Synthesis of antimicrobial agents. 3. Syntheses and antibacterial activities of 7-(4-hydroxypiperazin-1-yl)quinolones

A series of novel pyridone carboxylic acids having a 4-hydroxypiperazinyl group at the 7-position of norfloxacin and ciprofloxacin were prepared. The in vivo antibacterial efficacies of these compounds were superior to those of corresponding piperazinyl derivatives. From the results of the studies on the pharmacokinetic profile and toxicity, the 4-hydroxypiperazinyl derivatives were confirmed to be pharmacologically superior to corresponding piperazinyl derivatives. Thus, a 4-hydroxypiperazinyl group was revealed to be a beneficial substituent for potential use in future quinolone antibacterials.     

Synthesis of antimicrobial agents. 1. Syntheses and antibacterial activities of 7-(azole substituted)quinolones

A series of 6-fluoro- and 6,8-difluoro-7-(azole substituted)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids were prepared. Structure-activity relationship studies indicated that the antibacterial potency was better when the 6,8-substituents were fluorine atoms and the 7-substituent was either 1-imidazolyl, 20, or 4-methyl-1-imidazolyl, 25. From the results of studies on pharmacokinetic profile and toxicity, 20 and 25 were found to possess excellent antibacterial activities and to show high blood levels after oral administration to mice with low toxicity.     

Synthesis and antibacterial activity of new tetracyclic quinolone antibacterials.

A series of 8-substituted-9,1-(epoxymethano)-7-fluoro-5-oxo-5H- thiazolo[3,2-a]quinoline-4-carboxylic acids having a novel tetracyclic structure was synthesized and tested for antibacterial activity. The nature of the heteroatom (N, O, or S) substituted at the 8-position had little influence on the antibacterial activity. Among the six pyrrolidinyl derivatives and the five piperazinyl derivatives, the 8-(3-hydroxy-1-pyrrolidinyl) derivative 6h and the hydrochloride of the 8-(4-methyl-1-piperazinyl) derivative 6l showed the most potent activity against both Gram-positive and Gram-negative bacteria. Against nalidixic acid resistant strains, isolated from Escherichia coli KC-14, compound 6h was less potent than 6l. Replacement of the piperazinyl nitrogen atom by a carbon atom, an oxygen atom, or a sulfur atom (corresponding to the piperidino, morpholino, or thiomorpholino group, respectively) enhanced the activity against Gram-positive bacteria, but reduced the activity against Gram-negative bacteria. Compound 6l also showed potent in vivo antibacterial activity against Gram-positive and Gram-negative bacteria, and did not cause convulsions in mice with the concomitant administration of fenbufen. Replacement of the carboxy group by a sulfonic acid group in 6l resulted in a complete loss of antibacterial activity.     

Associative visual agnosia--a case report

A 61 year-old right-handed man, a president of a company fell downstairs and was found unconscious on January 1, 1985. He was admitted to a hospital and he had been unresponsive for 10 days. As he recovered from the consciousness disturbance, he complained of difficulties in discrimination of common objects and in recognition of familiar faces. The patient was admitted to our hospital for the closer examination on July 29, 1985. There was no abnormality in the general physical examination on admission. Neurological examinations revealed no significant deficits except visual field disturbance. In the results of WAIS, the verbal IQ was 108, but the performance IQ was unmeasurable because of a presence of object agnosia. His spontaneous speech was fluent without paraphasia, perseveration or dysprosody. His auditory comprehension of spoken language and repetition were spared. Neuropsychological examinations revealed an impairment in the recent verbal memory, alexia, agraphia, object agnosia, color naming difficulty, prosopagnosia and visuospatial constructional disability. The patient exhibited three major neuropsychological characteristics. Firstly, the recognition of the objects which were presented by the photograph or line drawing was more severely impaired than the real objects. Secondly, the object naming difficulty was more pronounced in the presentation at an unusual angle than in the free presentation. Thirdly, the patient made poor performance in reproduction of the models by photographic presentation as compared with the presentation of the real models in the three-dimensional block construction test. The CT scan performed on January 4, 1985 demonstrated subcortical hematomas with surrounding edema in the temporo-occipital regions of both hemispheres.(ABSTRACT TRUNCATED AT 250 WORDS)     

Supplementation Effect of Early Pregnancy Factor-Positive Serum into Bovine In Vitro Fertilization Culture Medium

PROBLEM: Early pregnancy factor (EPF) has been detected in pregnant bovine serum, and its activity appeared from 24 to 48 hr after insemination. However, in bovine in vitro fertilization (IVF), an EPF-like substance(s) had been detected in the culture medium of fertilized ovum. Therefore, we think that EPF and EPF-like substance(s) are very important materials for the development of the embryo. In this study, we examined the development of the embryo when fertilized bovine ova were cultured with IVF culture medium supplemented with EPF-positive or -negative serum. METHOD OF STUDY: EPF activity of each serum (fetal calf serum [FCS], calf serum [CS], estrus bovine serum, and pregnant bovine serum) was assessed by the bovine-rosette inhibition test. The sera were supplemented in TCM-199 culture medium, and IVF bovine ova were cultured with the media for 6 or 7 days, respectively. The culture media of each group were evaluated for EPF activity by the bovine-rosette inhibition test 48 hr after IVF. The cleavage rate of each group was calculated at 48 hr, and 6 or 7 days after IVF. The culture medium of cumulus cells was also tested for EPF activity. RESULTS: Only the pregnant bovine sera were EPF positive. All the culture media 48 hr after IVF became EPF positive. Additionally, the culture medium of cumulus cells did not have EPF activity. There was no significant difference in the cleavage rate of the EPF-positive and - negative sera 48 hr after IVF. However, the cleavage rate of EPF-positive sera tended to be higher than the negative sera. In contrast, the blastocyst development rates of EPF-positive sera were significantly higher than those of the negative sera 6 to 7 days after IVF (P < 0.05). CONCLUSIONS: The data suggest that an EPF-like substance(s) may be secreted from the in vitro fertilized bovine ovum but not from the cumulus cell, and that the EPF in the pregnant serum may accelerate the development of the bovine embryo in IVF.     

Difference of osteopontin gene regulation between bone and kidney

 Osteopontin is a sialoprotein that is expressed in various cells. It plays a variety of important roles in cell adhesion, migration, signaling, calcification, and immunity. Its diverse functions indicate that the regulation of osteopontin may also vary extensively among tissues. Although osteopontin promoter has been studied in vitro, in vivo analyses may be more appropriate for elucidating osteopontin's functions. In an attempt to investigate osteopontin gene expression, we generated transgenic mice in which the bacterial β-galactosidase reporter gene was conjugated downstream of osteopontin promoter. The osteopontin promoter was a mouse −910 bp upstream fragment, which we had previously found functional in 3T3 cells. Among 34 transgenic founders, 13 mice were transgenic, as determined with the polymerase chain reaction. Osteopontin and β-galactosidase signals were evaluated with in situ hybridization. Among the 13 transgenic mice, 3 were β-galactosidase-positive. In these transgenic mice, osteopontin signals were observed in bones and kidneys, whereas β-galactosidase message was detected only in bones. This suggests that the −910 bp osteopontin promoter is active in bones but not in kidneys. These data imply that the promoter region required for osteopontin expression in kidneys may differ from that in bones. Received: March 22, 2002 / Accepted: December 5, 2002 RID="*" ID="*" Offprint requests to: T. Sakuma Acknowledgments. We greatly appreciate the excellent histotechnological assistance of Mr. Kenji Morihana. This work was supported in part by a grant from The Ministry of Education, Science, and Culture, Japan (no. 12470056).