RESUMEN
A series of 4-diazoimidazole-5-carboxamides bearing in position 2 lipophilic substituents was synthesized and their antimicrobial activity was evaluated in vitro against pathogenic Gram-positive, Gram-negative bacteria and fungi. Some compounds presented antifungal activity, particularly two derivatives (1g and 1h) showed good MIC values (10-50 microg/ml) against both moulds and yeasts.
Asunto(s)
Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Antibacterianos , Antiinfecciosos/química , Enterococcus faecalis/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Imidazoles/química , Pruebas de Sensibilidad Microbiana , Hongos Mitospóricos/efectos de los fármacos , Estructura Molecular , Proteus mirabilis/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A series of 2-carbonyl analogues of the muscarinic antagonist diphenidol bearing 1-substituents of different lipophilic, electronic, and steric properties was synthesized and their affinity for the M2 and M3 muscarinic receptor subtypes was evaluated by functional tests. Two derivatives (2g and 2d) showed an M2-selective profile which was confirmed by functional tests on the M1 and M4 receptors. A possible relationship between M2 selectivity and lipophilicity of the 1-substituent was suggested by structure-activity analysis. This work showed that appropriate structural modification of diphenidol can lead to M2-selective muscarinic antagonists of possible interest in the field of Alzheimer's disease.
Asunto(s)
Antagonistas Muscarínicos/síntesis química , Antagonistas Muscarínicos/farmacología , Piperidinas/química , Receptores Muscarínicos/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Cobayas , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Masculino , Contracción Muscular/efectos de los fármacos , Piperidinas/síntesis química , Piperidinas/farmacología , Conejos , Receptores Muscarínicos/clasificaciónRESUMEN
A new series of 4-nitro-(imidazoles and pyrazoles) were synthesized as novel antimycotics and tested for their activation to mutagenic forms using Salmonella typhimurium TA98 and TA100, in the presence and in the absence of metabolic activation. TA100NR, TA100/1,8-DNP6, YG1026 and YG1029 strains were employed to identify a specific metabolic reaction which governs the mutagenic potency. Derivatives in the pyrazole group were generally found to be non mutagenic and active imidazoles were weak-direct-acting mutagens. For most of the compounds the mutagenic responses in TA98 were absent or 12- to 22-fold lower compared to TA100. The presence of a methyl or a benzylic group on the imidazole ring and substituents on the N1 and N3 positions were determinant for mutagenicity. Metabolism by bacterial enzyme systems was important to the expression of genotoxicity. Active compounds showed no mutagenicity toward the strain defective in classical nitroreductase and increased mutagenicity, from 2- to 7-fold depending on the test compound, toward the corresponding overproducing bacteria. On the other hand, compounds displayed reduced mutagenicity to the O-acetyltransferase strain without having increased activity in the corresponding overproducing bacteria, YG1029.
Asunto(s)
Imidazoles/toxicidad , Mutágenos/toxicidad , Pirazoles/toxicidad , Salmonella typhimurium/genética , Imidazoles/síntesis química , Imidazoles/metabolismo , Pruebas de Mutagenicidad , Pirazoles/síntesis química , Pirazoles/metabolismo , Relación Estructura-ActividadRESUMEN
A series of 2-substituted-5-diazoimidazole-4-carboxamides has been synthesized, and their antimicrobial activity has been tested in vitro. Some of the compounds show antifungal activity related to the presence of small groups on the 4-carbox-amido moiety, while the presence of substituents in position 2 was detrimental.
