Synthesis and Biological Activity of Novel Acridinylidene and Benzylidene thiazolidinediones

Mourão, Rosa Helena Veras; Silva, T.G.; Soares, A. L. M.; Vieira, Erika Souza; Santos, Juliette Noadya Costa; Lima, Manfredo; Lima, Vera L. M.; Galdino, Suely Lins; Barbe, Jacques; Pitta, Ivan R.

doi:10.1016/j.ejmech.2005.06.002

Cited by 47 publications

(20 citation statements)

References 15 publications

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“…1) is a synthetized acridinylidene thiazolidinedione, a monoacridinine structural analogue of m-amsacrine (6). LPSF/AC04 revealed antitumor activity with tumor inhibition of more than 85% in a murine sarcoma 180 model after 8 days of treatment with 100 mg/kg i.p./day (7).…”

Section: Introductionmentioning

confidence: 99%

Enhanced Antiproliferative Activity of the New Anticancer Candidate LPSF/AC04 in Cyclodextrin Inclusion Complexes Encapsulated into Liposomes

Mendonça

Lira

Rabello³

et al. 2012

AAPS PharmSciTech

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Abstract. LPSF/AC04 (5Z)-[5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione] is an acridine-based derivative, part of a series of new anticancer agents synthesized for the purpose of developing more effective and less toxic anticancer drugs. However, the use of LPSF/AC04 is limited due to its low solubility in aqueous solutions. To overcome this problem, we investigated the interaction of LPSF/AC04 with hydroxypropyl-β-cyclodextrin (HP-β-CyD) and hydroxypropyl-γ-cyclodextrin (HP-γ-CyD) in inclusion complexes and determine which of the complexes formed presents the most significant interactions. In this paper, we report the physical characterization of the LPSF/AC04-HP-CyD inclusion complexes by thermogravimetric analysis, differential scanning calorimetry, infrared spectroscopy absorption, Raman spectroscopy, 1 HNMR, scanning electron microscopy, and by molecular modeling approaches. In addition, we verified that HP-β-CyD complexation enhances the aqueous solubility of LPSF/AC04, and a significant increase in the antiproliferative activity of LPSF/AC04 against cell lines can be achieved by the encapsulation into liposomes. These findings showed that the nanoencapsulation of LPSF/AC04 and LPSF/AC04-HP-CyD inclusion complexes in liposomes leads to improved drug penetration into the cells and, as a result, an enhancement of cytotoxic activity. Further in vivo studies comparing free and encapsulated LPSF/AC04 will be undertaken to support this investigation.

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Section: Introductionmentioning

confidence: 99%

Enhanced Antiproliferative Activity of the New Anticancer Candidate LPSF/AC04 in Cyclodextrin Inclusion Complexes Encapsulated into Liposomes

Mendonça

Lira

Rabello³

et al. 2012

AAPS PharmSciTech

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“…At present, various research groups are dedicating efforts to identifying new schistosomicidal agents obtained from natural 7 , 8 and synthetic sources 9 , 10 . The importance of heterocyclic compounds as potential agents against several parasitic diseases, caused by protozoa and helminths, is well known 11 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of novel imidazolidine derivatives as candidates to schistosomicidal agents

Rocha

Lima

Silva

et al. 2017

Rev. Inst. Med. trop. S. Paulo

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Introduction: Schistosomiasis is an infectious parasitic disease caused by trematodes of the genus Schistosoma, which threatens at least 258 million people worldwide and its control is dependent on a single drug, praziquantel. The aim of this study was to evaluate the anti-Schistosoma mansoni activity in vitro of novel imidazolidine derivatives. Material and methods: We synthesized two novel imidazolidine derivatives: (LPSF/PTS10) (Z)-1-(2-chloro-6-fluorobenzyl)-4-(4-dimethylaminobenzylidene)-5-thioxoimidazolidin-2-one and (LPSF/PTS23) (Z)-1-(2-chloro-6-fluoro-benzyl)-5-thioxo-4-(2,4,6-trimethoxy-benzylidene)-imidazolidin-2-one. The structures of two compounds were determined by spectroscopic methods. During the biological assays, parameters such as motility, oviposition, mortality and analysis by Scanning Electron Microscopy were performed.Results: LPSF/PTS10 and LPSF/PTS23 were considered to be active in the separation of coupled pairs, mortality and to decrease the motor activity. In addition, LPSF/PTS23 induced ultrastructural alterations in worms, after 24 h of contact, causing extensive erosion over the entire body of the worms.Conclusion: The imidazolidine derivatives containing the trimetoxy and benzylidene halogens showed promising in vitro schistosomicidal activity.

