RESUMO
An organocatalytic [3+2] cycloaddition reaction between thiazolidine-containing ß-ketoester 1 and aryl azides 2 was employed to synthesize new 1,2,3-triazolyl-thiazolidine hybrids 3. In this metal-free approach, twelve compounds were isolated in yields ranging from 23 % to 96 % by using diethylamine (10â mol%) and DMSO at 75 °C for 24â hours. DNA-binding assays were conducted through absorption, emission spectroscopy and viscosimetry analysis, to evaluate the interaction capacity of the studied derivatives with nucleic acids. All the synthesized compounds were evaluated for their interactions with a specific group of compounds containing the pharmacophoric groups triazole and thiazolidine through a molecular docking speculative study, aimed at identifying the interaction profile of these compounds with DNA. The obtained results suggest that 1,2,3-triazolyl-thiazolidine hybrids could be a promising approach in the development of novel therapeutic agents targeting DNA-related processes.
Assuntos
Estrutura Molecular , Tiazolidinas/química , Simulação de Acoplamento Molecular , Reação de Cicloadição , Relação Estrutura-AtividadeRESUMO
AIMS: Antimicrobial resistance is one of the highest priorities in global public health with Staphylococcus aureus among the most important microorganisms due to its rapidly evolving antimicrobial resistance. Despite all the efforts of antimicrobial stewardship, research and development of new antimicrobials are still imperative. The thiazolidine ring is considered a privileged structure for the development of new antimicrobials. This study aimed to compare the antibacterial effects of two analogue series of thiazolidine-2,4-dione and 4-thioxo-thiazolidin-2-one against multidrug-resistant Staph. aureus clinical isolates. METHODS AND RESULTS: The derivatives 1a, 2a and 2b exhibited MIC between 1-32 µg ml-1 , with time-to-kill curves showing a bactericidal effect up to 24 h. In the antibiofilm assay, the most active derivatives were able to inhibit about 90% of biofilm formation. The 4-thioxo-thiazolidine-2-one derivatives were more active against planktonic cells, while the thiazolidine-2,4-dione derivatives were able to disrupt about 50% of the preformed biofilm. In the in vivo infection model using Caenorhabditis elegans as a host, the derivatives 1a, 2a and 2b increased nematode survival with a concentration-dependent effect. Exposure of Staph. aureus to the derivatives 2a and 2b induced surface changes and decrease cell size. None of the derivatives was cytotoxic for human peripheral blood mononuclear cells (PBMC) but showed moderate cytotoxicity for L929 fibroblasts. CONCLUSION: The 5-(3,4-dichlorobenzylidene)-4-thioxothiazolidin-2-one (2b) was the most active derivative against Staph. aureus and showed higher selective indices. SIGNIFICANCE AND IMPACT OF THE STUDY: 4-thioxo-thiazolidin-2-one is a promising scaffold for the research and development of new antimicrobial drugs against multidrug-resistant Staph. aureus.
Assuntos
Anti-Infecciosos , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Staphylococcus aureus , Tiazolidinas/farmacologia , Tiazolidinas/química , Testes de Sensibilidade Microbiana , Leucócitos Mononucleares , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Antibacterianos/farmacologia , Antibacterianos/química , Biofilmes , Anti-Infecciosos/farmacologiaRESUMO
Chagas disease causes more deaths in the Americas than any other parasitic disease. Initially confined to the American continent, it is increasingly becoming a global health problem. In fact, it is considered to be an "exotic" disease in Europe, being virtually undiagnosed. Benznidazole, the only drug approved for treatment, effectively treats acute-stage Chagas disease, but its effectiveness for treating indeterminate and chronic stages remains uncertain. Previously, our research group demonstrated that 4-thiazolidinones presented anti-T. cruzi activity including in the in vivo assays in mice, making this fragment appealing for drug development. The present work reports the synthesis and anti-T. cruzi activities of a novel series of 4-thiazolidinones derivatives that resulted in an increased anti-T. cruzi activity in comparison to thiosemicarbazones intermediates. Compounds 2c, 2e, and 3a showed potent inhibition of the trypomastigote form of the parasite at low cytotoxicity concentrations in mouse splenocytes. Besides, all the 2c, 2e, and 3a tested concentrations showed no cytotoxic activity on macrophages cell viability. When macrophages were submitted to T. cruzi infection and treated with 2c and 3a, compounds reduced the release of trypomastigote forms. Results also showed that the increased trypanocidal activity induced by 2c and 3a is independent of nitric oxide release. Flow cytometry assay showed that compound 2e was able to induce necrosis and apoptosis in trypomastigotes. Parasites treated with the compounds 2e, 3a, and 3c presented flagellum shortening, retraction and curvature of the parasite body, and extravasation of the internal content. Together, these data revealed a novel series of 4-thiazolidinones fragment-based compounds with potential effects against T. cruzi and lead-like characteristics.
