Anti-inflammatory and antinociceptive effects of the isatin derivative (Z)-2-(5-chloro-2-oxoindolin-3-ylidene)-N-phenyl-hydrazinecarbothioamide in mice

Several isatin derivatives have shown important biological activities, which have attracted interest from researchers. For this reason, the present study aimed to evaluate the anti-inflammatory and antinociceptive effects of the isatin derivative (Z)-2-(5-chloro-2-oxoindolin-3-ylidene)-N-phenyl-hydrazinecarbothioamide (COPHCT) in mice. Three doses of this compound were tested: 1.0, 2.5, and 5.0 mg/kg. The anti-inflammatory activity was assessed using the carrageenan-induced paw edema model and the zymosan-induced air pouch model. The evaluation of the antinociceptive effect was performed through the formalin test and the acetic acid-induced abdominal writhing test. The paw edema assay demonstrated that all doses of the compound showed a significant reduction of the edema in the second hour evaluated, but a better response was observed in the fourth hour. The zymosan-induced air pouch model indicated that the compound, in all doses, significantly reduced leukocyte migration and total protein concentration levels. In the formalin test, the doses 1.0, 2.5, and 5.0 mg/kg of COPHCT showed activity only in the second phase, with reduction in paw pain time of 73.61, 79.46, and 73.85%, respectively. The number of abdominal writhings decreased with the increasing dose, but only 5.0 mg/kg COPHCT exhibited a significant response, with a reduction of 24.88%. These results demonstrated the ability of this compound to interfere in the anti-inflammatory activity of edema, vascular permeability, and cell migration. In addition, its possible antinociceptive effect may be related to the dose used.

Synthesis, antibacterial activity and DNA interactions of lanthanide(IU) complexes of N(4)-substituted thiosemicarbazones / Síntesis, actividad antibacterial e interacciones con DNA de complejos lantánidos (III) de Tiosemicarbazonas N(4)-sustituídas / Síntese, atividade antibacteriana e interações com DNA de complexos lantanídeos (III) de tiosemicarbazonas N(4)-substituídas

Abstract This paper reports the synthesis and detailed characterization of six novel lanthanide complexes of La(III), Eu(III) and Nd(III) with N(4)-substituted thiosemicarbazones derived from the 2-carboxybenzaldehyde. The IR, 1H-NMR and 13C-NMR spectroscopic studies confirmed the coordination of the thiocarbonyl (C=S), azomethine (C=N) and carboxylate (COO-) groups to the metal centers, and the carboxylate was coordinated in a bidentate manner. The elemental and thermal analyses suggest that lanthanide complexes were formed in 1:2 molar ratios (metal:ligand). The molar conductivity values confirmed the non-electrolytic nature of the complexes. The interaction of these complexes with calf thymus DNA (CT-DNA) was investigated by UV absorption and viscosity measurements. It was found that the Eu(HI) and Nd(nI) complexes could roll along the DNA strands through groove interactions. Furthermore, lanthanide complexes could promote the oxidative cleavage of plasmid pBR322 in a high-oxidative stress environment. Finally, the Schiff base ligands (L) and their complexes were evaluated for their antibacterial activities against gram-positive and gram-negative bacteria using a microdilution procedure. The results indicate that the lanthanide complexes exhibit more potent antibacterial activity than the free ligands.

Resumen Este articulo reporta la síntesis y caracterización detallada de seis nuevos complejos lantánidos de La(III), Eu(III) y Nd(III) con tiosemicarbazonas N(4)-sustituidas derivadas del 2-carboxibenzaldehído. Los estudios espectroscópicos de IR, 1H-NMR y 13C-NMR confirmaron la coordinación de los grupos tiocarbonilo (C=S), azometina (C=N) y carboxilato (COO-) a los centros metálicos, y el carboxilato se coordinó de forma bidentada. Los análisis elemental y térmico sugieren que los complejos lantánidos se formaron en proporciones molares 1:2 (metal:ligando). Los valores de conductividad molar confirmaron la naturaleza no eléctrica de los complejos. Por medio de medidas de absorción UV y de viscosidad se investigó la interacción entre estos complejos con DNA de timo de ternera (CT-DNA). Se encontró que los complejos Eu(III) y Nd(III) podrían correr a lo largo de cadenas de DNA a través de interacciones en el surco. Además, los complejos lantánidos podrían promover el clivaje oxidativo del plásmido pBR322 en un ambiente de alto estrés oxidativo. Finalmente, se evaluaron las actividades antibacteriales de las bases de Schiff como ligandos (L) y sus complejos contra bacterias gram-positivas y gram-negativas usando un procedimiento de microdilución. Los resultados indican que los complejos lantánidos exhiben una actividad antibacterial más potente que los ligandos libres.

