RESUMEN
During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which maintained all of the in vitro activity seen with oxadiazoline 1, but also demonstrated a better pharmacokinetic profile, and dose-dependent in vivo activity. Over a 28 day study, indolyloxazoline 22g increased the life span of tumor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and others of its structural class, may prove to be useful in the development of new chemotherapeutic agents to treat human cancers.
Asunto(s)
Antineoplásicos/síntesis química , Oxazoles/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Cromatografía Líquida de Alta Presión , Colchicina/química , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Oxazoles/química , Oxazoles/farmacología , Relación Estructura-Actividad , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
Very little is known about the structure-activity relationship of quinolone antibacterials at the 2-position. Because of the loss of biological activity with 2-methyl and 2-hydroxyl substitution, modifications at C-2 were generally considered to be unfavourable. Quinolone derivatives having a ring between positions 1 and 2 were recently shown to have biological activity. The sulfur-bridged analogs such as the benzothiazolo[3,2-a]quinolone, KB-5246 and NAD-394 have been reported to be highly active in vitro. The authors have synthesized 2-methylthiociprofloxacin, 2-methylofloxacin, the 5-oxopyrrolo[1,2-a]quinoline and isothiazolonaphthyridine to assess the importance of the sulfur atom on biological activity as well as the effect of C-2 substituent on the spatial arrangements of N-1 or the 3-carboxylic group. It was found that the planarity between the 4-keto and 3-carboxylic acid groups of quinoline molecules is the most important criterion for biological activity. The syntheses of the above four compounds are also described.
Asunto(s)
Antiinfecciosos/farmacología , Quinolonas/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Quinolonas/química , Relación Estructura-Actividad , Inhibidores de Topoisomerasa IIRESUMEN
Over the past years it was found that modification of the 3-carboxylic acid group of quinolones generally produced compounds with a substantial decrease in antibacterial activity. The 3-carboxylic acid moiety together with the 4-carbonyl function are believed to be the most structurally critical sites for this class of compounds to DNA gyrase. The authors have designed and synthesized a series of quinolone analogues in which the 3-carboxylic acid group has been modified. These compounds, 2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-diones, possess biological activities far superior to their parent counterparts. For example, the MICs (microgram/ml) for A-62824 (ciprofloxacin 3-carboxylic acid modified analogue) and ciprofloxacin against some organisms are as follows: S. aureus ATCC 6538P (0.02, 0.2); S. epidermidis 3519 (0.05, 0.2); E. coli Juhl (0.005, 0.01); P. aeruginosa A5007 (0.05, 0.1) and Acinetobacter sp. CMX 699 (0.05, 0.78). This investigation has produced the first successful modification of the 3-carboxylic acid group of quinolones resulting in a series of extremely potent antibacterials. The design and synthesis as well as the biological activities of these new derivatives are described.
Asunto(s)
Antiinfecciosos/farmacología , Quinolonas/farmacología , Antiinfecciosos/síntesis química , ADN-Topoisomerasas de Tipo II/metabolismo , Composición de Medicamentos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Quinolonas/síntesis química , Relación Estructura-Actividad , Tiazoles/farmacologíaRESUMEN
Novel arylfluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids have been prepared and their antibacterial activity evaluated. 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. The in vitro antibacterial potency is greatest when the 1-substituent is either p-fluorophenyl or o,p-difluorophenyl and the 7-substituent is a 3-amino-1-pyrrolidinyl group. 1-(2,4-Difluorophenyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid (38) was found to possess excellent in vitro potency and in vivo efficacy.
Asunto(s)
Antibacterianos/síntesis química , Bacterias/efectos de los fármacos , Naftiridinas/síntesis química , Antibacterianos/farmacología , Flúor/farmacología , Naftiridinas/farmacología , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antibacterianos/uso terapéutico , Antiinfecciosos , Ciprofloxacina/análogos & derivados , Fluoroquinolonas , Quinolinas/farmacología , Acinetobacter/efectos de los fármacos , Animales , Antibacterianos/síntesis química , Antibacterianos/farmacología , Infecciones Bacterianas/tratamiento farmacológico , Fenómenos Químicos , Química , Enterobacter/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Femenino , Flúor/síntesis química , Flúor/farmacología , Klebsiella pneumoniae/efectos de los fármacos , Ratones , Norfloxacino/análogos & derivados , Norfloxacino/farmacología , Pefloxacina , Piperazinas/farmacología , Piperazinas/uso terapéutico , Pseudomonas aeruginosa/efectos de los fármacos , Quinolinas/síntesis química , Quinolinas/uso terapéutico , Staphylococcus/efectos de los fármacos , Streptococcus/efectos de los fármacos , Relación Estructura-ActividadAsunto(s)
Neoplasias Abdominales/diagnóstico por imagen , Neoplasias Pélvicas/diagnóstico por imagen , Absceso/diagnóstico por imagen , Adolescente , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Adulto , Neoplasias del Sistema Biliar/diagnóstico por imagen , Niño , Preescolar , Femenino , Enfermedades Gastrointestinales/diagnóstico por imagen , Neoplasias Gastrointestinales/diagnóstico por imagen , Humanos , Lactante , Recién Nacido , Enfermedades del Recién Nacido/diagnóstico por imagen , Enfermedades Renales/diagnóstico por imagen , Neoplasias Renales/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico por imagen , Linfoma/diagnóstico por imagen , Masculino , Quistes Ováricos/diagnóstico por imagen , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Pancreáticas/diagnóstico por imagen , Radiografía , Neoplasias Retroperitoneales/diagnóstico por imagen , Neoplasias Testiculares/diagnóstico por imagenRESUMEN
Congenital adenomatoid malformation (CAM) of the lung was diagnosed at 30 weeks gestation. The mother presented with preterm labor and polyhydramnios. A complex cystic mass was seen in the right lung of the fetus. Additional radiographic and sonographic investigations prior to delivery allowed differentiation of this rare lesion from other cystic thoracic pathology of the fetal period. Careful hospital obstetric management of the mother and fetus for over 3 weeks allowed the delivery of an infant with adequate pulmonary maturity to permit stabilization and surgery on the baby in the first days of life.