RESUMEN
A selective and sensitive UHPLC-MS/MS bioanalytical method to determine PT-31, an analgesic drug candidate, in rat plasma was developed and validated. Analyses were performed using a UHPLC-MS/MS system equipped with an electrospray ionization interface operating in the positive ionization mode using a C18 reversed-phase column with a mobile phase of water:acetonitrile (68:31, v/v) containing 0.1% acetic acid eluting in a gradient mode with a flow rate of 0.3 mL/min. Plasma samples were deproteinized with cold acetonitrile containing 0.01% TFA (1:2, v/v) and 50 µL of the supernatant were injected into the system. PT-31 and phenytoin (internal standard) retention times were roughly 1.0 and 1.5 min, respectively. Linear standard curves were plotted for the 0.01-10 µg/mL concentration range, with a coefficient of determination > 0.99. The method's precision was over 88%. Maximum intra- and inter-day relative standard deviations were 14.6% and 11.6%, respectively. Interfering substances were not detected in the chromatogram, indicating that the method was specific. PT-31 stability was assessed under different temperature and storage settings. The method was used to characterize PT-31 plasma pharmacokinetics following administration of 5 mg/kg i.v. to Wistar rats. Therefore, the method described is sensitive, linear, precise and specific enough to determine PT-31 in preclinical pharmacokinetic investigations. Copyright © 2015 John Wiley & Sons, Ltd.
Asunto(s)
Analgésicos/sangre , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Analgésicos/farmacocinética , Animales , Imidazolidinas/sangre , Imidazolidinas/farmacocinética , Límite de Detección , Ratas , Estándares de Referencia , Reproducibilidad de los ResultadosRESUMEN
A series of new thiazacridine agents were synthesized and evaluated as antitumor agents, in terms of not only their cytotoxicity but also their selectivity. The cytotoxicity assay confirmed that all compounds showed cytotoxic activity and selectivity. The new compound, 3-acridin-9-ylmethyl-5-(5-bromo-1 H-indol-3-ylmethylene)-thiazolidine-2,4-dione (LPSF/AA29 - 7a), proved to be the most promising compound as it presents lower half-maximal inhibitory concentration (IC50) values (ranging from 0.25 to 68.03 µM) depending on cell lineage. In HepG2 cells, the lowest IC50 value was exhibited by 3-acridin-9-ylmethyl-5-(4-piperidin-1-yl-benzylidene)-thiazolidine-2,4-dione (LPSF/AA36 - 7b; 46.95 µM). None of the synthesized compounds showed cytotoxic activity against normal cells (IC50 > 100 µM). The mechanism of death induction and cell cycle effects was also evaluated. Flow cytometric analysis revealed that the compounds LPSF/AA29 - 7a and LPSF/AA36 - 7b significantly increased the percentage of apoptotic cells and induced G2/M arrest in the cell cycle progression. Therefore, these new thiazacridine derivatives constitute promising antitumor agents whose cytotoxicity and selectivity properties indicate they have potential to contribute to or serve as a basis for the development of new cancer drugs in the future.
Asunto(s)
Acridinas/farmacología , Antineoplásicos/farmacología , Tiazolidinedionas/farmacología , Acridinas/síntesis química , Acridinas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Espectroscopía de Protones por Resonancia Magnética , Tiazolidinedionas/síntesis química , Tiazolidinedionas/químicaRESUMEN
A novel set of acridinylidene thiazolidinediones and benzylidene thiazolidinediones was synthesized by nucleophilic addition of cyanoacrylates. Some of these compounds were evaluated for their glucose lowering capability and their effects on the triglyceride level in alloxan diabetic mice.
Asunto(s)
Acridinas/síntesis química , Compuestos de Bencilo/síntesis química , Hipoglucemiantes/síntesis química , Tiazolidinedionas/síntesis química , Acridinas/química , Acridinas/farmacología , Animales , Compuestos de Bencilo/química , Compuestos de Bencilo/farmacología , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/mortalidad , Evaluación Preclínica de Medicamentos , Femenino , Hipoglucemiantes/farmacología , Masculino , Ratones , Rosiglitazona , Tiazolidinedionas/química , Tiazolidinedionas/farmacología , Triglicéridos/sangreRESUMEN
Synthesis and physico-chemical properties of 3-benzyl-5-(4-fluoro-benzylidene)-1-methyl-2-thioxo-imidazolidin-4-ones, 5-benzylidene-3-(4-nitro-benzyl)-2-thioxo-imidazolidin-4-ones and 4-acridin-9-ylmethylene-1-benzyl-5-thioxo-imidazolidin-2-ones compounds are described. These thioxo-imidazolidine derivatives were prepared by alkylation and condensation with 4-fluoro-benzaldehyde or nucleophilic Michael addition with cyanoacrylates. The schistosomicidal activity of 3-benzyl-5-(4-fluoro-benzylidene)-1-methyl-2-thioxo-imidazolidin-4-one compounds was evaluated.
