diones as masked catechol derivatives represent a novel type of siderophore components, whose growth promoting activity is low or not existing if tested alone. But after conjugation with beta-lactam antibiotics the resulting conjugates show a significantly increased antibacterial activity against Gram-negative bacteria compared with their parent antibiotics. Investigations using a set of penetration and iron transport mutants demonstrated that the conjugates use iron transport systems to penetrate the bacterial outer membrane. Title compounds were synthesized from (2,3-dimethoxycarbonyloxy)-benzoic acid and different amino compounds. Conjugates with penicillins and cephalosporins were prepared.

New synthetic catecholate-type siderophores based on amino acids and dipeptides.

New analogs of bacterial siderophores with one, two or three catecholate moieties were synthesized using various mono- and diamino acid and dipetide scaffolds, respectively. In addition to 2,3-dihydroxybenzoyl siderophore analogs and their acylated derivatives, 3,4-dihydroxybenzoyl derivatives were prepared. Furthermore, the synthesis of a new triscatecholate serving as an intimate model for enterobactin is reported. Most of the new compounds gave a positive CAS-test and were active as siderophores tested by growth promotion assays with a set of siderophore indicator mutants under iron limitation. Structure-activity-correlations have also been studied.

Semisynthetic derivatives of madurahydroxylactone and their antibacterial activities.

Madurahydroxylactone is a secondary metabolite from Nonomuria rubra (former Actinomadura rubra) with in vitro activity against gram-positive bacteria and belongs to the family of benzo[a]naphthacenequinones. A series of derivatives of madurahydroxylactone were synthesized to investigate the effect on the antibacterial activity. Reaction with alcohols and amines gave cyclic acetals or aminals derived from the lactone form, whereas other amino reagents like hydroxylamines and acyl or sulfonyl hydrazides led to the corresponding imine derivatives of the aldehyde. Hydrazine, alkyl and aryl hydrazines react with madurahydroxylactone under cyclization to give compounds of the new heterocyclic basic structure naphthaceno[1,2-g]phthalazine. Some new compounds strongly inhibit gram-positive bacteria, in part stronger than the parent compound.

Novel catecholate-type siderophore analogs based on a myo-inositol scaffold.

A novel 1,3,5-triamino-myo-inositol derivative is presented as a readily available scaffold for the design of tripodal siderophore mimetics. Based on this scaffold, various hexadentate catecholate-type siderophore analogs were synthesized by attaching the catechols to the inositol scaffold via spacer units of different structure and length. The potential to tune the polarity of the inositol containing siderophore analogs has also been demonstrated by varying the protection group strategy. The siderophore activity of the prepared siderophore analogs was examined by cross-feeding tests with various Gram-negative bacteria and mycobacteria.

[Synthesis and antibacterial action of new ureido- and dicarboxylic acid diamido- derivatives of acylpenicillins with and without catechol substituents]. / Synthese und antibakterielle Wirkung neuer Ureido- und Dicarbonsäurediamidoderivate von Acylpenicillinen mit und ohne Catecholsubstituenten.

New ureido, oxamoyl, fumaramoyl and terephthalamoyl derivatives of ampicillin or amoxicillin were synthesized by reaction of acylpenicillines with o-dihydroxy- or o-diacyloxy substituents containing aromatic amines bound over CO- or dicarboxylic groups. Corresponding compounds derived from 3,4-diacetoxyaniline showed significant increase of activity against pseudomonas and salmonella in contrast to derivatives without catechol substituents. No increase of activity was observed by corresponding derivatives of bi- and tricyclic amines. Derivatives with oxamoyl, fumaramoyl or terephthalamoyl groups were found to be more active than the corresponding ureido derivatives. Studies with mutants possessing higher membrane permeability have shown that the high activities of catechol containing derivatives are connected with the improved penetration through the outer membrane. Some new penicillin derivatives are more stable against beta-lactamases compared with azlocillin.

[Relationship between chemical structure and toxicologic-pharmacokinetic properties of new ampicillin derivatives]. / Beziehungen zwischen chemischer Struktur und toxikologisch-pharmakokinetischen Eigenschaften neuer Ampicillin-Derivate.

The toxicity and the bioavailability of new ampicillin derivatives with glyoxylic acid benzhydrazones as site chain depend on the hydrophobic properties of the site chain. Substituents with lower hydrophobicity (expressed by the hydrophobic substituent constant pi according to Hansch) show a lower toxicity (maximal tolerated doses) and also a lower bioavailability.