Assuntos
Cloro/química , Desenho de Fármacos , Tiazolidinas/síntese química , Tiazolidinas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Camundongos , Relação Estrutura-Atividade , Tiazolidinas/química , Tripanossomicidas/químicaRESUMO
The present study describes the synthesis of a novel series of thiazolidin-4-one and thiazinan-4-one using 1-(2-aminoethyl)pyrrolidine as amine precursor. All compounds were synthesised by one-pot three component cyclocondensation reaction from the amine, a substituted benzaldehyde and a mercaptocarboxylic acid. The compounds were obtained in moderate to good yields and were identified and characterised by 1H, 13 C, 2 D NMR and GC/MS techniques. The compounds also were screened for their in vitro acetylcholinesterase (AChE) activity in hippocampus and cerebral cortex on Wistar rats. The six most potent compounds have been investigated for their cytotoxicity by cell viability assay of astrocyte primary culture, an important cell of central nervous system. We highlighted two compounds (6a and 6k) that had the lowest IC50 in hippocampus (5.20 and 4.46 µM) and cerebral cortex (7.40 and 6.83 µM). These preliminary and important results could be considered a starting point for the development of new AChE inhibitory agents.
Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Tiazinas/farmacologia , Tiazolidinas/farmacologia , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/enzimologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/química , Tiazolidinas/síntese química , Tiazolidinas/químicaRESUMO
Among gliomas types, glioblastoma is considered the most malignant and the worst form of primary brain tumor. It is characterized by high infiltration rate and great angiogenic capacity. The presence of an inflammatory microenvironment contributes to chemo/radioresistance, resulting in poor prognosis for patients. Recent data show that thiazolidinones have a wide range of pharmacological properties, including anti-inflammatory and antiglioma activities. Nanocapsules of biodegradable polymers become an alternative to cancer treatment since they provide targeted drug delivery and could overcome blood-brain barrier. Therefore, here we investigated the in vitro antiglioma activity and the potential in vivo toxicity of 2- (2-methoxyphenyl) -3- ((piperidin-1-yl) ethyl) thiazolidin-4-one-loaded polymeric nanocapsules (4L-N). Nanocapsules were prepared and characterized in terms of particle size, polydispersity index, zeta potential, pH, molecule content and encapsulation efficiency. Treatment with 4L-N selectively decreased human U138MG and rat C6 cell lines viability and proliferation, being even more efficient than the free-form molecule (4L). In addition, 4L-N did not promote toxicity to primary astrocytes. We further demonstrated that the treatment with sub-therapeutic dose of 4L-N did not alter weight, neither resulted in mortality, toxicity or peripheral damage to Wistar rats. Finally, 4L as well as 4L-N did not alter makers of oxidative damage, such as TBARS levels and total sulfhydryl content, and did not change antioxidant enzymes SOD and CAT activity in liver and brain of treated rats. Taken together, these data indicate that the nanoencapsulation of 4L has potentiated its antiglioma effect and does not cause in vivo toxicity.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Nanocápsulas/química , Piperidinas/toxicidade , Piperidinas/uso terapêutico , Polímeros/química , Tiazolidinas/toxicidade , Tiazolidinas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Biomarcadores Tumorais/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Glioma/sangue , Glioma/patologia , Humanos , Luz , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/síntese química , Piperidinas/química , Polímeros/síntese química , Ratos Wistar , Tiazolidinas/síntese química , Tiazolidinas/química , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Testes de Toxicidade , Redução de Peso/efeitos dos fármacosRESUMO
The actin-related protein complex 2/3 (Arp2/3) generates branched actin networks important for many cellular processes such as motility, vesicular trafficking, cytokinesis, and intercellular junction formation and stabilization. Activation of Arp2/3 requires interaction with actin nucleation-promoting factors (NPFs). Regulation of Arp2/3 activity is achieved by endogenous inhibitory proteins through direct binding to Arp2/3 and competition with NPFs or by binding to Arp2/3-induced actin filaments and disassembly of branched actin networks. Arp2/3 inhibition has recently garnered more attention as it has been associated with attenuation of cancer progression, neurotoxic effects during drug abuse, and pathogen invasion of host cells. In this review, we summarize current knowledge on expression, inhibitory mechanisms and function of endogenous proteins able to inhibit Arp2/3 such as coronins, GMFs, PICK1, gadkin, and arpin. Moreover, we discuss cellular consequences of pharmacological Arp2/3 inhibition.