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“…The thiazolidine derivative was synthesized by the nucleophilic Michael addition of substituted 3-benzyl-thiazolidine-dione on substituted cyanoacrylate, to obtain thethiazolidine-2,4-diones (GQs) (Mourao et al, 2005;da Costa Leite et al, 2007). Pioglitazone, Jacobsen catalyst, formic acid, hydrogen peroxide, MgCl 2 , glucose-6-phosphate, β-nicotinamide adenine dinucleotide phosphate (NADP), and glucose-6-phosphate dehydrogenase were purchased from Sigma-Aldrich (St Louis, MO, USA).…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

“…Most of these candidates possess substitutions in the carbon 5 of the thiazolidinedione ring only. However, substitutions in the nitrogen at position 3 have shown good pharmacological activities in models of diabetes (Mourao et al, 2005) and atherosclerosis (Cesar et al, 2015). Mourão et al (2005) published a study on the synthesis of 5-benzylidene and 5-acridinylidene derivatives, both of which were N-3 substituted; these compounds showed hypoglycemic activity in mice.…”

Section: Introductionmentioning

confidence: 99%

New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione

et al. 2018

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Number of references: 55Number of words in the Abstract: 241 Number of words in the Introduction: 750Number of words in the Discussion: 828Nonstandard abbreviations: ADME, absorption, distribution, metabolism, and excretion; CL h , hepatic clearance; CL int , intrinsic clearance; ESI, electrospray ionization; GQ-11, 5-(indol-3-ylmethylene)-3-(4-methylbenzyl)-thiazolidine-2,4-dione; HLM, human liver microsome; LC-HRMS, liquid chromatography coupled to high resolution mass spectrometry; LC-MS/MS, liquid chromatography-tandem mass spectrometry; MRM, multiple reaction monitoring; PPARγ, peroxisome proliferatoractivated receptor gamma; RLM, rat liver microsome; t 1/2 , half-life; TZD, thiazolidinedione;This article has not been copyedited and formatted. The final version may differ from this version. AbstractThiazolidinediones are drugs used to treat type 2 diabetes mellitus; however, there remain several safety concerns regarding the available drugs in this class. Therefore, the search for new thiazolidinedione candidates is still ongoing; metabolism studies play a crucial step in the development of new candidates. Pioglitazone, which is one of the most commonly used thiazolidinediones, and GQ-11, a new N-substituted thiazolidinedione, were investigated in terms of their metabolic activity in rat and human liver microsomes, in order to assess their metabolic stability and to investigate their metabolites. Methods for preparation of samples were based on liquid-liquid extraction and protein precipitation. Quantitation was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the metabolite investigation was performed using Ultra-Performance Liquid Chromatography (UPLC) coupled to a hybrid quadrupole-time of flight (Q-Tof) mass spectrometer. The predicted intrinsic clearance of GQ-11 was 70.3 and 46.1 mL/kg/min for rats and humans, respectively. The predicted intrinsic clearance of pioglitazone was 24.1 and 15.9 mL/kg/min for rats and humans, respectively. The pioglitazone metabolite investigation revealed two unpublished metabolites (M-D and M-A). M-A is a hydration product, which may be related to the mechanism of ring opening, and the toxicity of pioglitazone. The metabolites of GQ-11 are products of oxidation; no ring opening metabolite was observed for GQ-11. In conclusion, in the same experimental conditions, a ring opening metabolite was observed only for pioglitazone. The resistance of GQ-11 to ring opening is probably related to N-substitution in the thiazolidinedione ring.

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Synthesis and Biological Activity of Novel Acridinylidene and Benzylidene thiazolidinediones

Cited by 47 publications

References 15 publications

Enhanced Antiproliferative Activity of the New Anticancer Candidate LPSF/AC04 in Cyclodextrin Inclusion Complexes Encapsulated into Liposomes

Enhanced Antiproliferative Activity of the New Anticancer Candidate LPSF/AC04 in Cyclodextrin Inclusion Complexes Encapsulated into Liposomes

Synthesis and biological evaluation of novel imidazolidine derivatives as candidates to schistosomicidal agents

New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione

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