Resumo Este artigo reporta a síntese e caracterização detalhada de seis novos complexos lantanídeos de La(III), Eu(III) e Nd(III) com tiosemicarbazonas N(4)-substituídas derivadas do 2-carboxibenzaldeído. Os estudos espectroscópicos de IR, 1H-RMN e 13C-RMN confirmaram a coordenação dos grupos tiocarbonilos (C = S), azometina (C=N) e carboxilato (COO-) com os centros metálicos, e o carboxilato se coordenou de forma bidentada. As análises elementares e térmicas sugerem que os complexos lantanídeos se formaram em proporções molares 1:2 (metal:ligante). Os valores de condutividades molar confirmaram a natureza não-elétrica dos complexos. Se avaliou a interação entre estes complexos com DNA de vitela (CT-DNA) por meio de medidas de absorção UV e de viscosidade. Se observou que os complexos Eu(III) e Nd(III) poderiam deslocar-se ao longo da cadeia de DNA através de interações no sulco. Adicionalmente, os complexos lantanídeos poderiam promover a clivagem oxidativa do plasmídeo pBR322 em um ambiente de alto estresse oxidativo. Finalmente, se avaliaram as atividades antibacterianas das bases de Schiff como ligantes (L) e seus complexos contra bactérias gram-positivas e gram- negativas, usando o método de microdiluição. Os resultados indicam que os complexos lantanídeos exibem uma atividade antibacteriana mais potente que os ligantes livres.

Synthesis and cytotoxicity evaluation of thiosemicarbazones and their thiazole derivatives

ABSTRACT The aims of this study were to synthesize a series of thiosemicarbazones and their thiazole derivatives, to investigate their cytotoxic activity against three human cancers and normal (Vero cells) cell lines, and to evaluate the pro-apoptotic potential of the most active compounds. Materials and Methods: The thiosemicarbazones were obtained by reacting an aromatic aldehyde with thiosemicarbazide (yield 71-96%), which were subjected to a cyclization with α-bromoacetophenone to yield the required thiazole heterocycles (yield 63-100%). All the synthesized compounds were screened at 50 µM concentration against three cell lines representing HL60 (promyelocytic leukemia), Jurkat (acute lymphoblastic leukemia), and MCF-7 (breast cancer). The pro-apoptotic effect was measured by flow cytometry as the percentage of cells with hypodiploid DNA. Results: Three thiazole compounds showed activity against at least one tumor cell line (IC50 = 43-76 µM) and low cytotoxicity against Vero cells (IC50 > 100 M). The most active compound of this series induced 91% and 51% DNA fragmentation in HL60 and MCF-7 cell lines, respectively, suggesting that this compound triggered apoptosis in these cells. Conclusion: Among the synthesized compounds, one in particular was found to exert antiproliferative and pro-apoptotic activity on tumor cells and can be considered promising as a lead molecule for the design of new analogues with improved activity.

RESUMO O estudo teve como objetivo a síntese de uma série de tiossemicarbazonas e seus derivados tiazólicos e a avaliação da atividade citotóxica contra três linhagens de células tumorais humanas e células normais (Vero), a fim de se avaliar o potencial pró-apoptótico dos compostos mais ativos. As tiossemicarbazonas foram obtidas por reação entre um aldeído aromático e tiossemicarbazida (rend. 71-96%), as quais foram submetidas à ciclização com α-bromoacetofenona, fornecendo os heterociclos tiazólicos desejados (rend. 63-100%). Todos os compostos sintetizados foram testados na concentração de 50 µM contra três linhagens de células tumorais: HL60 (leucemia promielocítica), Jurkat (leucemia linfoblástica aguda) e MCF-7 (câncer de mama). O efeito pró-apoptótico foi avaliado por citometria de fluxo como porcentagem de células com DNA hipodiplóide. Três compostos tiazólicos foram ativos contra, pelo menos, uma linhagem tumoral (CI50=43-76 µM), com baixa citotoxicidade contra células Vero (CI50 > 100 M). O composto mais ativo dessa série induziu fragmentação do DNA de 91% e 51% nas linhagens HL60 e MCF-7, respectivamente, sugerindo que este composto ativou a apoptose nessas células. Dentre os compostos sintetizados, um em particular apresentou atividade antiproliferativa e pró-apoptótica em células tumorais e pode ser considerado composto protótipo promissor na busca por novos análogos com atividade melhorada.

Synthesis, spectroscopic characterization and antimicrobial activity studies of 2-Butyl-4-chloro-5-formylimidazole thiosemicarbazone and its manganese (II) complex.

A novel chelating tridentate organic ligand, 2-Butyl-4-chloro-5-formylimidazole thiosemicarbazone(L) is synthesized and characterized by using spectroscopic techniques like elemental analysis, FT-IR, 1H and 13C NMR, UV-vis and Mass spectrometry. The free ligand is then used for the synthesis of Mn(II) complex thoroughly characterized by FT-IR, EPR and electronic spectral analysis. The complex is found to have characteristic d5 electronic spectrum and the geometry of the complex is identified as octahedron based on the g value obtained from the EPR spectrum. Both the ligand and Mn(II)L2 compounds are found to exhibit similar antimicrobial activity against the gram –ve and gram +ve bacteria.