Asunto(s)
Imidazolidinas/síntesis química , Imidazolidinas/farmacología , Esquistosomicidas/síntesis química , Esquistosomicidas/farmacología , Animales , Cristalografía por Rayos X , Femenino , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Schistosoma mansoni/efectos de los fármacos , Esquistosomicidas/toxicidadRESUMEN
The synthesis and physicochemical properties of 4-butyl-2H-benzo[1,4]thiazin-3-one derivatives are described. These new compounds were synthesised by alkylation in 4-N position and acylation and/or alkylation of 6-NH2 by phase transfer catalysis. Acid hydrolysis of 6-alkylacylamino group yielded 6-alkylamino-4-butyl-2H-benzo[1,4]thiazin-3-ones. The antimicrobial in vitro activity was determined on five compounds.
Asunto(s)
Antiinfecciosos/síntesis química , Tiazinas/síntesis química , Antiinfecciosos/química , Antiinfecciosos/farmacología , Pruebas de Sensibilidad Microbiana , Tiazinas/farmacologíaRESUMEN
Synthesis and physico-chemical properties of new 3-benzyl-4-thioxo-5-arylideneimidazolidine-2-ones and 3-benzyl-5-arylideneimidazolidine-2,4-dione are described. These compounds were synthesized by condensation reaction from aromatic aldehydes and 3-substituted imidazolidine-2,4-diones or 4-thioxoimidazolidine-2-ones. The N-alkylation of 5-benzylideneimidazolidine-2,4-dione led simultaneously to mono- and dialkylated derivatives. The nucleophilic addition of 1-methyl-3-benzylimidazolidine-2,4-dione with 2-cyano-3-(3,4-dichlorophenyl) acrylate also yielded the 3-substituted 5-arylideneimidazolidine-2,4-dione derivative. Antimicrobial in vitro activity was determined on some compounds.
Asunto(s)
Antibacterianos/síntesis química , Imidazoles/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Recuento de Colonia Microbiana , Cromatografía de Gases y Espectrometría de Masas , Imidazoles/química , Imidazoles/farmacologíaRESUMEN
The synthesis of five chlorobenzyl benzylidene imidazolidinediones and four fluorobenzyl benzylidene thiazolidinediones is described. In order to investigate their antimicrobial activity they are evaluated against microorganism such as Candida albicans, Neurospora crassa, Staphylococcus aureus, Mycobacterium smegmatis and Escherichia coli.
Asunto(s)
Antiinfecciosos/síntesis química , Compuestos de Bencilideno/síntesis química , Imidazoles/síntesis química , Tiazoles/síntesis química , Antibacterianos , Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Compuestos de Bencilo/síntesis química , Compuestos de Bencilo/farmacología , Compuestos de Bencilideno/farmacología , Hongos/efectos de los fármacos , Imidazoles/farmacología , Pruebas de Sensibilidad Microbiana , Tiazoles/farmacologíaRESUMEN
Synthesis and physico-chemical properties of six 3-(4-bromophenacyl)-5-arylidene-thiazolidine-2,4-diones and eight 3-(4-chlorobenzyl)-5-arylidene-4-thio-imidazolidine-2-ones are described. These products were synthesized by an aldolisation-crotonisation reaction from aromatic aldehydes and 3-substituted thiazolidine-2,4-diones or 4-thio-imidazolidine-2-ones. Hypoglycemic and peripheral antinociceptive activities were investigated for these compounds.
Asunto(s)
Analgésicos/síntesis química , Hipoglucemiantes/síntesis química , Imidazoles/síntesis química , Tiazoles/síntesis química , Alquilación , Analgésicos/farmacología , Animales , Glucemia/metabolismo , Hipoglucemiantes/farmacología , Imidazoles/farmacología , Espectroscopía de Resonancia Magnética , Ratones , Dimensión del Dolor/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/farmacologíaRESUMEN
The synthesis and physico-chemical properties of fourteen 4-thio-5-arylidene-thiazolidine-2-ones and eight 3-(4-bromophenacyl)-4-thio-5-arylidene-thiazolidine-2-ones are described. These products were synthetized by the aldolisation-crotonisation reaction between aromatic aldehydes and 4-thio-thiazolidine-2-one followed by N-alkylation of this substituted compounds.