[New ampicillin derivatives with glyoxyloylbenzhydrazone side chains]. / Neue Ampicillinderivate mit Glyoxyloylbenzhydrazon-Seitenketten.

New ampicillin derivatives were synthesized from glyoxylic acid benzhydrazones by reaction with chloroformates via mixed anhydrides and ampicillin. These compounds were tested in an agar diffusion test against six different bacterial strains and also for their stability against beta-lactamases. Studies about structure-activity relationships have shown, that the activity against different bacterial strains is influenced in different manner by hydrophilic or hydrophobic and electronic properties of substituents.

[Synthesis and antibacterial activity of benzoylaminoacyl-penicillins and related compounds with and without acylated catechol substituents]. / Synthese und antibakterielle Wirksamkeit von Benzoylaminoacyl-Penicillinen und verwandten Verbindungen mit und ohne acylierte Catechol-Substituenten.

Synthesis and Antibacterial Activity of Benzoylaminoacyl Penicillins and Related Compounds with and without Acylated Catechol Substituents. Syntheses of benzoyl, cinnamoyl, and benzoylhydrazido glyoxyloyl aminoacyl penicillins with and without acylated catechol substituents by condensation of corresponding acids or acylchlorides with ampicillin or amoxycillin and also of a 6-a-methoxy-derivative and corresponding esters are reported. Acylated catechol substituents improve the antibacterial activity against Gram-negative bacteria, especially against Pseudomonas strains and Salmonella. MIC tests of bacterial mutants with higher outer membrane penetrability and of the corresponding wild typs show that the increase of antibacterial activity by catechol substituents is caused by improvement of the penetration through the bacterial outer membran. The affinity to penicillin binding proteins is not influenced by catechol substituents. Stability against beta-lactamases is partly higher than that of azlocillin.

[Parkinson disease induced by flunarizine]. / Parkinsonismo induzido pela flunarizina.

The authors studied 19 patients with parkinsonism induced by flunarizine. All them improved when the drug therapy was discontinued for periods from 7 days to 10 months. Depression was observed in 68.5% of the patients.

[Spectroscopic studies on the formation of metal complexes and on the protein binding of antiviral thiosemicarbazone derivatives (author's transl)]. / Spektroskopische Untersuchungen zur Metallkomplexbildung und Proteinbindung antiviraler Thiosemicarbazonderivate.

The complexation of some thiosemicarbazones and isothiosemicarbazones of isatin and quinolin-2-aldehydes with Cu2+, Zn2+ and Mn2+ ions was spectrometrically investigated. Semiquantitative data, obtained from extinction values, about the relative complexing tendencies within some groups of homologous substances were brought in relation to their antiviral effects and binding to bovine serum albumin. The complexing tendencies were greatest in compounds with methyl substituents and decreased for higher alkyl substituents. whereas the binding to protein increased in the same order. The well-known maxima of the antiviral observed with medium alkyl groups may be explained by a superposition of these effects.

Inhibition of mengovirus RNA-dependent RNA polymerase by an isatinisothiosemicarbazone and a piperidine-thiocarbonyl-hydrazone derivative in a cell-free system.

The inhibitory action of two antiviral compounds used at the maximum tolerated dosis in a cellular system led to a complete suppression of the infectious mengovirus yield and to a 100% plaque reduction. The products of the RNA polymerase reaction catalyzed by the microsomal-mitochondrial fraction of mengovirus-infected FL cells were analyzed by linear sucrose gradient centrifugation and polyacrylamid gel electrophoresis. The results showed that the inhibitors cause a general reduction of the synthesis of single-stranded viral RNA. The influence on double-stranded viral RNA was more obvious in the case of the isatinisothiosemicarbazone derivative.

[Copper II complexes of N-heterocyclic formylisothiosemicarbazones with antimicrobial and beta-lactamase inhibitory activity]. / Kupfer-II-komplexe N-heterocyclischer Formylisothiosemicarbazone mit antimikrobieller und beta-Lactamasen inhibierender Wirkung.

The synthesis of copper(III)-complexes from quinoline-2- or quinoxaline-2-aldehyde-isothiosemicarbazones in pyridine and the elucidation of their structure are described. Some of the new substances exhibit an inhibitory action on growth of gram-positive bacteria, especially Bacillus subtilis (ATCC 6633), furthermore in vitro the beta-lactamase I action is inhibited. Using penicillin-resistant Staphylococci as test strains a strong penicillin-synergistic action was discovered.