Synthesis, Spectral Characterization of Mn(II) and Co(II) Complexes with Thiosemicarbazones and Semicarbazones Derived from Pyridine-2-Carboxaldehyde.

Mn(II) and Co(II) complexes are synthesized with L1(Pyridine-2-carboxaldehydethiosemicarbazones) and L2 (Pyridne-2-carboxaldehydesemicarbazones). These complexes were characterized by elemental analysis, molar conductance measurements, magnetic suscepectibility measurements, mass, IR, electronic and EPR spectral studies. The molar conductance measurement of the complexes in DMSO corresponds to non electrolytes nature with L1 and formulated as [M(L)2X2] where M=Mn(II) and Co(II) complexes. The molar conductance measurements with L2 lie in the range 208-217 Ω-1cm2mol-1 indicating the electrolytes nature of the complexes thus the complexes formulated as [M(L)2]X2 where M=Mn(II) and Co(II) complexes. On the basis of spectral studies an octahedral geometry has been assigned for Mn(II) and Co(II) complexes.

Synthesis, Spectral Characterization of Cu (Ii) and Ni (Ii) Complexes with Thiosemicarbazones and Semicarbazones Derived from Pyridine-2-Carboxaldehyde.

Ni (II) and Cu (II) complexes were synthesized with L1(Pyridine-2-carboxaldehydethiosemicarbazones) and L2 (Pyridine-2-carboxaldehydesemicarbazones). These complexes were characterized by elemental analysis, molar conductance measurements, magnetic susceptibility measurements, mass, IR, electronic and EPR spectral studies. The molar conductance measurements on the complexes in DMSO correspond to non electrolytes nature with L1. The molar conductance measurements with L2 lie in the range 210-226 Ω-1cm2mol-1 indicating the complexes were 1:2 electrolyte thus the complexes may be formulated as [M(L)2]X2 where M= Ni (II) and Cu (II) complexes. On the basis of spectral studies an octahedral geometry has been assigned for Ni (II) complexes. A tetragonal geometry suggested for Cu (II) complexes.

New Halogenated Thiosemicarbazones as Potential Antimicrobial Agents: synthesis and spectral characterization.

Three new chalcogenic thiosemicarbazones (3,4-difluoroacetophenone thiosemicarbazone(1), 2-bromo-4’- chloroacetophenone thiosemicarbazone(2) and 2, 4’-dibromoacetophenone thiosemicarbazone(3) are synthesized by using a conventional one step processes in which the respective halo-substituted acetophenones are condensed with thiosemicarbazide to result in the formation of the product. The chalcogenic thiosemicarbazones are then characterized by the spectroscopic techniques like FT-IR, FT-Raman, UV-Vis, 1H and 13C NMR (19F for 1), HRMS and LC-MS, TG-DTA. The compound 1 is unambiguously characterized by single crystal X-ray diffraction and is found to have monoclinic system. These compounds were further tested for their antimicrobial activity against some human pathogens like E. coli, B. subtilis, P. aureginosa and S. aureus. The MIC values have suggested that these are potential antimicrobial agents.

Synthesis, characterization and anti-trypanosomal activity of R-(-)carvone and arylketones-thiosemi carbazones and toxicity against Artemia salina Leach.

This work is focused on the synthesis and characterization of a series of N(4)- substituted thiosemicarbazones and the evaluation of their in-vitro anti-trypanosomal activity and toxicity. A series of thiosemicarbazones (1-4) and N(4)-phenyl-3-thiosemicarbazones (5-8) have been synthesized on R-(-)carvone, acetophenone, 4’-methylacetophenone and benzophenone by condensation reaction with good yields. All compounds were characterized by spectrometrical analysis methods infrared IR, nuclear magnetic resonance NMR (1H &13C) and mass spectrometry MS, confirming their structures respectively, and were evaluated for their invitro parasitic activity against the bloodstream form of the strain 427 of Trypanosoma brucei brucei using the “LILIT, Alamar Blue” method (Baltzet al., 1985; Hirumi et al., 1994; Räz et al.,1997). Their toxicity against brine shrimp larvae (Artemia salina Leach) was studied, according to the method of Michael et al. (1956) resumed byVanhaecke et al. (1981) and bySleet and Brendel (1983). Some of them have exhibited a strong trypanocidal activity, especially compounds 8, 3, 1 and 4 with their half-inhibitory concentrations (IC50) values equal to 8.48, 8.73, 39.71 and 67.17 micro-molar (μM) respectively. Except compounds 1 and 4whose half-lethal concentration (LC50) values were20.58 and 33.72 μM respectively and then toxics, all synthesized compounds showed negligible toxicity against Artemia salinaL. (LC50> 280 μM) and good selectivity (S) (SI “index” ≤1).