Asunto(s)
Tiazoles/síntesis química , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
The synthesis and the physico-chemical properties of four 3-(4-bromophenacyl)-5-arylidene-thiazolidine-2,4-diones, two 3-(4-bromobenzyl)-5-arylidene-thiazolidine-2,4-diones and seven 3-(4-chlorobenzyl)-5-arylidene-4-thio-imidazolidine-2-ones were described. These products were synthetized by the aldolisation-crotonisation reaction between aromatic aldehydes and substituted thiazolidinediones or thio-imidazolidinones.
Asunto(s)
Hipoglucemiantes/química , Hipoglucemiantes/síntesis química , Imidazoles/química , Imidazoles/síntesis química , Imidazolidinas , Tiazoles/química , Tiazoles/síntesis química , Tiazolidinedionas , Edema Encefálico/tratamiento farmacológico , Humanos , Hipoglucemiantes/farmacología , Imidazoles/farmacología , Tiazoles/farmacologíaRESUMEN
Synthesis and physico-chemical properties of five bromobenzyl-benzylidene-imidazolidinediones and five nitrobenzyl- or benzyl-benzylidene-thiazolidinediones are described. The microbiological activity of bromobenzyl-benzylidene-imidazolidinediones against microorganisms such as Candida albicans, Neurospora crassa and Mycobacterium smegmatis are evaluated.
Asunto(s)
Antiinfecciosos/síntesis química , Compuestos de Bencilideno/síntesis química , Etilenotiourea/síntesis química , Tiazoles/síntesis química , Antibacterianos , Antiinfecciosos/farmacología , Compuestos de Bencilo/síntesis química , Compuestos de Bencilo/farmacología , Compuestos de Bencilideno/farmacología , Candida albicans/efectos de los fármacos , Etilenotiourea/farmacología , Mycobacterium/efectos de los fármacos , Neurospora crassa/efectos de los fármacos , Tiazoles/farmacologíaRESUMEN
Synthesis and physico-chemical properties of 3-(4-bromobenzyl)-, 3-(4-chlorobenzyl)-5-arylidene-thiazolidine-2,4-diones and 3-(4-chlorobenzyl)-4-thioxo-5-arylidene-thiazolidin-2- ones are described. Twelve new products were synthesized by the aldolisation-crotonisation reaction from aromatic aldehydes and N-alkylated thiazolidinediones or thioxothiazolidinones. Seven compounds were preliminary tested for their bacteriostatic activity.
Asunto(s)
Antibacterianos/síntesis química , Tiazoles/síntesis química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Tiazoles/farmacologíaRESUMEN
Synthesis and physico-chemical properties of four 3-benzyl or 3-(4-chlorobenzyl)-4-thioxo-5-arylazo-imidazolidin-2-ones, five 3-(4-nitrobenzyl)-5-arylidenethiazolidine-2,4-diones and three 3-(4-phenyl-phenacyl)-4-thioxo-5-arylidenethiazolidin-2-ones have been described. These new products were synthesized by an aldolisation-crotonisation reaction from aromatic aldehydes and 3-substituted thioxothiazolidin-2-ones or thiazolidine-2,4-diones. The arylazo-imidazolidine compounds were synthesized by copulation of diazonium ions with imidazolidines. Antimicrobial activity was determined for some compounds.
Asunto(s)
Antiinfecciosos/síntesis química , Antifúngicos/síntesis química , Tiazoles/síntesis química , Antiinfecciosos/química , Antiinfecciosos/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
Synthesis and physico-chemical properties of some 3-benzyl- and 3-phenacyl-4-thioxo-5-benzylidenethiazolidin-2-one derivatives are described. Fifteen new compounds were synthesized from thiazolidin-2-one by thionation of the 4-carbonyle, alkylation of the 3-N and aldolisation-crotonisation of 5-CH(2) with aromatic aldehydes. Soon, these new compounds will be tested for their bacteriostatic activity.
Asunto(s)
Antiinfecciosos/síntesis química , Tiazoles/síntesis química , Tiazoles/farmacología , Alquilación , Antiinfecciosos/farmacología , Indicadores y ReactivosRESUMEN
The synthesis of six benzylidene thiazolidine-diones and three benzylidene imidazolidine-diones is described. In order to investigate their antimicrobial activity, they are evaluated against micro-organism such as Staphylococcus aureus, Streptococcus feacalis, Mycobacterium smegmatis and Neurospora crassa.