Asunto(s)
Antiinfecciosos/síntesis química , Imidazoles/síntesis química , Antibacterianos , Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Candida albicans/efectos de los fármacos , Fenómenos Químicos , Química Física , Imidazoles/farmacología , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
In pursuing our research on the NSAIDs, the diastereomeric (+/-)-erythro- and (+/-)-threo-2-(4-biphenylyl)-3-hydroxy-2-methyl-3-phenyl-propionic acids (4 and 5) were synthesized; the last was also resolved in its optical isomers (6 and 7). The attribution of the relative configuration to 4 and 5 was performed by means of X-ray analysis. The compounds were tested for their antiinflammatory activity. The acid 4, which resulted very interesting, was tested also for analgesic and antipyretic activity, as well as for behavioural effects, gastric tolerability and acute toxicity. On the basis of the obtained data, this compound resulted a very promising one.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Propionatos/química , Propionatos/farmacología , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Edema/tratamiento farmacológico , Ratones , Estructura Molecular , Dimensión del Dolor , RatasRESUMEN
Nitrobenzimidazole and nitroindole derivatives, related to oxiconazole and characterized by an oxyiminic function, have been synthesized as novel antimycotics and their mutagenic activity tested in Salmonella typhimurium strains TA100 and TA98 with and without an exogenous metabolizing system. TA98NR and TA98/1,8-DNP6 strains were employed to identify a specific metabolic reaction which governs the mutagenic potency. Active compounds are weak direct-acting mutagens. Only derivatives bearing a nitro group on the phenyl ring linked to the oxyiminic function and lacking halogenated substituents show mutagenic activity. Metabolism by bacterial enzyme systems is important to the expression of genotoxicity. The reductive activation of nitrobenzimidazoles and nitroindoles carried out by the 'classical' nitroreductase of Salmonella, which is defective in TA98NR, is required of mutagenicity. Similarly, the O-acetyltransferase defective in TA98/1,8-DNP6 is required for the efficient production of the ultimate electrophilic nitrogen species, which react with DNA. The role of bacterial metabolism in mutation induction needs careful consideration to assess the potential risk to humans from nitrobenzimidazole and nitroindole antimycotics.
Asunto(s)
Antifúngicos/toxicidad , Bencimidazoles/toxicidad , Indoles/toxicidad , Pruebas de Mutagenicidad , Mutágenos/toxicidad , Nitrocompuestos/toxicidad , Salmonella typhimurium/efectos de los fármacos , Biotransformación , Humanos , Conformación Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The synthesis, diastereomeric separation, assignment to erythro- and threo-configuration by 1HNMR, and optical resolution of 3-(p-trifluoromethyl-phenyl)- and (p-thioanisyl)-2-biphenylyl-3-hydroxypropionic acids are described. The enantiomers were submitted to a preliminary assay to determine antiinflammatory activity.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Compuestos de Bifenilo/síntesis química , Hidroxiácidos/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacología , Compuestos de Bifenilo/farmacología , Carragenina , Edema/tratamiento farmacológico , Edema/fisiopatología , Hidroxiácidos/farmacología , Espectroscopía de Resonancia Magnética , Masculino , Conformación Molecular , Ratas , Ratas Endogámicas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
As fluorenyl rigid analogues of previous biphenylyl alcanoic acids with very interesting antiinflammatory activity, the 3-(m-tolyl and m-anisyl)-3-hydroxy-3-(2-fluorenyl)-propionic acids have been prepared by means of the Reformatsky reaction and following hydrolysis of the obtained ethyl esters. The preliminary antiinflammatory assay showed that the structural modification inactivates the compounds.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Fluorenos/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacología , Carragenina/antagonistas & inhibidores , Edema/inducido químicamente , Edema/prevención & control , Fluorenos/farmacología , Masculino , Ratas , Ratas EndogámicasRESUMEN
The optically active diastereometric erythro- and threo-3-thienyl-analogues 6a-d of 3-aryl-2-biphenylyl-3-hydroxy-propionic acids have been prepared. Some stereoisomers of 3-(3-thienyl)derivative 6b showed inhibition around 40% in the carrageenan-induced rat paw edema test.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Lactatos/síntesis química , Tiofenos/síntesis química , Animales , Carragenina , Fenómenos Químicos , Química , Edema/inducido químicamente , Edema/prevención & control , Lactatos/farmacología , Espectroscopía de Resonancia Magnética , Masculino , Ratas , Ratas Endogámicas , Estereoisomerismo , Tiofenos/farmacologíaRESUMEN
A short series of di-functionalized benzodifurans and phenanthrolines were synthesized for in vitro antimicrobial activity. Dicarboxaldehydes, chiefly those with a phenanthroline supporting moiety, proved to be most effective, showing significant fungal growth inhibition.