Assuntos
Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/metabolismo , Citoesqueleto de Actina , Complexo 2-3 de Proteínas Relacionadas à Actina/antagonistas & inibidores , Ligação Competitiva , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Endossomos/metabolismo , Fator de Maturação da Glia/química , Fator de Maturação da Glia/metabolismo , Humanos , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Tiazolidinas/química , Tiazolidinas/metabolismoRESUMO
BACKGROUND: PIM-1 is a kinase which has been related to the oncogenic processes like cell survival, proliferation, and multidrug resistance (MDR). This kinase is known for its ability to phosphorylate the main extrusion pump (ABCB1) related to the MDR phenotype. OBJECTIVE: In the present work, we tested a new mechanistic insight on the AZD1208 (PIM-1 specific inhibitor) under interaction with chemotherapy agents such as Daunorubicin (DNR) and Vincristine (VCR). MATERIALS AND METHODS: In order to verify a potential cytotoxic effect based on pharmacological synergism, two MDR cell lines were used: Lucena (resistant to VCR) and FEPS (resistant to DNR), both derived from the K562 non-MDR cell line, by MTT analyses. The activity of Pgp was ascertained by measuring accumulation and the directional flux of Rh123. Furthermore, we performed a molecular docking simulation to delve into the molecular mechanism of PIM-1 alone, and combined with chemotherapeutic agents (VCR and DNR). RESULTS: Our in vitro results have shown that AZD1208 alone decreases cell viability of MDR cells. However, co-exposure of AZD1208 and DNR or VCR reverses this effect. When we analyzed the ABCB1 activity AZD1208 alone was not able to affect the pump extrusion. Differently, co-exposure of AZD1208 and DNR or VCR impaired ABCB1 activity, which could be explained by compensatory expression of abcb1 or other extrusion pumps not analyzed here. Docking analysis showed that AZD1208 is capable of performing hydrophobic interactions with PIM-1 ATP- binding-site residues with stronger interaction-based negative free energy (FEB, kcal/mol) than the ATP itself, mimicking an ATP-competitive inhibitory pattern of interaction. On the same way, VCR and DNR may theoretically interact at the same biophysical environment of AZD1208 and also compete with ATP by the PIM-1 active site. These evidences suggest that AZD1208 may induce pharmacodynamic interaction with VCR and DNR, weakening its cytotoxic potential in the ATP-binding site from PIM-1 observed in the in vitro experiments. CONCLUSION: Finally, the current results could have a pre-clinical relevance potential in the rational polypharmacology strategies to prevent multiple-drugs resistance in human leukemia cancer therapy.
Assuntos
Compostos de Bifenilo/farmacologia , Resistência a Múltiplos Medicamentos , Leucemia Eritroblástica Aguda/tratamento farmacológico , Leucemia Eritroblástica Aguda/enzimologia , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Tiazolidinas/farmacologia , Compostos de Bifenilo/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia Eritroblástica Aguda/patologia , Conformação Molecular , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Tiazolidinas/química , Células Tumorais CultivadasRESUMO
BACKGROUND: Thiazolidinone derivatives show inhibitory activity (IC50) against the Toxoplasma gondii parasite, as well as high selectivity with high therapeutic index. To disclose the target proteins of the thiazolidinone core in this parasite, we explored in silico the active sites of different T. gondii proteins and estimated the binding-free energy of reported thiazolidinone molecules with inhibitory effect on invasion and replication of the parasite inside host cells. This enabled us to describe some of the most suitable structural characteristics to design a compound derived from the thiazolidinone core. RESULTS: The best binding affinity was observed in the active site of kinase proteins, we selected the active site of the T. gondii ROP18 kinase, because it is an important factor for the virulence and survival of the parasite. We present the possible effect of a derivative of thiazolidinone core in the active site of T. gondii ROP18 and described some characteristics of substituent groups that could improve the affinity and specificity of compounds derived from the thiazolidinone core against T. gondii. CONCLUSIONS: The results of our study suggest that compounds derived from the thiazolidinone core have a preference for protein kinases of T. gondii, being promising compounds for the development of new drugs with potential anti-toxoplasmosis activity. Our findings highlight the importance of use computational studies for the understanding of the action mechanism of compounds with biological activity.
