ABSTRACT
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.
Subject(s)
Acridines/pharmacology , Antineoplastic Agents/pharmacology , Thiazolidinediones/pharmacology , Acridines/chemical synthesis , Acridines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Cells, Cultured , Humans , Leukocytes, Mononuclear/drug effects , Proton Magnetic Resonance Spectroscopy , Thiazolidinediones/chemical synthesis , Thiazolidinediones/chemistryABSTRACT
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.
Subject(s)
Analgesics/blood , Chromatography, High Pressure Liquid/methods , Tandem Mass Spectrometry/methods , Analgesics/pharmacokinetics , Animals , Imidazolidines/blood , Imidazolidines/pharmacokinetics , Limit of Detection , Rats , Reference Standards , Reproducibility of ResultsABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents/chemistry , Antioxidants/chemistry , Macrophages/drug effects , Thiazolidinediones/pharmacology , Animals , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/chemistry , Lipopolysaccharides/pharmacology , Macrophage Activation , Macrophages/metabolism , Macrophages/pathology , Mice , Rosiglitazone , Thiazolidinediones/chemistry , Thiazolidinediones/therapeutic useABSTRACT
Schistosomiasis is a major public health problem with 207 million people infected and more than 779 million at risk. The drug of choice for treating schistosomiasis is praziquantel (PZQ); however, it is inefficient against immature forms of schistosomes. The aim of this study was to test new imidazolidine derivatives LPSF/PT09 and LPSF/PT10 against adult Schistosoma mansoni worms. IC50, cytotoxicity, immune response and cell viability assays were also available for these imidazolidines. Different concentrations of imidazolidine, from 32 to 320 »M, promoted motor abnormalities in breeding and unpaired worms, and death in 24 hours at higher concentrations. Although LPSF/PT09 and LPSF/PT10 did not affect IFN-³ and IL-10 production, they induced nitric oxide production and showed a similar behavior to praziquantel on cell death test. Thus, these new imidazolidine derivatives should undergo further study to develop schistosomiasis drugs.
Subject(s)
Animals , Female , Rats , Imidazolidines/immunology , Schistosoma mansoni/immunology , Public HealthABSTRACT
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.
Subject(s)
Acridines/chemical synthesis , Benzyl Compounds/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Thiazolidinediones/chemical synthesis , Acridines/chemistry , Acridines/pharmacology , Animals , Benzyl Compounds/chemistry , Benzyl Compounds/pharmacology , Blood Glucose/drug effects , Body Weight/drug effects , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/mortality , Drug Evaluation, Preclinical , Female , Hypoglycemic Agents/pharmacology , Male , Mice , Rosiglitazone , Thiazolidinediones/chemistry , Thiazolidinediones/pharmacology , Triglycerides/bloodABSTRACT
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.
Subject(s)
Imidazolidines/chemical synthesis , Imidazolidines/pharmacology , Schistosomicides/chemical synthesis , Schistosomicides/pharmacology , Animals , Crystallography, X-Ray , Female , Indicators and Reagents , Magnetic Resonance Spectroscopy , Male , Mice , Schistosoma mansoni/drug effects , Schistosomicides/toxicityABSTRACT
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.
Subject(s)
Imidazoles/chemistry , Thiazoles/chemistry , Thiones/chemistry , Alkylation , Chemical Phenomena , Chemistry, Physical , Imidazoles/chemical synthesis , Indicators and Reagents , Magnetic Resonance Spectroscopy , Thiazoles/chemical synthesis , Thiones/chemical synthesisABSTRACT
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.
Subject(s)
Anti-Infective Agents/chemical synthesis , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Alkylation , Anti-Infective Agents/pharmacology , Indicators and ReagentsABSTRACT
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.
Subject(s)
Anti-Infective Agents/chemical synthesis , Thiazines/chemical synthesis , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Microbial Sensitivity Tests , Thiazines/pharmacologyABSTRACT
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.
Subject(s)
Imidazoles/chemical synthesis , Thiazines/chemical synthesis , Chemical Phenomena , Chemistry, Physical , Magnetic Resonance Spectroscopy , StereoisomerismABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Thiazoles/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Microbial Sensitivity Tests , Thiazoles/pharmacologyABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Imidazoles/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Colony Count, Microbial , Gas Chromatography-Mass Spectrometry , Imidazoles/chemistry , Imidazoles/pharmacologyABSTRACT
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.
Subject(s)
Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
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.
Subject(s)
Anti-Infective Agents/chemical synthesis , Antifungal Agents/chemical synthesis , Thiazoles/chemical synthesis , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
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.
Subject(s)
Analgesics/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Imidazoles/chemical synthesis , Thiazoles/chemical synthesis , Alkylation , Analgesics/pharmacology , Animals , Blood Glucose/metabolism , Hypoglycemic Agents/pharmacology , Imidazoles/pharmacology , Magnetic Resonance Spectroscopy , Mice , Pain Measurement/drug effects , Structure-Activity Relationship , Thiazoles/pharmacologyABSTRACT
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.
Subject(s)
Hypoglycemic Agents/chemistry , Hypoglycemic Agents/chemical synthesis , Imidazoles/chemistry , Imidazoles/chemical synthesis , Imidazolidines , Thiazoles/chemistry , Thiazoles/chemical synthesis , Thiazolidinediones , Brain Edema/drug therapy , Humans , Hypoglycemic Agents/pharmacology , Imidazoles/pharmacology , Thiazoles/pharmacologyABSTRACT
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.