Asunto(s)
Antiinfecciosos/síntesis química , Compuestos de Bencilideno/síntesis química , Hidantoínas/síntesis química , Tiazoles/síntesis química , Antibacterianos , Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Compuestos de Bencilideno/farmacología , Hongos/efectos de los fármacos , Hidantoínas/farmacología , Pruebas de Sensibilidad Microbiana , Tiazoles/farmacologíaRESUMEN
Synthesis and physico-chemical properties of nine 3-(4-fluoro or chlorobenzyl)-5-arylidène-imidazolidine-2,4-diones, four 3-(4-fluoro or bromobenzyl)-5-arylidène-thiazolidine-2,4-diones and three 3-)4-bromophénacyl)-5-arylidène-thiazolidine-2,4- diones has been described. These compounds were synthesized by aldolisation-crotonisation reaction from aromatic aldehydes and 3-substituted imidazolidine-2,4-diones or thiazolidine-2,4-diones. In vitro cytotoxic activity was determined for compounds 8, 17, 18, 21 and 22.
Asunto(s)
Antineoplásicos/síntesis química , Imidazoles/síntesis química , Tiazoles/síntesis química , Antineoplásicos/farmacología , Humanos , Imidazoles/farmacología , Células KB , Tiazoles/farmacologíaRESUMEN
Synthesis and physico-chemical properties of six 5-arylidène-3-benzyl-1-methyl-2-thioxoimidazolidin-4-ones and three 2-arylidene-6-nitro-2H-1,4-benzothiazin-3(4H)-ones have been described. These new compounds were synthetised by Knoevenagel condensation reaction from aromatic aldehydes. The N-alkylation reaction of arylidenebenzothiazines by methyl iodide give the N-methylarylidenebenzothiazines.
Asunto(s)
Imidazoles/síntesis química , Tiazinas/síntesis química , Fenómenos Químicos , Química Física , Espectroscopía de Resonancia Magnética , EstereoisomerismoRESUMEN
A new set of derivative thioxothiazolidinones and thioxoimidazolidinones 3,5-dissubstituted has been synthesized with satisfactory yield from the condensation Knoevenagel type between benzaldéhydes and 4-thioxothiazolidin-2-one, 2-thioxothiazolidin-4-one and 1-méthyl-2-thioxoimidazolidin-4-one compounds following by N-alkylation with aryl or acyl halides. The physico-chemical properties of the 5-benzylidene-3-[2-(4-chlorophenyl)-2-oxoethyl]-2 (or 4)-thioxothiazolidin-4 (or 2)-ones and 5-benzylidene-1-methyl-2-thioxoimidazolidin-4-ones synthesized have been described.
Asunto(s)
Imidazoles/química , Tiazoles/química , Tionas/química , Alquilación , Fenómenos Químicos , Química Física , Imidazoles/síntesis química , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Tiazoles/síntesis química , Tionas/síntesis químicaRESUMEN
Thiazolidinediones (TZDs) are a class of drugs used for treatment of type 2 diabetes. However, the therapy with currently available TDZs (e.g. rosiglitazone) is associated with important side effects, such as edema and weight gain, suggesting that the investigation of alternative TZDs with better pharmacological properties is warranted. In this study, we investigated both anti-inflammatory and antioxidant properties of a new chemically modified TZD, the arylidene-thiazolidinedione 5-(4-methanesulfonyl-benzylidene)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione (SF23), and compared the results to those obtained with rosiglitazone. We found that our SF23 displays a weaker affinity for PPARγ, up-regulating in a lower magnitude the expression of both PPARγ and CD36 compared to rosiglitazone. In lipopolysaccharide (LPS)-stimulated macrophages, SF23 decreased nitrite production and attenuated the mRNA expression of both iNOS and COX-2. These anti-inflammatory effects were comparable to those obtained with rosiglitazone. Interestingly, SF23, but not rosiglitazone, prevented LPS-induced mitochondrial membrane hyperpolarization, apoptosis, reactive oxygen species (ROS) generation, and the expression of NADPH oxidase subunits, Nox1 and Nox2. In addition, in macrophages from Nrf2â»/â» mice, SF23 protected against LPSinduced cellular death and ROS production, whereas rosiglitazone was only able to protect normal Nrf2âº/⺠cells against oxidative injury, suggesting that, unlike rosiglitazone, the antioxidant activity of SF23 might be Nrf2-independent. Finally, in macrophages exposed to high concentrations of glucose, SF23 induced significant increases in the mRNA expression of glucose transporters, insulin receptor substrate and mitoNEET. Altogether, our data indicate that our new chemically modified TDZ displays similar anti-inflammatory properties, but superior antioxidant effects on the LPS-stimulated macrophages compared to rosiglitazone.