Assuntos
Proteínas Serina-Treonina Quinases/metabolismo , Tiazolidinas/farmacologia , Toxoplasma/metabolismo , Sítios de Ligação , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Análise de Componente Principal , Proteínas de Protozoários , Tiazolidinas/química , Toxoplasma/efeitos dos fármacosRESUMO
Toxoplasma gondii is one of the most successful parasites due to its ability to infect a wide variety of warm-blooded animals. It is estimated that one-third of the world's population is latently infected. The generic therapy for toxoplasmosis has been a combination of antifolates such as pyrimethamine or trimethoprim with either sulfadiazine or antibiotics such as clindamycin with a combination with leucovorin to prevent hematologic toxicity. This therapy shows limitations such as drug intolerance, low bioavailability or drug resistance by the parasite. There is a need for the development of new molecules with the capacity to block any stage of the parasite's life cycle in humans or in a different type of hosts. Heterocyclic compounds are promissory drugs due to its reported biological activity; for this reason, thiazolidinone and its derivatives are presented as a new alternative not only for its inhibitory activity against the parasite but also for its high selectivity-level with high therapeutic index. Thiazolidinones are an important scaffold known to be associated with anticancer, antibacterial, antifungal, antiviral, antioxidant, and antidiabetic activities. The molecule possesses an imidazole ring that has been described as an antiprotozoal agent with antiparasitic properties and less toxicity. Thiazolidinone derivatives have been reportedly as building blocks in organic chemistry and as scaffolds for drug discovery. Here we present a perspective of how structural modifications of the thiazolidinone core could generate new compounds with high anti-parasitic effect and less toxic results.
Assuntos
Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Desenvolvimento de Medicamentos , Tiazolidinas/farmacologia , Tiazolidinas/uso terapêutico , Toxoplasma/efeitos dos fármacos , Toxoplasmose/tratamento farmacológico , Animais , Antiprotozoários/química , Humanos , Índice Terapêutico do Medicamento , Tiazolidinas/químicaRESUMO
Although there is a variety of biological activity reports regarding compounds derived from thiazolidin-4-ones, no data related to ovicidal activity against trematodes, particularly Fasciola hepatica are available. Since there are reports about anthelmintic resistance in F. hepatica, new drugs are required. Thus, this study evaluated ovicidal action in vitro against F. hepatica eggs in two systematic series of thiazolidin-4-ones: 2-aryl-3-(2-morpholinoethyl)thiazolidin-4-ones (1a-h) and 2-aryl-3-(3-morpholinopropyl)thiazolidin-4-ones (2a-h) at different concentrations (20, 2, 0.2, 0.02 and 0.002⯵g/ml). The egg hatch assay (EHA) was used to evaluate the ovicidal action property of such compounds. In addition, potential negative effects of the compounds on metabolic activity of bovine kidney (MDBK) cells were evaluated by determining mitochondrial dehydrogenase activity. The eggs used in the EHA were obtained from parasites removed from the liver of cattle, which were discarded by slaugh after sanitary inspection. The results of EHA showed that compounds 2a-h exhibited ovicidal activity, especially compounds 2b which showed 90% ovicidal activity and viability of 93% MDBK cells at the concentration of 2⯵g/ml; and 2e with 96-99% ovicidal activity at 0.2⯵g/ml, 0.02⯵g/ml and 0.002⯵g/ml. The results show the potential of compound 2b to continue the studies in the production of new compounds with anthelmintic action.